Open Access

Properties of flavonoids in the treatment of bladder cancer (Review)

  • Authors:
    • Yue Lv
    • Zhonghao Liu
    • Haixing Jia
    • Youcheng Xiu
    • Zan Liu
    • Leihong Deng
  • View Affiliations

  • Published online on: September 19, 2022
  • Article Number: 676
  • Copyright: © Lv et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Given its high recurrence and rapid progress, bladder cancer (BLCA) treatment has become a major problem for clinicians. BLCA is difficult to control even with surgical resection and extensive use of chemotherapeutic drugs. The non‑toxicity and ease of accessibility of natural compounds have attracted much attention in recent years. Flavonoids serve an essential role given their antioxidant, antibacterial, anticancer and cardiovascular properties. They are mainly divided into several subclasses; flavones, flavanones, flavonols, flavanols, anthocyanins isoflavones and chalcones. Over the years, the role of flavonoids in BLCA has been extensively studied. The present review provided a comprehensive overview of the classification of flavonoids and substantiate the role of epithelial‑mesenchymal transition, cancer stem cells, angiogenesis, epigenetic regulation and programmed cell death in BLCA. The present review emphasized that flavonoids for BLCA treatment are worthy of further study and anti‑BLCA drugs have huge prospects for clinical use.

1. Introduction

Bladder cancer

The number of patients diagnosed with bladder cancer (BLCA) is the tenth highest globally and men are ~3-4 times more likely to develop BLCA than women (1,2). BLCA can be divided into muscle-invasive BLCA (MIBC) and non-muscle invasive BLCA (NMIBC). However, given the high mortality and progression of MIBC and the high recurrence rate of NMIBC, bladder cancer remains a difficult problem worldwide (3,4). The value of bacillus Calmette Guerin (BCG) against immunotherapy in NMIBC is widely recognized. Nonetheless, with the use of BCG, a number of problems have appeared, such as BCG intolerance, poor effectiveness and tumor recurrence (5). Radical cystectomy and peripheral lymph node dissection is the gold standard treatment for advanced MIBC. However, in some cases, patients cannot tolerate surgery or want to retain urinary bladder function because of other disease conditions (6). Accordingly, a new therapeutic approach for BLCA is warranted.

Over the years, next-generation sequencing has revealed a number of therapeutic targets for BLCA and the use of immune checkpoints inhibitor (ICI) has offered hope for BLCA patients (7). Nevertheless, since ICI is expensive and patient response rates are low, significant emphasis has been placed on combining drugs, hoping they will complement each other (8). Natural plant compounds are considered a good source of combination chemotherapy due to their availability (9).


Phytochemicals are bioactive compounds extracted from natural plants, which have been widely studied to treat diseases, especially cancer, in vivo and in vitro, since they are easily obtained, highly safe and non-toxic (10). Polyphenolic compounds are widely recognized because of their wide distribution and variety. More than 8,000 polyphenol compounds have been identified in nature. They represent essential plant products that can be used against cardiovascular diseases and for cancer prevention and treatment in humans (11). Flavonoids are a subgroup of polyphenols which represent secondary metabolites. Flavonoids are widely regarded as the most common polyphenols in fruits, chocolate, flowers, vegetables and tea. Their pharmacological effects have attracted much interest, including antioxidant, antibacterial anti-inflammatory, cardiac and liver protective and anticancer properties (12,13). In addition, they have been documented to prevent breast, colorectal, thyroid, prostate, lung and ovarian cancers (13). However, flavonoids are rarely used clinically, possibly because of their low solubility, poor absorption and lack of accurate epidemiological data (13).

The effects of flavonoids on BLCA have also been studied in vivo and in vitro, but no study has hitherto systematically cataloged them. Several types of flavonoids have been reported to interfere with BLCA through biological mechanisms such as reactive oxygen species (ROS), apoptosis, ferroptosis, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and cell cycle arrest. The present study summarized current evidence based on the mechanism and classification to provide a foothold for future research.

2. Mechanism

DNA damage and cell cycle arrest

DNA damage is usually caused by damage to single-base or double strands of DNA in tumor cells by external and internal stimuli such as chemotherapy drugs. Double strand breaks have the most lethal effects on cells (14). Cells can activate several biological signals and processes in response to DNA damage, including cell cycle arrest, apoptosis and checkpoint activation, collectively called DNA damage response (15). The cell cycle is roughly divided into four phases: G1 (proteins preparation), S (DNA replication), G2 (checking the integrity of replication) and M (Mitosis). The daughter cells then go into a resting state, known as the G0 phase (16). It is well-established that cell cycle progression is largely regulated by cyclin-dependent kinases (CDKs), which phosphorylate key substrates to maintain the normal course of the cell cycle (17). Cell cycle arrest in the G1/S phase mainly depends on Ataxia telangiectasia mutated (ATM) activation. Notably, ATM directly activates P38MAPK, checkpoint kinases 2 (CHK-2) and P53 leading to the accumulation of P21. The activation of ATM- and Rad3-related (ATR) and checkpoint kinases 1 (CHK1) lead to phosphorylated CDC25 and S or G2/M phases arrest (18,19). DNA damage in cancer cells provides an opportunity for DNA repair by blocking the cell cycle. However, if cancer cells are not repaired properly, they will die (20) (Fig. 1). Treatment with flavonoids can damage DNA in BLCA cells, leading to cell cycle arrest. The sustained action of the drug can eventually lead to cell death, such as apoptosis and other programmed cell death.


ROS are free radicals or molecules with one or more unpaired electrons. The production of ROS in the cell depends mainly on the oxidative stress signal stimulation by the electron transport chain of mitochondria (21). In addition, inflammatory cells and several enzymatic cell complexes are involved in ROS production. The extrinsic sources of ROS mainly include radiation or drugs (22). ROS exhibit a two-way regulatory effect on cancer cells. Cancer cells exhibit a mild to moderate increase in ROS due to genetic mutations or metabolic changes, which help activate ROS-sensitive signaling pathways and promote proliferation, invasion and differentiation of cancer cells. Nevertheless, as a result of chemotherapy and other drugs, the level of ROS is significantly elevated, which can cause cancer cells to exceed existing redox limits, leading to apoptosis, autophagy, or DNA damage (23). A number of flavonoids can reportedly activate ROS levels and induce BLCA cell death.

Apoptosis, autophagy and ferroptosis

Apoptosis. The therapeutic role of apoptosis in cancer has been extensively explored and understanding the mechanism of apoptosis can help to improve knowledge of the role of flavonoids. Apoptosis can lead to cell shrinkage, even the secretion of vesicles, nuclear fragmentation and chromatin condensation. Apoptosis can be divided into mitochondrial apoptosis and death receptor apoptosis (24). The death receptor signal originates from the activation of death receptors, including TNFR1 and Fas (CD95), through the stimulation of TNF and Fas ligand in extrinsic cells (25). The death receptors can recruit associated adaptive proteins (TNF receptor type 1-associated death domain protein and Fas-associated death domain protein) to further induce caspase-8 splicing activation (26). Finally, pro-caspase-3 is activated by cleaved caspase-8 and executes the apoptotic signal (27). The intrinsic apoptotic pathway, also known as mitochondrial-dependent apoptosis, is stimulated by high concentrations of intracellular Ca2+, oxidative stress and hypoxia. This phenomenon leads to changes in mitochondrial membrane permeability, BAK/BAX activation and oligomer formation and the release of cytochrome-c (28). However, the release is dynamically regulated by the intracellular pro-apoptotic proteins BAD and BID and the anti-apoptotic protein BL-2. Cytochrome c, Apaf-1 and caspase-9, an apoptosome complex, activate apoptosis by cleaving caspase-3(29). In addition, prolonged endoplasmic reticulum (ER) stress may induce apoptosis, related to the activation of caspase-12 to induce cleaved caspase-3/9(30).

Autophagy. Autophagy (macroautophagy) is the process of breaking down intracellular material by forming double membraned vesicles (autophagosomes) to engulf proteins or organelles for their degradation and transport to lysosomes (31). The activation of mTOR and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways and the formation of angiotensinogen protein complexes, including UNC-51-like kinase-1 (ULK1)/Autophagy related protein 13 (ATG13)/focal adhesion kinase-interacting protein of 200 kDa (FIP200)/Autophagy related protein 101 (ATG101) and Beclin1/Vacuolar protein-sorting 34 (VPS34)/Autophagy related protein 14 (ATG14)/Autophagy/Beclin1 regulator 1 (AMBRA1) complexes, are necessary conditions for the formation of autophagosomes (32). Subsequently, damaged proteins or organelles are loaded by autophagy cargo receptors such as P62 to dock with LC3 on the vesicles and enter the autophagosome. The autophagosome ultimately depends on the fusion of lysosomes for degradation (33). The role of autophagy in cancer is a two-way process that inhibits cancer growth and contributes to cancer progression (34). Therefore, more emphasis should be placed on the expression of autophagy-related proteins in different doses of flavonoid intervention.

Ferroptosis. The discovery of iron death has given new directions to the treatment mechanisms of cancer. The activation of lipid ROS mainly depends on the breakdown of the glutathione (GSH) reduction system and the regulation of system xc-(xCT) transporters, including cysteine (Cys2) and glutamate (35). Depletion of GSH often results from decreased intracellular Cys2. GSH is an essential adjunct to glutathione peroxidase 4 (GPX4) in reducing peroxide. Depletion of GSH leads to intracellular peroxide overload and induces ferroptosis (36). Transferrin can transport Fe3+ inside the cell and is catalyzed and reduced to Fe2+ by the six-transmembrane epithelial antigen of prostate 3. Then the divalent metal transporter 1 can transport Fe2+ to the labile iron pool and induce ferroptosis (37). As a classical tumor suppressor gene, the activation of P53 seems to activate ferroptosis by inhibiting the expression of SLC7A11 to regulate the uptake of cystine (38). However, ferroptosis in natural compounds against cancer has been largely understudied. The mechanism of flavonoid in BLCA of mutant P53 and wild-type P53 may be different and further studies are needed to study whether ferroptosis is involved (Fig. 2).

Epigenetics and modification

Epigenetics refers to the indirect regulation of genes in the DNA sequence, which causes gene silencing or overexpression and affects cell phenotype and biological function (39). Epigenetic regulation and modification can be divided into DNA methylation, histone methylation, acetylation, ubiquitination and ncRNA (noncoding RNAs) (40). DNA methylation is one of the earliest and most widely studied modifications, involving methylation of the 5-carbon of the Cytosine-phosphate-Guanine islands cytosine residue, called 5-methylcytosine (41). Aberrant DNA methylation is common in cancer genomes. Natural plant compounds are thought to influence DNA methylation patterns by altering the global hypomethylation of oncogenes and the hypermethylation of suppressor genes, affecting the progression of cancer (42). The methylation and acetylation of histone modifications are the most widely studied. Histone methylation changes the structure and function of chromatin, mainly through histone methyltransferases and histone demethylases, associated with prognosis in a variety of cancers and regulated by the active ingredients of Chinese herbs (43). The acetylation of histones is mainly achieved by histone acetyltransferases and histone deacetylases (HDACs). The acetyl group of acetyl coenzyme A can be transferred to the terminal of histone amino acids by histone acetyltransferase to enhance DNA expression and transcription. However, HDAC removes the acetyl group, resulting in chromatin densification and gene transcription suppression (44). Proto-oncogenes may be activated by hyperacetylation, while hypoacetylation of tumor suppressor genes is usually limited to the promoter and induces gene silencing, closely related to cancer phenotypes and traits (45). These epigenetic regulatory enzymes may be used as therapeutic targets for BLCA.

microRNAs (miRNAs) are noncoding RNAs of ~17-25 nucleotides involved in almost all biological functions of cancer, including proliferation, invasion, metastasis, angiogenesis and apoptosis (46). miRNAs have been found to act on the 3' UTR site of mRNA to suppress its expression. Large numbers of miRNAs are reportedly upregulated or downregulated in cancer, suggesting that they can act as biomarkers in cancer (47). Researchers have investigated the relationship between competitive endogenous RNAs (ceRNAs) and cancer. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) can directly target mRNAs and sponge miRNA to regulate mRNAs expression. Notably, lncRNA/miRNA/mRNA and circRNA miRNA/mRNA interact to form ceRNAs networks that serve regulatory roles in cancer progression or suppression (48).


Angiogenesis primarily involves the growth of new capillary blood vessels from the existing vascular system complex process (49), usually due to the proliferation and migration of endothelial cells following stimulation to form primary sprouts. The new vascular structures are formed by forming the basement membrane (50). Cancer cells require nutrients and oxygen to maintain their growth through pathological angiogenesis, which depends mainly on the overactivation of angiogenic factors. The most important of these is the VEGF family, which serves a role in tumor progression (51). Nevertheless, a single angiogenesis inhibitor can only block tumor progression to some extent. Angiogenesis inhibitors interfere with other normal physiological functions in humans, including blood pressure maintenance, kidney function and wound healing. It should be borne in mind that inhibiting VEGF signaling to block tumor angiogenesis is associated with a risk of hypertension (52).

CSCs and EMT

CSCs. Similar to adult stem cells, cancer stem cells (CSCs) are special cells capable of unlimited renewal and differentiation, thus contributing to the progression, metastasis and chemotherapy resistance of malignant tumors (53). The quest for molecular markers of CSCs has become a research hotspot in recent years leading to the discovery of CD34+CD38- leukemic cells and CD44+CD24- breast cancer cells. These CSCs play a role in drug resistance in each type of cancer and are associated with poor pathological characteristics (54). CD133 is reportedly responsible for tumorigenesis in CSCs (55). Transcription factors (TFs) are inducers of CSCs and promoters of their function. Key TFs such as octamer-binding transcription factor 4 (OCT4), Krüppel-like factor 4 (KLF4), Sry-related HMG box 2, Nanog and c-MYC play a key role in this process. Moreover, WNT, NF-KB. STAT3 and Hedgehog signal pathways can help maintain and transform CSCs (56). The anticancer effects of drugs could be mediated by targeting and inhibiting specific biomarkers and the cancer-promoting pathways involved in maintaining CSCs.

EMT. EMT is a process in which epithelial cells lose apical adhesion and transform into more invasive mesenchymal cells. The loss of E-cadherin and the increase of N-cadherin and Vimentin expression are important mechanisms of EMT (57). In addition to the morphological changes, EMTcells possess stem cell properties. This phenomenon enables EMT and GSCs regulation by similar pathways, including the WNT, STAT3 and NF-κB and Hedgehog pathways (58,59). The PI3K/AKT/mTOR signal pathway is a classical pathway regulating cell growth and differentiation. It also regulates and induces EMT and CSCs to control cancer cells, proliferation, invasion and metastasis (60). It is widely acknowledged that these EMT-related signaling pathways contribute to tumor cell progression, invasion and drug resistance (53) (Fig. 3).

3. Flavonoids on BLCA


Flavonoids have a basic skeleton consisting of a 15-carbon (C6-C3-C6) phenylpropanoid chain, with two aromatic rings (A and B) and a C heterocyclic pyran ring in the middle connected to A and B (61). Compounds that are connected to the 3C position of the C ring to the B ring are termed isoflavones. However, in other types of flavonoids, B rings are linked to the 2C, including flavones, flavanones, flavonols, flavanols and anthocyanins. Flavones have only one keto group at the 4C position and have a double bond between 2C and 3C, while flavanones (dihydroflavones) have no double bond structure. Flavanols have no keto group but have one hydroxyl group at the 3C position and no double bonds between positions 2 and 3. The anthocyanins are replaced by multiple hydroxyl groups, including the 3C position and the C ring has double bonds. Flavonols have a hydroxyl group at 3C and a keto group at 4C. Finally, chalcones lack the ring C of the basic flavonoid structure (62,63). (Fig. 4). The flavonoids inhibit the development of BLCA through different mechanisms, which will be discussed in detail later (Table I).

Table I

The classification and mechanism of flavonoids on BLCA.

Table I

The classification and mechanism of flavonoids on BLCA.

Author, yearFlavonoidsSourceCompoundsTechniqueMechanisms(Refs.)
(Zhu, Mao et al, 2013; Shi Shiao et al, 2015; Xia, Yuan et al, 2018)  Apigeninin vitroROS; GSH; apoptosis; cell cycle; PI3K/AKT; uPAR(65-67)
(Kilani-Jaziri, Frachet et al, 2012; Yang, Wang et al, 2014; Iida, Naiki et al, 2020)  Luteolinin vitro; in vivoApoptosis; cell cycle; mTOR(69-71)
(Lin, Huang et al, 2019)  Tangeretinin vitroApoptosis; mitochondrial dysfunction(72)
(Xu, Tong et al, 2018; Lima, Almeida et al, 2020)  Chrysinin vitroER stress; apoptosis; ROS; STAT3; TP53(74,75)
(Li, Zhang et al, 2013; Wu, Tsai et al, 2013; Choi, Park et al, 2016; Yang, Liu et al, 2018; Kong, Chen et al, 2021)FlavonesFlowers, tea, parsley, citrus fruits, leavesBaicaleinin vitro; in vivoApoptosis; ROS; ferroptosis; cell cycle(76-80)
(Lv, Liu et al, 2019)  Scutellarinin vitroEMT; PI3K/AKT; MAPK(82)
(Goan, Wu et al, 2019)  Nobiletinin vitroPI3K/AKT; ER stress; mitochondrial dysfunction(84)
(Tian, Tong et al, 2019)  Orientinin vitroHedgehog; NF-κB; apoptosis(85)
(Wei, Liu et al, 2012; Rockenbach, Bavaresco et al, 2013; Oršolić, Karač et al, 2016; Su, Peng et al, 2016; Tan and Liu, 2017; Oršolić, Odeh et al, 2020; Adami, Diz et al, 2021; Cho, Yu et al, 2021; Dong, Hao et al, 2021)FlavonolsFruits vegetables (apples onions, kale, tomatoes, grapes berries)Quercetinin vitro; in vivoApoptosis; DNA damage; ROS; cell cycle; autophagy; nucleotides catabolism; chemotherapy sensitization; network pharmacology(88-93,95-97)
(Tao, He et al, 2017; Lee and Tuyet, 2019; Alban, Monteiro et al, 2020)  New complexes of quercetinin vitroRadiosensitization; AKT; AMPK/mTOR(98-100)
(Chen, Chen et al, 2016; Ran, Wang et al, 2016; Wu, Liu et al, 2017)  Isoquercitrinin vitro; in vivoPI3K/AKT; PKC; AMPK; STAT3; cell cycle(102-104)
(Xie, Su et al, 2013; Dang, Song et al, 2015; Qiu, Lin et al, 2017; Wu, Meng et al, 2018)  Kaempferolin vitro; in vivoDNA methylation; apoptosis; cell cycle; c-met/p38; PTEN TP53; apoptosis; cell cycle(106-109)
(Wu, Ning et al, 2013; Gándara, Sandes et al, 2014; DT, Savio et al, 2017; Imai-Sumida, Chiyomaru et al, 2017; Sun, Guan et al, 2017; Li, Sun et al, 2018; Prack Mc Cormick, Langle et al, 2018; Barros, Lima et al, 2020)  Silibininin vitro; in vivoDNA acetylation; Angiogenesis lncRNA; PI3K/AKT; KRAS; EMT; NF-κB; CSCs(110-117)
(Chung and Kim, 2016; Huang, Cheng et al, 2019; Xu, Shi et al, 2022)  Casticinin vitroRadiosensitivity; PDT; TM7SF4; DNA damage; ROS(119-121)
(Shin, Won et al, 2017)  Morinin vitroMMP9; cell cycle(123)
(Pan, Li et al, 2016)      
(Pan, Li et al, 2016)  Icaritinin vitroAutophagy(124)
(Kim, Lee et al, 2008)FlavanonesCitrus fruits (oranges), grapesNaringinin vitroCell cycle; Ras/Raf/ERK(126)
(Liao, Kuo et al, 2014)  Naringeninin vitroMMP2; AKT(127)
(Juhem, Boumendjel et al, 2013)  Flavanone derivativein vitroCell cycle; apoptosis; mitotic spindle formation(128)
(Chen, Yu et al, 2016)FlavanolsFruits (bananas, apples, peaches and pears)Catechinin vitro; in vivoNanoparticles; PI3K/AKT; CSCs; apoptosis; Hedgehog; NF-κB; MMP-9; autophagy; chemotherapy sensitization(135)
(Qin, Wang et al, 2012; Jankun, Keck et al, 2014; Feng, Ho et al, 2017; Luo, Wei et al, 2017; Luo, Lung et al, 2018; Lee, Chen et al, 2019; Sun, Song et al, 2019; Luo, Zhu et al, 2020; Yin, Li et al, 2021)  EGCGin vitro; in vivo (136-144)
(Li, Ji et al, 2018; Li, Yu et al, 2018)AnthocyaninsFlowers, Fruits (cranberries, red grapes, raspberries strawberries, blackberries blueberries)PSPAin vitroApoptosis; cell cycle; PI3K/AKT(148,149)
(Fishman, Johnson et al, 2012; Liu, Zhang et al, 2016; Yang, Gao et al, 2021)  GSPsin vitroTGF-β; EMT; cell cycle; apoptosis(150-152)
(He, Wu et al, 2016)IsoflavonesLeguminous plantsDaidzeinin vitro; in vivoFGFR3; cell cycle; apoptosis(154)
(Wang, Wang et al, 2013; Park, Cha et al, 2019)  Genisteinin vitro; in vivoApoptosis; cell cycle; PI3K/AKT; NF-κB(156,157)
(Köksal Karayildirim, Nalbantsoy et al, 2021)  Prunetinin vitroTNF-α; apoptosis; cell cycle(158)
(Jiang, Chen et al, 2018; Liu, Li et al, 2018; Ye, Kan et al, 2019; Du, Zhang et al, 2020)  Puerarinin vitro; in vivoApoptosis; cell cycle; mTOR/p70S6K; SIRT1/P53; ncRNAs(160,161,163,164)
(Wu, Zhang et al, 2017)  Formononetinin vitromiR-21; PTEN(165)
(Yuan, Li et al, 2013; Jiang,Yuan et al, 2014; Yang, Jiang et al, 2016; Hong, Cha et al, 2019)ChalconesFruits (tomatoes, strawberries, bearberries, pears)Licochalcone Ain vitroER stress; apoptosis; ROS; Cell cycle; Ca2+; GSH/GSSH; mitochondrial dysfunction(167-170)
(Yuan, Li et al, 2014; Zhao, Yuan et al, 2014)  Licochalcone Bin vitro; in vivoCell cycle; apoptosis; MMP9; NF-κB(171,172)
(Wang, Yuan et al, 2015)  Licochalcone Cin vitroApoptosis(173)
(Patricia Moreno-Londoño, Bello-Alvarez et al, 2017)   Isoliquiritigeninin vitroCisplatin-induced toxicity(175)
(Liu, Xu et al, 2013; Li, Xu et al, 2014; Liu, Song et al, 2022)  Flavokawain Ain vitro; in vivoP53; UPII; Apoptosis; Ha-ras pathway(176-178)
(Wu, Lin et al, 2014)  Chalcone derivativesin vitroCOX-1; Cell cycle; ROS(179)
(Martel-Frachet, Keramidas et al, 2015)  IPP51in vitro; in vivoCell cycle; Apoptosis; Mitotic arrest(180)

[i] BLCA, bladder cancer; ROS, reactive oxygen species; EMT, epithelial-mesenchymal transition; PTEN, phosphatase and tensin homolog; CSCs, cancer stem cells; ncRNAs, non-coding RNAs; miRNA, microRNA; GSH, glutathione; GSSH, glutathione persulfide; UPII, uroplakin II.


Flavones are characterized by being unmodified at 3C and can be oxidized at 4C. They can coexist with anthocyanins and flavonols in flowers and act as plant protectors. They are usually found in tea, parsley and citrus fruits (64).

Apigenin. Apigenin (4',5,7,-trihydroxyflavone), usually extracted from parsley, has been found to induce the loss of mitochondrial membrane potential leading to T24 cell apoptosis and cell cycle arrest via the PI3K/AKT pathway (65,66). Apigenin can reduce GSH levels in cells and activate ROS. This suggests that Apigenin might induce ferroptosis in BLCA cells and warrants further study (65,66). The urokinase-type plasminogen activator receptor (uPAR) is a cell surface glycoprotein and serves a role in inhibiting tumor invasion. Apigenin has been found to control the expression of uPAR and T24 cell invasion by inhibiting AP-1 and NF-kB signals (67).

Luteolin. Luteolin (3,4,5,7-tetrahydroxyflavone) is found in various plants and has attracted much interest for its anticancer role (68). Luteolin can exert more significant damage to BLCA cells than Apigenin by inducing apoptosis and cell cycle arrest (69). It was found that Luteolin could upregulate P21 expression and inhibit mTOR signal transduction to control the progression of BLCA in T24 cells and mouse xenograft models (70). The Bacillus Calmette-Guerin (BCG) vaccine is well known for its role in preventing recurrence and controlling the progression of BLCA. Interestingly, the combination of Luteolin and BCG has been reported to induce apoptosis of BLCA cells and increase the sensitivity of BCG. This finding suggests that Luteolin has great clinical potential in the treatment of BLCA (71).

Tangeretin. As one of the abundant ingredients in citrus peel, tangeretin (4',5,6,7,8-Pentamethoxyflavone) has anticancer and antioxidant properties. Proteomics technology analysis of tangeretin-related targets and signals suggests it could lead to mitochondrial dysfunction and apoptosis in BLCA cells via the release of cytochrome c (72).

Chrysin. Chrysin (5, 7-dihydroxyflavone) is mainly found in honey, propolis and some plants (73). Chrysin can activate ROS and ER stress to induce BLCA cell apoptosis and growth arrest via reducing STAT3 activation (74). Chrysin inhibits cell proliferation and migration through DNA damage. The anticancer mechanism depends on the state of TP53. In mutated TP53 cells, chrysin causes G2/M arrest in BLCA cells and the downregulation of SRC, PLK1 and HOXB3 genes. DNA hypermethylation is also found to be involved (75).


Baicalein (5,6,7-Trihydroxyflavone) is a flavone isolated from Oroxylum indicum that can induce BLCA cell apoptosis (T24; 5637; 253J). Current evidence suggests that caspase enzymes (caspase-3/9) and ROS can be activated in T24 and 5637 cells by baicalein (76-78). Ferritin heavy chain 1 is a key determinant of BLCA cell ferroptosis following baicalein treatment. Moreover, the inhibition of BLCA cells is associated with the accumulation of ROS and intracellular iron (79). In addition, baicalein has been found to inhibit Cyclin B1 and Cyclin D1 expression leading to cell cycle arrest and MMP2/9 mediated cell invasion and migration. In in vivo mouse models, only a weak role has been observed (80).

Scutellarin. Scutellarin (4', 5, 6-hydroxyl-flavone-7-glucuronide) is a natural compound obtained from Erigeron breviscapus with anti-oxidation and antitumor properties (81). EMT has been established to modulate tumor progression. Scutellarin is widely thought to inhibit metastasis and invasion of BLCA by suppressing EMT, PI3K/AKT and MAPK signaling pathways (82).

Nobiletin. Nobiletin (3', 4', 5, 6, 7, 8-Hexamethoxyflavone) is a ubiquitous compound extracted from citrus fruits (83). Like other flavonoids, nobiletin inhibits PI3K/AKT/mTOR and induces PERK/elF2α/ATF4/CHOP pathways, leading to mitochondrial dysfunction, ER stress and apoptosis of human BLCA cells (84).

Orientin. Orientin (8-C-β-glucopyranosyl-3', 4', 5, 7-tetrahydroxyflav-2-en-3-one) is a flavone isolated from traditional Chinese medicine. In vitro, orientin has been found to inhibit T24 cell proliferation and promote apoptosis by inhibiting the Hedgehog and NF-KB signaling pathways (85) (Fig. 5).

Figure 5

Flavones including Apigenin, Luteolin, Baicalein, Chrysin, Scutellarin, Tangeretin, Nobiletin and Orientin act on BLCA through various mechanisms such as apoptosis, cell cycle arrest and ROS activation. Apigenin is found to inhibit GSH production and promote ferroptosis. Additionally, Apigenin can inhibit UPAR, AP-1, or PI3K/AKT and NF-κB pathways to promote apoptosis, cell cycle arrest and ROS activation. Luteolin can inhibit mTOR and promote P21 expression to promote apoptosis and cell cycle arrest of BLCA cells. Tangeretin causes mitochondrial dysfunction and promotes the expression of apoptosis genes such as cytochrome C and cleaved caspase-3/9. Chrysin inhibits oncogenes such as SRC PLK1 HOXB3 and STAT3 expression. Baicalein can promote cell cycle arrest by regulating genes such as Cyclin B 1and D1. It also promotes the expression of cleaved caspase-3/9 and the occurrence of ferroptosis. Scutellarin can inhibit tumor EMT progression by inhibiting PI3K/AKT and MAPK pathways. Nobiletin has also been found to inhibit the activation of ER stress and apoptosis by inhibiting PI3K/AKT pathway. Orientin can promote apoptosis of BLCA cells by inhibiting Hedgehog and NF-KB pathways. The 2D structures of the compounds were obtained from the Pubchem database. Apigenin: PubChemIdentifier: CID 5280443 URL ( Luteolin: PubChemIdentifier: CID 5280445 URL ( Baicalein: PubChemIdentifier: CID 5281605 URL ( Chrysin: PubChemIdentifier: CID 5281607 URL ( Scutellarin: PubChemIdentifier: CID 185617 URL ( Tangeretin: PubChemIdentifier: CID 68077 URL ( Nobiletin: PubChemIdentifier: CID 72344 URL ( Orientin: PubChemIdentifier: CID 5281675 URL ( BLCA, bladder cancer; ROS, reactive oxygen species; GSH, glutathione; EMT, epithelial-mesenchymal transition.


Flavonols are also abundantly found in fruits and vegetables. Compared with flavones, Flavonols have a hydroxyl group which can be glycosylated on the C ring. Flavonols such as quercetin and kaempferol have been extensively studied. Their intake is strongly associated with health, reducing the risk of vascular disease (63).

Quercetin. Quercetin (3,5,7,3',4'-pentahydroxyflavone) is a flavonol found in a number of fruits and vegetables (86) and a Solanum nigrum L. herbal active ingredient. It has long been recognized as a natural anticancer agent with high potential and has been extensively studied in animal models and cell lines for numerous cancers (87). Quercetin can reportedly inhibit the proliferation of T24 cells and damage cell morphology, leading to a decreased number of cell bodies, retraction and condensation of cytoplasm and membrane and the aggregation and roughness of membrane proteins, indicating that apoptosis and senescence are necessary for this process (88). The damage to DNA is reportedly regulated by quercetin, reducing cell colony formation in proliferating BLCA cells (89). In terms of apoptosis, the AMPK pathway is involved in inhibiting signaling pathways in BLCA by quercetin and regulates BLCA cell apoptosis (90). In BIU-87 cells, quercetin can promote BLCA cell apoptosis and autophagy. After blocking autophagy, apoptosis becomes more evident (91). In addition to stimulating apoptosis, quercetin can inhibit cell cycle progression through the TAK1/JNK signaling pathway, leading to an increased number of cells in the G2/M phase (92). Quercetin regulates nucleotide metabolism to inhibit BLCA cells via increasing ADP hydrolysis and inhibiting the activity of ecto-5'-nucleotidase/CD73(93). Network pharmacology can predict the relationship between drugs, targets and pathways and is widely used to study diseases and drugs (94). Network pharmacology analysis reveals that quercetin is closely related to the target genes of BLCA and apoptosis and that the PI3K/AKT pathway is involved in it (95). Quercetin may serve a role in improving BLCA cell drug resistance. Quercetin and gemcitabine exert an additive effect on gemcitabine resistance cells (T24-GCB), reducing the expression of ABC transporter (ABCC2) proteins and metabolic proteins (DCK and TKs) (96). In addition, the combination of cisplatin and quercetin promotes tumor cell death and enhances immune response and mice survival (97).

The development of new compounds based on quercetin has led to improved and more significant effects. Q-ZnCPX, a novel compound consisting of quercetin and zinc, has a stronger inhibition and anti-metastasis effect, which may ameliorate the disadvantages of quercetin, including low absorption and rapid metabolism (98). Recently, researchers have synthesized 8-trifluoromethyl-3, 5, 7, 3', 4'-O-pentamethyl-quercetin (TFQ) based on the chemical modification of quercetin by fluorination. TFQ is believed to affect BLCA growth through the AMPK/mTOR pathway (99). The usefulness and biocompatibility of nanostructures have attracted much attention. Research has shown that they could interfere with the proliferation and enhance the radiosensitization of BLCA cells by loading quercetin into titanate nanotubes (TNT) (100).

Isoquercitrin. Isoquercitrin (quercetin-3-O-glucoside) is a natural flavonoid found extensively in Chinese bayberry and other plants (101). Isoquercetin has been found to reduce protein kinase c (PKC) expression and phosphorylation of PI3K and AKT in BLCA cells. Isoquercetin can also inhibit the progression of BLCA in vitro and in vivo (102). In addition, Isoquercetin is similar to quercetin and could inhibit BLCA by activating the AMPK pathway (103). Moreover, Isoquercetin can inhibit the proliferation of EJ cells and increase G1 phase cells by regulating the expression of STAT3 and STAT3-inhibiting factors (PIAS3) (104).

Kaempferol. Kaempferol (3, 4, 5, 7-tetrahydroxyflavone) is a flavonoid found in a number of natural plant products, such as beans and vegetables. Kaempferol has anti-inflammatory, antimicrobial heart and nerve protective and antitumor pharmacological properties (105). Kaempferol is found to regulate DNA methylation in BLCA depending on the level of DNA methyltransferases (DNMTs). Kaempferol can reportedly suppress the protein levels of DNMT3B by increasing its ubiquitination (106). Kaempferol has been reported to be safe for normal bladder cells but yields a strong inhibitory effect on BLCA cells, promoting cell apoptosis and S phase arrest (107). The c-Met/p38 signal pathway has also been revealed to be involved in inhibiting BLCA by kaempferol (108). In addition, the expression of PTEN is significantly increased by kaempferol and Akt phosphorylation is inhibited, leading to cell apoptosis (109).

Silibinin. Silibinin is a natural flavonol derived from milk thistle seeds. Its antitumor properties in bladder cancer is dependent on TP53 expression levels. A study demonstrates that in wild-type TP53 cell lines, the FRAP/mTOR, AKT2, DNMT1 and FGFR3 genes were downregulated by silibinin, while only miR203 gene expression was altered in the mutant cell line. Both could inhibit cells proliferation and promote RT4 and T24 cell apoptosis (110). In addition, G2/M cell cycle arrest in TP53 mutant cells has been demonstrated and HTA, HDAC and HOXB3 genes are regulated via modulating mutant BLCA cell DNA acetylation, deacetylation and angiogenesis (111). It has been shown that silibinin can inhibit the expression of cyclooxygenase (COX)-2 and EMT induced by TGF-β1, which significantly inhibits transitional cell carcinoma migration and invasion (112). EMT serves an essential role in the interference effect and silibinin inhibits the ability of CSCs to control migration via regulating the β-catenin/ZEB1 signaling pathway (113). As well as inhibiting tumor cell invasion, migration and apoptosis, silibinin can regulate the actin cytoskeleton and PI3K/AKT pathways. In addition, KRAS regulated by histone H3 lysine 4 and acetylated H3 are reportedly significantly inhibited (114). lncRNAs (HOTAIR and ZFAS1) are also reported as oncogenic factors inhibited by silibinin (114). Silibinin can also relieve drug resistance to chemotherapy and radiotherapy. Improvement of chemodrug-induced chemoresistance by silibinin treatment is reportedly mediated by the NF-κB pathway (115). In mice, radiotherapy (RT)-inhibited NF-κB and PI3K pathways are enhanced by silybin (silibinin diastereomer), resulting in increased radiosensitivity of invasive cells (116). Photodynamic therapy is an anticancer therapy based on a photosensitizer that can inhibit malignant cells. 5-aminolevulinic acid is a precursor of Protoporphyrin IX with synergistic or additive effects with silybin, thus enhancing the inhibitory effect on BLCA metastases (117).

Casticin. The flavonoid casticin (3', 5-dihydroxy-3, 4', 6, 7-tetramethoxyflavone) is extracted and isolated from the Vitex species (118). Casticin can inhibit the migration and invasion of BLCA cells by inhibiting the expression of TM7SF4. MMP-2, MMP-9 and CyclinD1(119). In addition, casticin has been shown to inhibit the proliferation of BLCA by inducing DNA damage via decreasing the expression of p-p53 and P-AKT (120). The role of ROS in cell damage and activation of apoptosis is well-established. Casticin has also been reported to cause changes in mitochondrial membrane potential and ROS activation in T24 cells by upregulating XAF1 and TAp73 expression (121).

Morin. Morin (2', 3, 4', 5, 7-pentahydroxyflavone) is a natural flavonoid obtained from Moraceae plants with antioxidant and antibacterial activities (122). Its inhibitory effect against invasion and migration of BLCA is regulated by MMP9 by suppressing AP-1, NF-κB and Sp-1 levels. In addition, G1 cell cycle arrest and the decrease of CyclinD1, Cyclin E and CDK2/4 expression are reportedly induced by morin (123).

Icaritin. Icaritin (3,5,7-trihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)chromen-4-one) is a flavonol glycoside extracted from the genus Epimedium with synergistic effects with epirubicin (EPI) that can inhibit autophagy and BT5637 and T24 cell proliferation (124) (Fig. 6).

Figure 6

Flavonols can inhibit CSCs, angiogenesis and EMT of BLCA. In addition, they can promote BLCA apoptosis, autophagy, DNA damage, cell cycle arrest and so on. Quercetin inhibits BLCA progression by multiple mechanisms including promoting ROS, apoptosis, autophagy, cell cycle arrest nucleotides catabolism and DNA damage. Isoquercitrin can promote AMPK and inhibit STAT3, PI3K/AKT and PKC to regulate cell cycle. In addition to promoting apoptosis, Kaempferol also regulates epigenetics. Notably, silibinin can inhibit CSCs, EMT and angiogenesis. Casticin promotes DNA damage and ROS activation in BLCA cells by regulating XAF1 and TAp73. Morin can promote cell cycle arrest by inhibiting Cyclin D1, Cyclin E and CDK2/4. Icaritin is shown to promote the production of LC3II and inhibit the expression of ATG3/5/7/12 to promote autophagy. The 2D structures of the compounds were obtained from the Pubchem database. Quercetin: PubChemIdentifier: CID 5280343 URL ( Isoquercitrin: PubChemIdentifier: CID 5280804 URL ( Kaempferol: PubChemIdentifier: CID 5280863 URL ( Silibinin: PubChemIdentifier: CID 31553 URL ( Casticin: PubChemIdentifier: CID 5315263 URL ( Morin: PubChemIdentifier: CID 5281670 URL ( Icaritin: PubChemIdentifier: CID 5318980 URL ( CSCs, cancer stem cells; EMT, epithelial-mesenchymal transition; BLCA, bladder cancer; ROS, reactive oxygen species.


It is well-established that flavanones, also known as dihydroflavones, have a saturated c-ring. Flavanones are found mainly in citrus fruits such as oranges and lemons (63). Among them, hesperidin and naringin are the most abundant ingredients with anti-oxidation and anti-inflammatory properties and even maintain intestinal health (125).

Naringin. Current evidence suggests that naringin (4', 5, 7-trihydroxyflavanone 7-rhamnoglucoside) could upregulate p21WAF1 expression and induce G1 cycle phase arrest through the RAS/RAF/ERK signal pathway in 5637 cells (126).

Naringenin. Naringenin (4', 5, 7-Trihydroxyflavanone) is a bioactive flavanone that can inhibit BLCA cell migration by suppressing MMP-2 expression and AKT activation (127).

Flavanone derivative. AG11 obtained from CB11 chalcone precursor has been reported to induce G2/M phase cell cycle arrest and apoptosis of RT4 cells. AG11 can prevent purified tubulin from polymerizing and disrupt mitotic processes of BLCA cells in vitro (128).

Flavanols Tea polyphenols (catechins)

Green tea has attracted much interest worldwide for its effects on cancer prevention (129). Current evidence suggests that polyphenols, the main active compounds in tea, serve an important anticancer role (130). Catechins belong to the flavanol class of the flavonoid family and are the main component of tea polyphenols (130,131). Of these, epigallocatechin gallate (EGCG) is the most abundant and biologically active member of the catechin family, accounting for >50% of the family (132). High consumption of green tea could reduce the recurrence and progression of urothelial carcinoma (133). Notably, it has been shown that green tea polyphenols can inhibit cytoplasmic human antigen R expression in a BLCA model. In addition, it can suppress BLCA cell proliferation and angiogenesis and the expression of related proteins, including VEGF-A, heme oxygenase (HO)-1 and COX-2(134). Mg (II)-catechin nanoparticles (Mg (II)-Cat NPs) display a significant inhibitory effect on BLCA, given their improved biocompatibility and stronger cellular uptake. In addition, eukaryotic translation initiation factor 5A2 (EIF5A2) small interfering RNA (siRNA) can be loaded into the tumor site to further enhance the anti-BLCA effect via the PI3K/AKT pathway (135).


In animal models, EGCG prevents bladder tumor implantation and development by reducing proteolytic activity, with a slightly higher therapeutic effect compared with mitomycin C (136). Next-generation sequencing reveals the related mRNAs, miRNAs and mechanisms of EGCG on BFTC-905 cells (137). EGCG can inhibit the proliferation and migration of BLCA cells (SW780, 5637 and T24) and promote cell apoptosis by suppressing NF-KB and MMP9 and PI3k/AKT pathways (138-140). As well as apoptosis, tissue factor pathway inhibitor 2 is reported to be upregulated by EGCG to inhibit the growth of BLCA cells via decreasing promoter hypermethylation (141). Notably, low-dose EGCG promotes LC3I to LC3II, suggesting the occurrence of autophagy. The autophagy effect is blocked by a PI3K/AKT inhibitor (LY294002) (142). The effect of EGCG on bladder CSCs has also been studied. In this respect, EGCG has been shown to inhibit the expression of CD133, CD44, ALDH1A1, OCT4 and Nanog and sonic hedgehog signaling pathways to inhibit bladder CSCs (143). It has been suggested that EGCG can be combined with docetaxel to enhance the induction of apoptosis in BLCA cells by modulating the NF-κB/MDM2/p53 pathway (144).


Anthocyanins and anthocyanidins are plant pigments that account for various colors in plants and fruits. Anthocyanins are anthocyanidins structurally modified by sugar and acyl acids found mainly in dark fruits with excellent potential to inhibit tumor progression (145,146). The combination of anthocyanins, a bladder cancer preventive agent and mitomycin C has been reported to increase BLCA cell death (147).

Purple sweet potato anthocyanin (PSPA). Purple sweet potato (PSP) is well-acknowledged as a healthy food, given its anthocyanins content. When anthocyanins cause a decline in BIU87 cell proliferation, individual volume reduction and weakened cell adhesion are observed (148). In addition, the anti-BLCA effect of PSPA is achieved by interference with apoptosis and the cell cycle via the PI3K/AKT pathway (149).

Grape seed proanthocyanidins (GSPs). GSPs have been found to further inhibit EMT by suppressing the TGF-β signal pathway and improving the invasion and migration of BLCA cells (150). Interferon (IFN) has been used for immunotherapy of BLCA for some time (151). Notably, GSPs combined with IFN enhances BLCA cell inhibition and G1 cycle arrest (151). In addition to cell cycle interference, GSPs can induce BIU87 cell apoptosis by increasing caspase-3 activation (152).


Isoflavones are mainly derived from soybean and soybean products foods. A high content of daidzein and genistein is present in isoflavones. Isoflavones are also thought to be protective agents against hormonal disorders and suppress a wide range of cancers, including prostate and breast cancer (153).

Daidzein. Daidzein (4',7-Dihydroxyisoflavone) is a natural isoflavone compound that is mainly extracted from soybeans. It suggests that daidzein can induce BLCA cell apoptosis and G1/S cycle arrest through the FGFR3 pathway. In vivo, it is also demonstrated that Daidzein could inhibit the growth of xenograft tumors of RT112 cells (154).

Genistein. The anticancer effects of genistein (4', 5, 7-Trihydroxyisoflavone), a soybean isoflavone, have been documented in vitro and in vivo (155). In bladder cancer, like daidzein, genistein induces T24 cell cycle arrest and apoptosis via ROS activation and the PI3k/AKT pathway (156). Hydroxycamptothecin (HCPT) is a DNA topoisomerase I inhibitor used to treat BLCA for nearly 40 years. The NF-kB pathway is thought to mediate the effect of genistein on HCPT sensitivity (157).

Prunetin. The majority of isoflavones have an estrogenic effect and there are few pieces of research on Prunetin (5, 4'-dihydroxy-7-methoxyisoflavone). Prunetin, a phytoestrogen, had been found to upregulate the expression of CASP3 and TNF-α to activate RT-4 cell apoptosis and G0/G1 phase cell cycle arrest (158).

Puerarin. Puerarin (7,4'-dihydroxyisoflavone-8β-glucopyranoside) is extracted from plants in the genus Pueraria, widely used in heart cerebrovascular disease, cancer and bone diseases (159). BLCA cell apoptosis can be regulated by inhibiting SIRT1/P53 and mTOR/P70S6K signaling pathways through puerarin treatment. Cell cycle arrest at the G0/G1 phase can be induced by puerarin (160,161). miRNA-16 has long been hypothesized to be a tumor suppressor gene that inhibits the proliferation of BLCA (162). Puerarin has been found to upregulate the expression of miR-16(163). The circ_0020394/miR-328-3p/NRBP1 axis is also thought to be regulated by puerarin to interfere with BLCA cell migration and invasion and promote apoptosis (164).

Formononetin. Formononetin (7-hydroxy-4'-methoxyisoflavone) is mainly obtained from Astragalus membranaceus and can reportedly reduce the expression of miR-21 and increase PTEN expression, thus promoting T24 cells apoptosis and inhibiting invasion (165) (Fig. 7).

Figure 7

Flavanones include naringin and naringenin. They inhibit BLCA migration and promote cell cycle arrest by inhibiting MMP-2, AKT or RAS/RAF/ERK pathway. EGCG can inhibit CSCs and promote BLCA cells apoptosis and autophagy. Isoflavones including daidzein, genistein, prunetin, puerarin and formmononetin are revealed to inhibit BLCA migration and be regulated by epigenetics. Daidzein inhibits FGFR3 expression and thus promotes cell cycle arrest. Genistein is found to inhibit the PI3K/AKT and NF-KB pathways. Prunetin promotes the expression of apoptosis genes (cleaved caspase-3 and TNF-α). Puerarin inhibits BLCA growth by regulating epigenetic regulation. Formononetin inhibits miR-21 and upregulates PTEN expression to inhibit BLCA cell proliferation and promote apoptosis. The 2D structures of the compounds were obtained from the Pubchem database. Naringin: PubChemIdentifier: CID 442428 URL ( Naringenin: PubChemIdentifier: CID 932 URL ( EGCG: PubChemIdentifier: CID 65064 URL ( Daidzein: PubChemIdentifier: CID 5281708 URL ( Genistein: PubChemIdentifier: CID 5280961 URL ( Prunetin: PubChemIdentifier: CID 5281804 URL ( Puerarin: PubChemIdentifier: CID 5281807 URL ( Formononetin: PubChemIdentifier: CID 5280378 URL ( BLCA, bladder cancer; EGCG, epigallocatechin gallate; CSCs, cancer stem cells; miR, microRNA; PTEN, phosphatase and tensin homolog.


Chalcones are widely found in fruits and vegetables and are important components and biological precursors of flavonoids. They have a basic 1, 3-diaryl-2-propen-1-one chemical scaffold and two aromatic rings connected by an unsaturated α, β-carbonyl system (166). The effect of chalcones on BLCA has been extensively studied in recent years.

Licochalcones. Licochalcone A (LCA) is a licorice chalcone hypothesized to have anticancer activity (167). LCA activates ROS production, mitochondrial dysfunction and ER stress leading to T24 cell apoptosis (167). A study demonstrates that T24 cells treated with LCA exhibit increased intracellular Ca2+ levels, Apaf-1 and caspase-3/9 expression, activation of calpain 2 and caspase-4 and ultimately leads to apoptosis ROS, the key step to promoting BLCA cell apoptosis (168). LCA is found to inhibit cell proliferation by increasing ROS levels and reducing the ratio of GSH to GSSG, which suggests the role of iron death (169). In addition, LCA is found to inhibit cell proliferation by promoting ROS-dependent G2/M phase cell cycle arrest by decreasing cyclin A and cyclin B1 expression (170).

In addition, Licochalcone B (LCB) can reduce the expression of MMP-9 mRNA and protein, but MMP-2 does not. LCB can promote nuclear translocation of NFκB and suppress NF-кBP65 protein expression. This indicates that LCB exerts a potential therapeutic effect on the invasion and metastasis of BLCA (171). In addition, LCB can regulate the cell cycle by inhibiting cyclin A and CDK 1/2 mRNA. LCB inhibits colony formation and promoted apoptosis of BLCA cells (172).

Licochalcone C (LCC) has also been shown to induce T24 cell apoptosis by regulating the biological function of the Bcl-2 family (173).

Isoliquiritigenin (IOS). IOS is a bioactive chalcone compound derived from licorice (174). IOS can protect proximal tubular cells (LLC-PK1) from cisplatin via the HO-1 pathway to a certain extent. Furthermore, it shows antitumor activity against BLCA cells (175).

Flavokawain A (FKA). FKA (2'-Hydroxy-4,4',6'-trimethoxychalcone) is the main chalcone extracted from the Kava plant, with non-toxic and cancer-protective characteristics in mice (176). P53 defect is widely hypothesized to contribute to the inhibitory effect of FKA on BLCA growth. SV40 large T antigen (SV40T) driven by the urothelium-specific uroplakin II (UPII) promoter can inactivate the p53 gene in BLCA. FKA in UPII-SV40T transgenic mice yields a significant inhibitory effect on solid tumors, reducing tumor burden and prolonging mice survival (177). In Ha-ras transgenic mice with UPII mutation, FKA has been shown to inhibit the proliferation of solid tumors and promote apoptosis by the Ki67 cell proliferation assay and TUNEL assay. This finding suggested that FAK could inhibit the activation of the Ha-ras gene to prevent and treat NMIBC in vivo (178) (Fig. 8).

Figure 8

Chalcones can activate ER stress and ROS to induce BLCA cells apoptosis, ferroptosis and cell cycle arrest. Licochalcone A can promote intracellular Ca2+ level and activation of Calpain2, cleaved caspase-3/4/9 and Apaf-1 expression to induce cells apoptosis, ER stress and ROS. In addition, it can promote the occurrence of ferroptosis by regulating GSH. Licochalcone B is found to promote apoptosis and cell cycle arrest by inhibiting Cyclin A and CDK 1/2. Licochalcone C can inhibit the expression of the classical anti-apoptosis gene Bcl-2. Isoliquiritigenin protects the kidney by inhibiting cisplatin-induced ROS production. Flavokawain A mainly induces apoptosis of BLCA cells by promoting P27 and DR5 or inhibiting Ki67, Ha-ras, Xiap and Survivin expression. The 2D structures of the compounds were obtained from the Pubchem database. Licochalcone A: PubChemIdentifier: CID 5318998 URL ( Licochalcone B: PubChemIdentifier: CID 5318999 URL ( Licochalcone C: PubChemIdentifier: CID 9840805 URL ( Isoliquiritigenin: PubChemIdentifier: CID 638278 URL ( Flavokawain A: PubChemIdentifier: CID 5355469 URL ( ER, endoplasmic reticulum; ROS, reactive oxygen species; BLCA, bladder cancer; GSH, glutathione.

Chalcone derivatives. Chalcone derivatives have been found to regulate BLCA cell growth and cycle by inhibiting COX-1 activity and platelet aggregation (179).

IPP51 (1-(2,4-dimethoxyphenyl)-3-(1-methylindolyl) propenone) is a novel derivative for chalcone that can promote apoptosis and G2+M accumulation in BLCA cells and inhibit mitosis and destroy microtubules by promoting the production of soluble tubulin and inhibiting tubulin polymerization. In addition, IPP51 exerts an anti-angiogenesis effect (180,181).

Chemotherapy Sensitization

Flavonoids have been found to serve a powerful role in sensitizing patients to chemotherapy. Cisplatin is one of the most common chemotherapy drugs in clinical practice. It has been used for a number of years and is still the cornerstone of chemotherapy for advanced BLCA and metastasis. Reducing its side effects and making it more sensitive to patients has become a research hotspot (182,183). Current evidence suggests that isoliquiritigenin can improve the nephrotoxicity of cisplatin and increase the damage to BLCA cells (175). In addition, silibinin has been shown to alleviate chemodrug-induced chemoresistance through the NF-κB pathway (115). Chemotherapy remains an important means to treat cancer; chemotherapy drugs combined with other drugs, including immune checkpoint inhibitors, have been used to treat BLCA. However, due to the high selectivity of patients to checkpoint inhibitors, the effect is not ideal. Flavonoids represent a promising candidate for a new class of drugs that can be combined with chemotherapy to suppress the recurrence and progression of BLCA. Given that they are harmless and widely available, they bring less financial burden and psychological stress to patients.


The modification of nanoparticles offsets some of the drawbacks of flavonoids. Flavonoids are widely acknowledged for their poor targeting ability and faster metabolism, which are major concerns affecting their efficacy (184). Nanoparticles can be encapsulated and target tumors to increase their half-life and reduce immunogenicity. In addition, nanoparticles can be loaded with various drugs to improve drug resistance and with diagnostic agents for integrated treatment (185). Notably, the Mg (II)-Cat/siEIF5A2 nanoparticle combined with flavonoid and siRNA yields a stronger BLCA inhibitory effect (135). The combination of flavonoids and nanoparticles remains rare in the treatment of BLCA and deserves further study.

4. Discussion and outlook

The mechanisms underlying the therapeutic effect of flavonoids are quite extensive and the generation of ROS seems to act as a switch in a variety of mechanisms (22). Further work on ROS is warranted. The majority of studies have primarily investigated the mechanism of cell cycle arrest and apoptosis, with more emphasis needed on autophagy and ferroptosis. Indeed, autophagy has both positive and negative effects on cancer (31). Different concentrations of drugs may have different effects on autophagy. In addition, inhibition of autophagy appears to promote cell apoptosis. The autophagy changes can be accurately assessed by detecting the transformation from LC3I to LC3II (31). Accordingly, there is still much room for research on ferroptosis in flavonoids. Notably, the change in the GSH/GSSG ratio and the expression of GPX4 can reflect the occurrence of ferroptosis (36). ROS activation is also key to the occurrence of ferroptosis. P53 is not only a tumor suppressor gene but also a regulator of ferroptosis. Its upregulation can promote ferroptosis in cells by inhibiting the system Xc-transporter. CSCs play an important role in the progression of BLCA and multiple marker genes are overafctivated in CSCs. Targeting these genes, including OCT4, KLF4, c-MYC and Nanog, can inhibit the transformation of BLCA stem cells. In addition, CSCs and EMT have been documented in the abnormal activation of multiple common pathways, including the WNT, STAT3 and NF-KB pathways, which can be investigated in future studies.

5. Conclusion

In conclusion, the present study summarized the effects of flavonoid on BLCA in vitro and in vivo for the first time. It emphasized that flavonoids have good prospects for clinical application to treat BLCA.


Figs. 1, 2, 3 and 4 were drawn using Pathway Builder Tool 2.0 (Protein Lounge; (186).


Funding: No funding was received.

Availability of data and materials

Data sharing is not applicable to this article, as no data sets were generated or analyzed during the current study.

Authors' contributions

YL, ZhL and HJ wrote the first draft and drew the figures and tables. ZaL and LD designed this article and modified it. YX revised the draft and the figures. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.



Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018.PubMed/NCBI View Article : Google Scholar


Dobruch J, Daneshmand S, Fisch M, Lotan Y, Noon AP, Resnick MJ, Shariat SF, Zlotta AR and Boorjian SA: Gender and bladder cancer: A collaborative review of etiology, biology, and outcomes. Eur Urol. 69:300–310. 2016.PubMed/NCBI View Article : Google Scholar


Richters A, Aben KKH and Kiemeney LALM: The global burden of urinary bladder cancer: An update. World J Urol. 38:1895–1904. 2020.PubMed/NCBI View Article : Google Scholar


Xia Y, Chen R, Lu G, Li C, Lian S, Kang TW and Jung YD: Natural phytochemicals in bladder cancer prevention and therapy. Front Oncol. 11(652033)2021.PubMed/NCBI View Article : Google Scholar


Han J, Gu X, Li Y and Wu Q: Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect. Biomed Pharmacother. 129(110393)2020.PubMed/NCBI View Article : Google Scholar


Kimura T, Ishikawa H, Kojima T, Kandori S, Kawahara T, Sekino Y, Sakurai H and Nishiyama H: Bladder preservation therapy for muscle invasive bladder cancer: The past, present and future. Jpn J Clin Oncol. 50:1097–1107. 2020.PubMed/NCBI View Article : Google Scholar


Tran L, Xiao JF, Agarwal N, Duex JE and Theodorescu D: Advances in bladder cancer biology and therapy. Nat Rev Cancer. 21:104–121. 2021.PubMed/NCBI View Article : Google Scholar


Bednova O and Leyton JV: Targeted molecular therapeutics for bladder cancer-A new option beyond the mixed fortunes of immune checkpoint inhibitors? Int J Mol Sci. 21(7268)2020.PubMed/NCBI View Article : Google Scholar


Rutz J, Janicova A, Woidacki K, Chun FK, Blaheta RA and Relja B: Curcumin-A viable agent for better bladder cancer treatment. Int J Mol Sci. 21(3761)2020.PubMed/NCBI View Article : Google Scholar


Zanoaga O, Braicu C, Jurj A, Rusu A, Buiga R and Berindan-Neagoe I: Progress in research on the role of flavonoids in lung cancer. Int J Mol Sci. 20(4291)2019.PubMed/NCBI View Article : Google Scholar


Niedzwiecki A, Roomi MW, Kalinovsky T and Rath M: Anticancer efficacy of polyphenols and their combinations. Nutrients. 8(552)2016.PubMed/NCBI View Article : Google Scholar


Kumar S and Pandey AK: Chemistry and biological activities of flavonoids: An overview. ScientificWorldJournal. 2013(162750)2013.PubMed/NCBI View Article : Google Scholar


Amawi H, Ashby CR Jr and Tiwari AK: Cancer chemoprevention through dietary flavonoids: What's limiting? Chin J Cancer. 36(50)2017.PubMed/NCBI View Article : Google Scholar


Lama-Sherpa TD and Shevde LA: An emerging regulatory role for the tumor microenvironment in the DNA damage response to double-strand breaks. Mol Cancer Res. 18:185–193. 2020.PubMed/NCBI View Article : Google Scholar


Srinivas US, Tan BWQ, Vellayappan BA and Jeyasekharan AD: ROS and the DNA damage response in cancer. Redox Biol. 25(101084)2019.PubMed/NCBI View Article : Google Scholar


Harashima H, Dissmeyer N and Schnittger A: Cell cycle control across the eukaryotic kingdom. Trends Cell Biol. 23:345–356. 2013.PubMed/NCBI View Article : Google Scholar


Lim S and Kaldis P: Cdks, cyclins and CKIs: Roles beyond cell cycle regulation. Development. 140:3079–3093. 2013.PubMed/NCBI View Article : Google Scholar


Carusillo A and Mussolino C: DNA Damage: From threat to treatment. Cells. 9(1665)2020.PubMed/NCBI View Article : Google Scholar


Solier S, Zhang YW, Ballestrero A, Pommier Y and Zoppoli G: DNA damage response pathways and cell cycle checkpoints in colorectal cancer: Current concepts and future perspectives for targeted treatment. Curr Cancer Drug Targets. 12:356–371. 2012.PubMed/NCBI View Article : Google Scholar


Kastan MB and Bartek J: Cell-cycle checkpoints and cancer. Nature. 432:316–323. 2004.PubMed/NCBI View Article : Google Scholar


de Sá Junior PL, Câmara DAD, Porcacchia AS, Fonseca PMM, Jorge SD, Araldi RP and Ferreira AK: The roles of ROS in cancer heterogeneity and therapy. Oxid Med Cell Longev. 2017(2467940)2017.PubMed/NCBI View Article : Google Scholar


Aggarwal V, Tuli HS, Varol A, Thakral F, Yerer MB, Sak K, Varol M, Jain A, Khan MA and Sethi G: Role of reactive oxygen species in cancer progression: Molecular mechanisms and recent advancements. Biomolecules. 9(735)2019.PubMed/NCBI View Article : Google Scholar


Perillo B, Di Donato M, Pezone A, Di Zazzo E, Giovannelli P, Galasso G, Castoria G and Migliaccio A: ROS in cancer therapy: the bright side of the moon. Exp Mol Med. 52:192–203. 2020.PubMed/NCBI View Article : Google Scholar


Xu X, Lai Y and Hua ZC: Apoptosis and apoptotic body: Disease message and therapeutic target potentials. Biosci Rep. 39(BSR20180992)2019.PubMed/NCBI View Article : Google Scholar


Hengartner MO: Apoptosis: Corralling the corpses. Cell. 104:325–328. 2001.PubMed/NCBI View Article : Google Scholar


Schneider P and Tschopp J: Apoptosis induced by death receptors. Pharm Acta Helv. 74:281–286. 2000.PubMed/NCBI View Article : Google Scholar


Indran IR, Tufo G, Pervaiz S and Brenner C: Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim Biophys Acta. 1807:735–745. 2011.PubMed/NCBI View Article : Google Scholar


Bertheloot D, Latz E and Franklin BS: Necroptosis, pyroptosis and apoptosis: An intricate game of cell death. Cell Mol Immunol. 18:1106–1121. 2021.PubMed/NCBI View Article : Google Scholar


Wong RS: Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Cancer Res. 30(87)2011.PubMed/NCBI View Article : Google Scholar


Szegezdi E, Fitzgerald U and Samali A: Caspase-12 and ER-stress-mediated apoptosis: The story so far. Ann N Y Acad Sci. 1010:186–194. 2003.PubMed/NCBI View Article : Google Scholar


Levy JMM, Towers CG and Thorburn A: Targeting autophagy in cancer. Nat Rev Cancer. 17:528–542. 2017.PubMed/NCBI View Article : Google Scholar


Amaravadi RK, Kimmelman AC and Debnath J: Targeting autophagy in cancer: Recent advances and future directions. Cancer Discov. 9:1167–1181. 2019.PubMed/NCBI View Article : Google Scholar


White E, Mehnert JM and Chan CS: Autophagy, metabolism, and cancer. Clin Cancer Res. 21:5037–5046. 2015.PubMed/NCBI View Article : Google Scholar


Amaravadi R, Kimmelman AC and White E: Recent insights into the function of autophagy in cancer. Genes Dev. 30:1913–1930. 2016.PubMed/NCBI View Article : Google Scholar


Mou Y, Wang J, Wu J, He D, Zhang C, Duan C and Li B: Ferroptosis, a new form of cell death: Opportunities and challenges in cancer. J Hematol Oncol. 12(34)2019.PubMed/NCBI View Article : Google Scholar


Xu T, Ding W, Ji X, Ao X, Liu Y, Yu W and Wang J: Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med. 23:4900–4912. 2019.PubMed/NCBI View Article : Google Scholar


Bebber CM, Müller F, Prieto Clemente L, Weber J and von Karstedt S: Ferroptosis in cancer cell biology. Cancers (Basel). 12(164)2020.PubMed/NCBI View Article : Google Scholar


Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, Sun B and Wang G: Ferroptosis: past, present and future. Cell Death Dis. 11(88)2020.PubMed/NCBI View Article : Google Scholar


Tiffon C: The impact of nutrition and environmental epigenetics on human health and disease. Int J Mol Sci. 19(3425)2018.PubMed/NCBI View Article : Google Scholar


Margueron R and Reinberg D: Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet. 11:285–296. 2010.PubMed/NCBI View Article : Google Scholar


Mahmoud AM and Ali MM: Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients. 11(608)2019.PubMed/NCBI View Article : Google Scholar


Jasek K, Kubatka P, Samec M, Liskova A, Smejkal K, Vybohova D, Bugos O, Biskupska-Bodova K, Bielik T, Zubor P, et al: DNA methylation status in cancer disease: Modulations by plant-derived natural compounds and dietary interventions. Biomolecules. 9(289)2019.PubMed/NCBI View Article : Google Scholar


Huang Z, Huang Q, Ji L, Wang Y, Qi X, Liu L, Liu Z and Lu L: Epigenetic regulation of active Chinese herbal components for cancer prevention and treatment: A follow-up review. Pharmacol Res. 114:1–12. 2016.PubMed/NCBI View Article : Google Scholar


Qin J, Wen B, Liang Y, Yu W and Li H: Histone modifications and their role in colorectal cancer (Review). Pathol Oncol Res. 26:2023–2033. 2020.PubMed/NCBI View Article : Google Scholar


Audia JE and Campbell RM: Histone modifications and cancer. Cold Spring Harb Perspect Biol. 8(a019521)2016.PubMed/NCBI View Article : Google Scholar


Lee YS and Dutta A: MicroRNAs in cancer. Annu Rev Pathol. 4:199–227. 2009.PubMed/NCBI View Article : Google Scholar


Ali Syeda Z, Langden SSS, Munkhzul C, Lee M and Song SJ: Regulatory mechanism of MicroRNA expression in cancer. Int J Mol Sci. 21(1723)2020.PubMed/NCBI View Article : Google Scholar


Tay Y, Rinn J and Pandolfi PP: The multilayered complexity of ceRNA crosstalk and competition. Nature. 505:344–352. 2014.PubMed/NCBI View Article : Google Scholar


Hanahan D and Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 86:353–364. 1996.PubMed/NCBI View Article : Google Scholar


Koch AE and Distler O: Vasculopathy and disordered angiogenesis in selected rheumatic diseases: Rheumatoid arthritis and systemic sclerosis. Arthritis Res Ther. 9 (Suppl 2)(S3)2007.PubMed/NCBI View Article : Google Scholar


Ramjiawan RR, Griffioen AW and Duda DG: Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis. 20:185–204. 2017.PubMed/NCBI View Article : Google Scholar


Rajabi M and Mousa SA: The role of angiogenesis in cancer treatment. Biomedicines. 5(34)2017.PubMed/NCBI View Article : Google Scholar


Pan G, Liu Y, Shang L, Zhou F and Yang S: EMT-associated microRNAs and their roles in cancer stemness and drug resistance. Cancer Commun (Lond). 41:199–217. 2021.PubMed/NCBI View Article : Google Scholar


Eun K, Ham SW and Kim H: Cancer stem cell heterogeneity: Origin and new perspectives on CSC targeting. BMB Rep. 50:117–125. 2017.PubMed/NCBI View Article : Google Scholar


Barzegar Behrooz A, Syahir A and Ahmad S: CD133: Beyond a cancer stem cell biomarker. J Drug Target. 27:257–269. 2019.PubMed/NCBI View Article : Google Scholar


Huang T, Song X, Xu D, Tiek D, Goenka A, Wu B, Sastry N, Hu B and Cheng SY: Stem cell programs in cancer initiation, progression, and therapy resistance. Theranostics. 10:8721–8743. 2020.PubMed/NCBI View Article : Google Scholar


Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014.PubMed/NCBI View Article : Google Scholar


Du B and Shim JS: Targeting epithelial-mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules. 21(965)2016.PubMed/NCBI View Article : Google Scholar


Lehman HL, Kidacki M and Stairs DB: Twist2 is NFkB-responsive when p120-catenin is inactivated and EGFR is overexpressed in esophageal keratinocytes. Sci Rep. 10(18829)2020.PubMed/NCBI View Article : Google Scholar


Luongo F, Colonna F, Calapà F, Vitale S, Fiori ME and De Maria R: PTEN tumor-suppressor: The dam of stemness in cancer. Cancers (Basel). 11(1076)2019.PubMed/NCBI View Article : Google Scholar


Kopustinskiene DM, Jakstas V, Savickas A and Bernatoniene J: Flavonoids as anticancer agents. Nutrients. 12(457)2020.PubMed/NCBI View Article : Google Scholar


Abotaleb M, Samuel SM, Varghese E, Varghese S, Kubatka P, Liskova A and Büsselberg D: Flavonoids in cancer and apoptosis. Cancers (Basel). 11(28)2018.PubMed/NCBI View Article : Google Scholar


Panche AN, Diwan AD and Chandra SR: Flavonoids: An overview. J Nutr Sci. 5(e47)2016.PubMed/NCBI View Article : Google Scholar


Hostetler GL, Ralston RA and Schwartz SJ: Flavones: Food sources, bioavailability, metabolism, and bioactivity. Adv Nutr. 8:423–435. 2017.PubMed/NCBI View Article : Google Scholar


Shi MD, Shiao CK, Lee YC and Shih YW: Apigenin, a dietary flavonoid, inhibits proliferation of human bladder cancer T-24 cells via blocking cell cycle progression and inducing apoptosis. Cancer Cell Int. 15(33)2015.PubMed/NCBI View Article : Google Scholar


Zhu Y, Mao Y, Chen H, Lin Y, Hu Z, Wu J, Xu X, Xu X, Qin J and Xie L: Apigenin promotes apoptosis, inhibits invasion and induces cell cycle arrest of T24 human bladder cancer cells. Cancer Cell Int. 13(54)2013.PubMed/NCBI View Article : Google Scholar


Xia Y, Yuan M, Li S, Thuan UT, Nguyen TT, Kang TW, Liao W, Lian S and Jung YD: Apigenin Suppresses the IL-1β-induced expression of the urokinase-type plasminogen activator receptor by inhibiting MAPK-Mediated AP-1 and NF-κB signaling in human bladder cancer T24 cells. J Agric Food Chem. 66:7663–7673. 2018.PubMed/NCBI View Article : Google Scholar


Lin Y, Shi R, Wang X and Shen HM: Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets. 8:634–646. 2008.PubMed/NCBI View Article : Google Scholar


Kilani-Jaziri S, Frachet V, Bhouri W, Ghedira K, Chekir-Ghedira L and Ronot X: Flavones inhibit the proliferation of human tumor cancer cell lines by inducing apoptosis. Drug Chem Toxicol. 35:1–10. 2012.PubMed/NCBI View Article : Google Scholar


Iida K, Naiki T, Naiki-Ito A, Suzuki S, Kato H, Nozaki S, Nagai T, Etani T, Nagayasu Y, Ando R, et al: Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway. Cancer Sci. 111:1165–1179. 2020.PubMed/NCBI View Article : Google Scholar


Yang G, Wang Z, Wang W, Zhou X, Hu X and Yang J: Anticancer activity of Luteolin and its synergism effect with BCG on human bladder cancer cell line BIU-87. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 39:371–378. 2014.PubMed/NCBI View Article : Google Scholar : (In Chinese).


Lin JJ, Huang CC, Su YL, Luo HL, Lee NL, Sung MT and Wu YJ: Proteomics analysis of tangeretin-induced apoptosis through mitochondrial dysfunction in bladder cancer cells. Int J Mol Sci. 20(1017)2019.PubMed/NCBI View Article : Google Scholar


Mani R and Natesan V: Chrysin: Sources, beneficial pharmacological activities, and molecular mechanism of action. Phytochemistry. 145:187–196. 2018.PubMed/NCBI View Article : Google Scholar


Xu Y, Tong Y, Ying J, Lei Z, Wan L, Zhu X, Ye F, Mao P, Wu X, Pan R, et al: Chrysin induces cell growth arrest, apoptosis, and ER stress and inhibits the activation of STAT3 through the generation of ROS in bladder cancer cells. Oncol Lett. 15:9117–9125. 2018.PubMed/NCBI View Article : Google Scholar


Lima APB, Almeida TC, Barros TMB, Rocha LCM, Garcia CCM and da Silva GN: Toxicogenetic and antiproliferative effects of chrysin in urinary bladder cancer cells. Mutagenesis: Aug 13, 2020 (Epub ahead of print).


Yang Y, Liu K, Yang L and Zhang G: Bladder cancer cell viability inhibition and apoptosis induction by baicalein through targeting the expression of anti-apoptotic genes. Saudi J Biol Sci. 25:1478–1482. 2018.PubMed/NCBI View Article : Google Scholar


Choi EO, Park C, Hwang HJ, Hong SH, Kim GY, Cho EJ, Kim WJ and Choi YH: Baicalein induces apoptosis via ROS-dependent activation of caspases in human bladder cancer 5637 cells. Int J Oncol. 49:1009–1018. 2016.PubMed/NCBI View Article : Google Scholar


Li HL, Zhang S, Wang Y, Liang RR, Li J, An P, Wang ZM, Yang J and Li ZF: Baicalein induces apoptosis via a mitochondrial-dependent caspase activation pathway in T24 bladder cancer cells. Mol Med Rep. 7:266–270. 2013.PubMed/NCBI View Article : Google Scholar


Kong N, Chen X, Feng J, Duan T, Liu S, Sun X, Chen P, Pan T, Yan L, Jin T, et al: Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1. Acta Pharm Sin B. 11:4045–4054. 2021.PubMed/NCBI View Article : Google Scholar


Wu JY, Tsai KW, Li YZ, Chang YS, Lai YC, Laio YH, Wu JD and Liu YW: Anti-bladder-tumor effect of baicalein from scutellaria baicalensis georgi and its application in vivo. Evid Based Complement Alternat Med. 2013(579751)2013.PubMed/NCBI View Article : Google Scholar


Peng L, Wen L, Shi QF, Gao F, Huang B, Meng J, Hu CP and Wang CM: Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial-mesenchymal transition and inflammation. Cell Death Dis. 11(978)2020.PubMed/NCBI View Article : Google Scholar


Lv WL, Liu Q, An JH and Song XY: Scutellarin inhibits hypoxia-induced epithelial-mesenchymal transition in bladder cancer cells. J Cell Physiol. 234:23169–23175. 2019.PubMed/NCBI View Article : Google Scholar


Ashrafizadeh M, Zarrabi A, Saberifar S, Hashemi F, Hushmandi K, Hashemi F, Moghadam ER, Mohammadinejad R, Najafi M and Garg M: Nobiletin in cancer therapy: How this plant derived-natural compound targets various oncogene and onco-suppressor pathways. Biomedicines. 8(110)2020.PubMed/NCBI View Article : Google Scholar


Goan YG, Wu WT, Liu CI, Neoh CA and Wu YJ: Involvement of mitochondrial dysfunction, endoplasmic reticulum stress, and the PI3K/AKT/mTOR pathway in nobiletin-induced apoptosis of human bladder cancer cells. Molecules. 24(2881)2019.PubMed/NCBI View Article : Google Scholar


Tian F, Tong M, Li Z, Huang W, Jin Y, Cao Q, Zhou X and Tong G: The effects of orientin on proliferation and apoptosis of T24 human bladder carcinoma cells occurs through the inhibition of nuclear factor-kappaB and the hedgehog signaling pathway. Med Sci Monit. 25:9547–9554. 2019.PubMed/NCBI View Article : Google Scholar


Stavric B: Quercetin in our diet: From potent mutagen to probable anticarcinogen. Clin Biochem. 27:245–248. 1994.PubMed/NCBI View Article : Google Scholar


Rauf A, Imran M, Khan IA, Ur-Rehman M, Gilani SA, Mehmood Z and Mubarak MS: Anticancer potential of quercetin: A comprehensive review. Phytother Res. 32:2109–2130. 2018.PubMed/NCBI View Article : Google Scholar


Adami BS, Diz FM, Oliveira Gonçalves GP, Reghelin CK, Scherer M, Dutra AP, Papaléo RM, de Oliveira JR, Morrone FB, Wieck A and Xavier LL: Morphological and mechanical changes induced by quercetin in human T24 bladder cancer cells. Micron. 151(103152)2021.PubMed/NCBI View Article : Google Scholar


Oršolić N, Karač I, Sirovina D, Kukolj M, Kunštić M, Gajski G, Garaj-Vrhovac V and Štajcar D: Chemotherapeutic potential of quercetin on human bladder cancer cells. J Environ Sci Health A Tox Hazard Subst Environ Eng. 51:776–781. 2016.PubMed/NCBI View Article : Google Scholar


Su Q, Peng M, Zhang Y, Xu W, Darko KO, Tao T, Huang Y, Tao X and Yang X: Quercetin induces bladder cancer cells apoptosis by activation of AMPK signaling pathway. Am J Cancer Res. 6:498–508. 2016.PubMed/NCBI


Wei L, Liu JJ, Cao J, Du NC, Ji LN and Yang XL: Role of autophagy in quercetin-induced apoptosis in human bladder carcinoma BIU-87 cells. Zhonghua Zhong Liu Za Zhi. 34:414–418. 2012.PubMed/NCBI(In Chinese).


Tan DQ and Liu XH: Mechanism in growth inhibition of quercetin on human bladder cancer cell line. Zhongguo Zhong Yao Za Zhi. 42:1742–1746. 2017.PubMed/NCBI View Article : Google Scholar : (In Chinese).


Rockenbach L, Bavaresco L, Fernandes Farias P, Cappellari AR, Barrios CH, Bueno Morrone F and Oliveira Battastini AM: Alterations in the extracellular catabolism of nucleotides are involved in the antiproliferative effect of quercetin in human bladder cancer T24 cells. Urol Oncol. 31:1204–1211. 2013.PubMed/NCBI View Article : Google Scholar


Berger SI and Iyengar R: Network analyses in systems pharmacology. Bioinformatics. 25:2466–2472. 2009.PubMed/NCBI View Article : Google Scholar


Dong Y, Hao L, Fang K, Han XX, Yu H, Zhang JJ, Cai LJ, Fan T, Zhang WD, Pang K, et al: A network pharmacology perspective for deciphering potential mechanisms of action of Solanum nigrum L. in bladder cancer. BMC Complement Med Ther. 21(45)2021.PubMed/NCBI View Article : Google Scholar


Cho CJ, Yu CP, Wu CL, Ho JY, Yang CW and Yu DS: Decreased drug resistance of bladder cancer using phytochemicals treatment. Kaohsiung J Med Sci. 37:128–135. 2021.PubMed/NCBI View Article : Google Scholar


Oršolić N, Odeh D, Jembrek MJ, Knežević J and Kučan D: Interactions between cisplatin and quercetin at physiological and hyperthermic conditions on cancer cells in vitro and in vivo. Molecules. 25(3271)2020.PubMed/NCBI View Article : Google Scholar


Lee YH and Tuyet PT: Synthesis and biological evaluation of quercetin-zinc (II) complex for anti-cancer and anti-metastasis of human bladder cancer cells. In Vitro Cell Dev Biol Anim. 55:395–404. 2019.PubMed/NCBI View Article : Google Scholar


Tao T, He C, Deng J, Huang Y, Su Q, Peng M, Yi M, Darko KO, Zou H and Yang X: A novel synthetic derivative of quercetin, 8-trifluoromethyl-3,5,7,3',4'-O-pentamethyl-quercetin, inhibits bladder cancer growth by targeting the AMPK/mTOR signaling pathway. Oncotarget. 8:71657–71671. 2017.PubMed/NCBI View Article : Google Scholar


Alban L, Monteiro WF, Diz FM, Miranda GM, Scheid CM, Zotti ER, Morrone FB and Ligabue R: New quercetin-coated titanate nanotubes and their radiosensitization effect on human bladder cancer. Mater Sci Eng C Mater Biol Appl. 110(110662)2020.PubMed/NCBI View Article : Google Scholar


Shui L, Wang W, Xie M, Ye B, Li X, Liu Y and Zheng M: Isoquercitrin induces apoptosis and autophagy in hepatocellular carcinoma cells via AMPK/mTOR/p70S6K signaling pathway. Aging (Albany NY). 12:24318–24332. 2020.PubMed/NCBI View Article : Google Scholar


Chen F, Chen X, Yang D, Che X, Wang J, Li X, Zhang Z, Wang Q, Zheng W, Wang L, et al: Isoquercitrin inhibits bladder cancer progression in vivo and in vitro by regulating the PI3K/Akt and PKC signaling pathways. Oncol Rep. 36:165–172. 2016.PubMed/NCBI View Article : Google Scholar


Wu P, Liu S, Su J, Chen J, Li L, Zhang R and Chen T: Apoptosis triggered by isoquercitrin in bladder cancer cells by activating the AMPK-activated protein kinase pathway. Food Funct. 8:3707–3722. 2017.PubMed/NCBI View Article : Google Scholar


Ran J, Wang Y, Zhang W, Ma M and Zhang H: Research on the bioactivity of isoquercetin extracted from marestail on bladder cancer EJ cell and the mechanism of its occurrence. Artif Cells Nanomed Biotechnol. 44:859–864. 2016.PubMed/NCBI View Article : Google Scholar


Imran M, Salehi B, Sharifi-Rad J, Aslam Gondal T, Saeed F, Imran A, Shahbaz M, Tsouh Fokou PV, Umair Arshad M, Khan H, et al: Kaempferol: A key emphasis to its anticancer potential. Molecules. 24(2277)2019.PubMed/NCBI View Article : Google Scholar


Qiu W, Lin J, Zhu Y, Zhang J, Zeng L, Su M and Tian Y: Kaempferol modulates DNA methylation and downregulates DNMT3B in bladder cancer. Cell Physiol Biochem. 41:1325–1335. 2017.PubMed/NCBI View Article : Google Scholar


Wu P, Meng X, Zheng H, Zeng Q, Chen T, Wang W, Zhang X and Su J: Kaempferol attenuates ROS-Induced hemolysis and the molecular mechanism of its induction of apoptosis on bladder cancer. Molecules. 23(2592)2018.PubMed/NCBI View Article : Google Scholar


Dang Q, Song W, Xu D, Ma Y, Li F, Zeng J, Zhu G, Wang X, Chang LS, He D and Li L: Kaempferol suppresses bladder cancer tumor growth by inhibiting cell proliferation and inducing apoptosis. Mol Carcinog. 54:831–840. 2015.PubMed/NCBI View Article : Google Scholar


Xie F, Su M, Qiu W, Zhang M, Guo Z, Su B, Liu J, Li X and Zhou L: Kaempferol promotes apoptosis in human bladder cancer cells by inducing the tumor suppressor, PTEN. Int J Mol Sci. 14:21215–21226. 2013.PubMed/NCBI View Article : Google Scholar


DE Oliveira DT, Savio AL, Marcondes JP, Barros TM, Barbosa LC, Salvadori DM and DA Silva GN: Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status. J Biosci. 42:91–101. 2017.PubMed/NCBI View Article : Google Scholar


Barros TMB, Lima APB, Almeida TC and da Silva GN: Inhibition of urinary bladder cancer cell proliferation by silibinin. Environ Mol Mutagen. 61:445–455. 2020.PubMed/NCBI View Article : Google Scholar


Li F, Sun Y, Jia J, Yang C, Tang X, Jin B, Wang K, Guo P, Ma Z, Chen Y, et al: Silibinin attenuates TGF-β1-induced migration and invasion via EMT suppression and is associated with COX-2 downregulation in bladder transitional cell carcinoma. Oncol Rep. 40:3543–3550. 2018.PubMed/NCBI View Article : Google Scholar


Wu K, Ning Z, Zeng J, Fan J, Zhou J, Zhang T, Zhang L, Chen Y, Gao Y, Wang B, et al: Silibinin inhibits β-catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial-mesenchymal transition and stemness. Cell Signal. 25:2625–2633. 2013.PubMed/NCBI View Article : Google Scholar


Imai-Sumida M, Chiyomaru T, Majid S, Saini S, Nip H, Dahiya R, Tanaka Y and Yamamura S: Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways. Oncotarget. 8:92032–92042. 2017.PubMed/NCBI View Article : Google Scholar


Sun Y, Guan Z, Zhao W, Jiang Y, Li Q, Cheng Y and Xu Y: Silibinin suppresses bladder cancer cell malignancy and chemoresistance in an NF-κB signal-dependent and signal-independent manner. Int J Oncol. 51:1219–1226. 2017.PubMed/NCBI View Article : Google Scholar


Prack Mc Cormick B, Langle Y, Belgorosky D, Vanzulli S, Balarino N, Sandes E and Eiján AM: Flavonoid silybin improves the response to radiotherapy in invasive bladder cancer. J Cell Biochem. 119:5402–5412. 2018.PubMed/NCBI View Article : Google Scholar


Gándara L, Sandes E, Di Venosa G, Prack Mc Cormick B, Rodriguez L, Mamone L, Batlle A, Eiján AM and Casas A: The natural flavonoid silybin improves the response to Photodynamic Therapy of bladder cancer cells. J Photochem Photobiol B. 133:55–64. 2014.PubMed/NCBI View Article : Google Scholar


Ramchandani S, Naz I, Lee JH, Khan MR and Ahn KS: An Overview of the potential antineoplastic effects of casticin. Molecules. 25(1287)2020.PubMed/NCBI View Article : Google Scholar


Xu H, Shi HL, Hao JW, Shu KP, Zhang YT and Hou TQ: Casticin inhibits the proliferation, migration and invasion of bladder cancer cells by inhibition of TM7SF4 expression. Zhonghua Zhong Liu Za Zhi. 44:334–340. 2022.PubMed/NCBI View Article : Google Scholar : (In Chinese).


Huang AC, Cheng YD, Huang LH, Hsiao YT, Peng SF, Lu KW, Lien JC, Yang JL, Lin TS and Chung JG: Casticin induces DNA damage and impairs DNA repair in human bladder cancer TSGH-8301 cells. Anticancer Res. 39:1839–1847. 2019.PubMed/NCBI View Article : Google Scholar


Chung YH and Kim D: RIP kinase-mediated ROS production triggers XAF1 expression through activation of TAp73 in casticin-treated bladder cancer cells. Oncol Rep. 36:1135–1142. 2016.PubMed/NCBI View Article : Google Scholar


Gao X, Xu J, Jiang L, Liu W, Hong H, Qian Y, Li S, Huang W, Zhao H, Yang Z, et al: Morin alleviates aflatoxin B1-induced liver and kidney injury by inhibiting heterophil extracellular traps release, oxidative stress and inflammatory responses in chicks. Poult Sci. 100(101513)2021.PubMed/NCBI View Article : Google Scholar


Shin SS, Won SY, Noh DH, Hwang B, Kim WJ and Moon SK: Morin inhibits proliferation, migration, and invasion of bladder cancer EJ cells via modulation of signaling pathways, cell cycle regulators, and transcription factor-mediated MMP-9 expression. Drug Dev Res. 78:81–90. 2017.PubMed/NCBI View Article : Google Scholar


Pan XW, Li L, Huang Y, Huang H, Xu DF, Gao Y, Chen L, Ren JZ, Cao JW, Hong Y and Cui XG: Icaritin acts synergistically with epirubicin to suppress bladder cancer growth through inhibition of autophagy. Oncol Rep. 35:334–342. 2016.PubMed/NCBI View Article : Google Scholar


Stevens Y, Rymenant EV, Grootaert C, Camp JV, Possemiers S, Masclee A and Jonkers D: The intestinal fate of citrus flavanones and their effects on gastrointestinal health. Nutrients. 11(1464)2019.PubMed/NCBI View Article : Google Scholar


Kim DI, Lee SJ, Lee SB, Park K, Kim WJ and Moon SK: Requirement for Ras/Raf/ERK pathway in naringin-induced G1-cell-cycle arrest via p21WAF1 expression. Carcinogenesis. 29:1701–1709. 2008.PubMed/NCBI View Article : Google Scholar


Liao AC, Kuo CC, Huang YC, Yeh CW, Hseu YC, Liu JY and Hsu LS: Naringenin inhibits migration of bladder cancer cells through downregulation of AKT and MMP-2. Mol Med Rep. 10:1531–1536. 2014.PubMed/NCBI View Article : Google Scholar


Juhem A, Boumendjel A, Touquet B, Guillot A, Popov A, Ronot X and Martel-Frachet V: AG11, a novel dichloroflavanone derivative with anti-mitotic activity towards human bladder cancer cells. Anticancer Res. 33:4445–4452. 2013.PubMed/NCBI


Khan N, Afaq F and Mukhtar H: Cancer chemoprevention through dietary antioxidants: Progress and promise. Antioxid Redox Signal. 10:475–510. 2008.PubMed/NCBI View Article : Google Scholar


Khan N and Mukhtar H: Tea polyphenols in promotion of human health. Nutrients. 11(39)2018.PubMed/NCBI View Article : Google Scholar


Bernatoniene J and Kopustinskiene DM: The role of catechins in cellular responses to oxidative stress. Molecules. 23(965)2018.PubMed/NCBI View Article : Google Scholar


Khan N, Afaq F, Saleem M, Ahmad N and Mukhtar H: Targeting multiple signaling pathways by green tea polyphenol (-)-epigallocatechin-3-gallate. Cancer Res. 66:2500–2505. 2006.PubMed/NCBI View Article : Google Scholar


Yasuda T, Miyata Y, Nakamura Y, Sagara Y, Matsuo T, Ohba K and Sakai H: High Consumption of Green tea suppresses urinary tract recurrence of urothelial cancer via down-regulation of human antigen-R expression in never smokers. In Vivo. 32:721–729. 2018.PubMed/NCBI View Article : Google Scholar


Matsuo T, Miyata Y, Asai A, Sagara Y, Furusato B, Fukuoka J and Sakai H: Green tea polyphenol induces changes in cancer-related factors in an animal model of bladder cancer. PLoS One. 12(e0171091)2017.PubMed/NCBI View Article : Google Scholar


Chen Z, Yu T, Zhou B, Wei J, Fang Y, Lu J, Guo L, Chen W, Liu ZP and Luo J: Mg(II)-Catechin nanoparticles delivering siRNA targeting EIF5A2 inhibit bladder cancer cell growth in vitro and in vivo. Biomaterials. 81:125–134. 2016.PubMed/NCBI View Article : Google Scholar


Jankun J, Keck RW and Selman SH: Epigallocatechin-3-gallate prevents tumor cell implantation/growth in an experimental rat bladder tumor model. Int J Oncol. 44:147–152. 2014.PubMed/NCBI View Article : Google Scholar


Lee HY, Chen YJ, Chang WA, Li WM, Ke HL, Wu WJ and Kuo PL: Effects of epigallocatechin gallate (EGCG) on urinary bladder urothelial carcinoma-next-generation sequencing and bioinformatics approaches. Medicina (Kaunas). 55(768)2019.PubMed/NCBI View Article : Google Scholar


Luo KW, Wei Chen, Lung WY, Wei XY, Cheng BH, Cai ZM and Huang WR: EGCG inhibited bladder cancer SW780 cell proliferation and migration both in vitro and in vivo via down-regulation of NF-κB and MMP-9. J Nutr Biochem. 41:56–64. 2017.PubMed/NCBI View Article : Google Scholar


Luo KW, Lung WY, Chun-Xie Luo XL and Huang WR: EGCG inhibited bladder cancer T24 and 5637 cell proliferation and migration via PI3K/AKT pathway. Oncotarget. 9:12261–12272. 2018.PubMed/NCBI View Article : Google Scholar


Qin J, Wang Y, Bai Y, Yang K, Mao Q, Lin Y, Kong D, Zheng X and Xie L: Epigallocatechin-3-gallate inhibits bladder cancer cell invasion via suppression of NF-κB-mediated matrix metalloproteinase-9 expression. Mol Med Rep. 6:1040–1044. 2012.PubMed/NCBI View Article : Google Scholar


Feng C, Ho Y, Sun C, Xia G, Ding Q and Gu B: Epigallocatechin gallate inhibits the growth and promotes the apoptosis of bladder cancer cells. Exp Ther Med. 14:3513–3518. 2017.PubMed/NCBI View Article : Google Scholar


Yin Z, Li J, Kang L, Liu X, Luo J, Zhang L, Li Y and Cai J: Epigallocatechin-3-gallate induces autophagy-related apoptosis associated with LC3B II and Beclin expression of bladder cancer cells. J Food Biochem. 45(e13758)2021.PubMed/NCBI View Article : Google Scholar


Sun X, Song J, Li E, Geng H, Li Y, Yu D and Zhong C: (-)-Epigallocatechin-3-gallate inhibits bladder cancer stem cells via suppression of sonic hedgehog pathway. Oncol Rep. 42:425–435. 2019.PubMed/NCBI View Article : Google Scholar


Luo KW, Zhu XH, Zhao T, Zhong J, Gao HC, Luo XL and Huang WR: EGCG enhanced the anti-tumor effect of doxorubicine in bladder cancer via NF-κB/MDM2/p53 pathway. Front Cell Dev Biol. 8(606123)2020.PubMed/NCBI View Article : Google Scholar


Mottaghipisheh J, Doustimotlagh AH, Irajie C, Tanideh N, Barzegar A and Iraji A: The promising therapeutic and preventive properties of anthocyanidins/anthocyanins on prostate cancer. Cells. 11(1070)2022.PubMed/NCBI View Article : Google Scholar


Alappat B and Alappat J: Anthocyanin pigments: Beyond aesthetics. Molecules. 25(5500)2020.PubMed/NCBI View Article : Google Scholar


Higgins JA, Zainol M, Brown K and Jones GD: Anthocyans as tertiary chemopreventive agents in bladder cancer: Anti-oxidant mechanisms and interaction with mitomycin C. Mutagenesis. 29:227–235. 2014.PubMed/NCBI View Article : Google Scholar


Li WL, Ji GH, Zhang XZ and Yu HY: The influence and mechanisms of purple sweet potato anthocyanins on the growth of bladder cancer BIU87 cell. Zhonghua Yi Xue Za Zhi. 98:457–459. 2018.PubMed/NCBI View Article : Google Scholar : (In Chinese).


Li WL, Yu HY, Zhang XJ, Ke M and Hong T: Purple sweet potato anthocyanin exerts antitumor effect in bladder cancer. Oncol Rep. 40:73–82. 2018.PubMed/NCBI View Article : Google Scholar


Yang N, Gao J, Hou R, Xu X, Yang N and Huang S: Grape seed proanthocyanidins inhibit migration and invasion of bladder cancer cells by reversing EMT through suppression of TGF-β signaling pathway. Oxid Med Cell Longev. 2021(5564312)2021.PubMed/NCBI View Article : Google Scholar


Fishman AI, Johnson B, Alexander B, Won J, Choudhury M and Konno S: Additively enhanced antiproliferative effect of interferon combined with proanthocyanidin on bladder cancer cells. J Cancer. 3:107–112. 2012.PubMed/NCBI View Article : Google Scholar


Liu J, Zhang WY, Kong ZH and Ding DG: Induction of cell cycle arrest and apoptosis by grape seed procyanidin extract in human bladder cancer BIU87 cells. Eur Rev Med Pharmacol Sci. 20:3282–3291. 2016.PubMed/NCBI


Křížová L, Dadáková K, Kašparovská J and Kašparovský T: Isoflavones. Molecules. 24(1076)2019.PubMed/NCBI View Article : Google Scholar


He Y, Wu X, Cao Y, Hou Y, Chen H, Wu L, Lu L, Zhu W and Gu Y: Daidzein exerts anti-tumor activity against bladder cancer cells via inhibition of FGFR3 pathway. Neoplasma. 63:523–531. 2016.PubMed/NCBI View Article : Google Scholar


Russo M, Russo GL, Daglia M, Kasi PD, Ravi S, Nabavi SF and Nabavi SM: Understanding genistein in cancer: The ‘good’ and the ‘bad’ effects: A review. Food Chem. 196:589–600. 2016.PubMed/NCBI View Article : Google Scholar


Park C, Cha HJ, Lee H, Hwang-Bo H, Ji SY, Kim MY, Hong SH, Jeong JW, Han MH, Choi SH, et al: Induction of G2/M cell cycle arrest and apoptosis by genistein in human bladder cancer T24 cells through Inhibition of the ROS-Dependent PI3k/Akt signal transduction pathway. Antioxidants (Basel). 8(327)2019.PubMed/NCBI View Article : Google Scholar


Wang Y, Wang H, Zhang W, Shao C, Xu P, Shi CH, Shi JG, Li YM, Fu Q, Xue W, et al: Genistein sensitizes bladder cancer cells to HCPT treatment in vitro and in vivo via ATM/NF-κB/IKK pathway-induced apoptosis. PLoS One. 8(e50175)2013.PubMed/NCBI View Article : Google Scholar


Köksal Karayildirim Ç, Nalbantsoy A and Karabay Yavaşoğlu NU: Prunetin inhibits nitric oxide activity and induces apoptosis in urinary bladder cancer cells via CASP3 and TNF-α genes. Mol Biol Rep. 48:7251–7259. 2021.PubMed/NCBI View Article : Google Scholar


Zhou YX, Zhang H and Peng C: Puerarin: A review of pharmacological effects. Phytother Res. 28:961–975. 2014.PubMed/NCBI View Article : Google Scholar


Jiang K, Chen H, Tang K, Guan W, Zhou H, Guo X, Chen Z, Ye Z and Xu H: Puerarin inhibits bladder cancer cell proliferation through the mTOR/p70S6K signaling pathway. Oncol Lett. 15:167–174. 2018.PubMed/NCBI View Article : Google Scholar


Ye G, Kan S, Chen J and Lu X: Puerarin in inducing apoptosis of bladder cancer cells through inhibiting SIRT1/p53 pathway. Oncol Lett. 17:195–200. 2019.PubMed/NCBI View Article : Google Scholar


Jiang QQ, Liu B and Yuan T: MicroRNA-16 inhibits bladder cancer proliferation by targeting Cyclin D1. Asian Pac J Cancer Prev. 14:4127–4130. 2013.PubMed/NCBI View Article : Google Scholar


Liu X, Li S, Li Y, Cheng B, Tan B and Wang G: Puerarin inhibits proliferation and induces apoptosis by upregulation of miR-16 in bladder cancer cell line T24. Oncol Res. 26:1227–1234. 2018.PubMed/NCBI View Article : Google Scholar


Du L, Zhang L and Sun F: Puerarin inhibits the progression of bladder cancer by regulating circ_0020394/miR-328-3p/NRBP1 axis. Cancer Biother Radiopharm. 37:435–450. 2020.PubMed/NCBI View Article : Google Scholar


Wu Y, Zhang X, Li Z, Yan H, Qin J and Li T: Formononetin inhibits human bladder cancer cell proliferation and invasiveness via regulation of miR-21 and PTEN. Food Funct. 8:1061–1066. 2017.PubMed/NCBI View Article : Google Scholar


Ouyang Y, Li J, Chen X, Fu X, Sun S and Wu Q: Chalcone derivatives: Role in anticancer therapy. Biomolecules. 11(894)2021.PubMed/NCBI View Article : Google Scholar


Yuan X, Li D, Zhao H, Jiang J, Wang P, Ma X, Sun X and Zheng Q: Licochalcone A-induced human bladder cancer T24 cells apoptosis triggered by mitochondria dysfunction and endoplasmic reticulum stress. Biomed Res Int. 2013(474272)2013.PubMed/NCBI View Article : Google Scholar


Yang X, Jiang J, Yang X, Han J and Zheng Q: Licochalcone A induces T24 bladder cancer cell apoptosis by increasing intracellular calcium levels. Mol Med Rep. 14:911–919. 2016.PubMed/NCBI View Article : Google Scholar


Jiang J, Yuan X, Zhao H, Yan X, Sun X and Zheng Q: Licochalcone A inhibiting proliferation of bladder cancer T24 cells by inducing reactive oxygen species production. Biomed Mater Eng. 24:1019–1025. 2014.PubMed/NCBI View Article : Google Scholar


Hong SH, Cha HJ, Hwang-Bo H, Kim MY, Kim SY, Ji SY, Cheong J, Park C, Lee H, Kim GY, et al: Anti-proliferative and pro-apoptotic effects of licochalcone A through ROS-Mediated cell cycle arrest and apoptosis in human bladder cancer cells. Int J Mol Sci. 20(3820)2019.PubMed/NCBI View Article : Google Scholar


Zhao H, Yuan X, Jiang J, Wang P, Sun X, Wang D and Zheng Q: Antimetastatic effects of licochalcone B on human bladder carcinoma T24 by inhibition of matrix metalloproteinases-9 and NF-кB activity. Basic Clin Pharmacol Toxicol. 115:527–533. 2014.PubMed/NCBI View Article : Google Scholar


Yuan X, Li T, Xiao E, Zhao H, Li Y, Fu S, Gan L and Wang Z, Zheng Q and Wang Z: Licochalcone B inhibits growth of bladder cancer cells by arresting cell cycle progression and inducing apoptosis. Food Chem Toxicol. 65:242–251. 2014.PubMed/NCBI View Article : Google Scholar


Wang P, Yuan X, Wang Y, Zhao H, Sun X and Zheng Q: Licochalcone C induces apoptosis via B-cell lymphoma 2 family proteins in T24 cells. Mol Med Rep. 12:7623–7628. 2015.PubMed/NCBI View Article : Google Scholar


Wang KL, Yu TC and Hsia SM: Perspectives on the role of isoliquiritigenin in cancer. Cancers (Basel). 13(115)2021.PubMed/NCBI View Article : Google Scholar


Patricia Moreno-Londoño A, Bello-Alvarez C and Pedraza-Chaverri J: Isoliquiritigenin pretreatment attenuates cisplatin induced proximal tubular cells (LLC-PK1) death and enhances the toxicity induced by this drug in bladder cancer T24 cell line. Food Chem Toxicol. 109(Pt 1):143–154. 2017.PubMed/NCBI View Article : Google Scholar


Li X, Xu X, Ji T, Liu Z, Gu M, Hoang BH and Zi X: Dietary feeding of Flavokawain A, a Kava chalcone, exhibits a satisfactory safety profile and its association with enhancement of phase II enzymes in mice. Toxicol Rep. 1:2–11. 2014.PubMed/NCBI View Article : Google Scholar


Liu Z, Xu X, Li X, Liu S, Simoneau AR, He F, Wu XR and Zi X: Kava chalcone, flavokawain A, inhibits urothelial tumorigenesis in the UPII-SV40T transgenic mouse model. Cancer Prev Res (Phila). 6:1365–1375. 2013.PubMed/NCBI View Article : Google Scholar


Liu Z, Song L, Xie J, Simoneau AR, Uchio E and Zi X: Chemoprevention of urothelial cell carcinoma tumorigenesis by dietary flavokawain A in UPII-Mutant Ha-ras transgenic mice. Pharmaceutics. 14(496)2022.PubMed/NCBI View Article : Google Scholar


Wu CM, Lin KW, Teng CH, Huang AM, Chen YC, Yen MH, Wu WB, Pu YS and Lin CN: Chalcone derivatives inhibit human platelet aggregation and inhibit growth in human bladder cancer cells. Biol Pharm Bull. 37:1191–1198. 2014.PubMed/NCBI View Article : Google Scholar


Martel-Frachet V, Keramidas M, Nurisso A, DeBonis S, Rome C, Coll JL, Boumendjel A, Skoufias DA and Ronot X: IPP51, a chalcone acting as a microtubule inhibitor with in vivo antitumor activity against bladder carcinoma. Oncotarget. 6:14669–14686. 2015.PubMed/NCBI View Article : Google Scholar


Martel-Frachet V, Areguian J, Blanc M, Touquet B, Lamarca A, Ronot X and Boumendjel A: Investigation of a new 1,3-diarylpropenone as a potential antimitotic agent targeting bladder carcinoma. Anticancer Drugs. 20:469–476. 2009.PubMed/NCBI View Article : Google Scholar


Desilets A, Adam JP and Soulières D: Management of cisplatin-associated toxicities in bladder cancer patients. Curr Opin Support Palliat Care. 14:286–292. 2020.PubMed/NCBI View Article : Google Scholar


Cai Z, Zhang F, Chen W, Zhang J and Li H: MiRNAs: A promising target in the chemoresistance of bladder cancer. Onco Targets Ther. 12:11805–11816. 2019.PubMed/NCBI View Article : Google Scholar


Dobrzynska M, Napierala M and Florek E: Flavonoid nanoparticles: A promising approach for cancer therapy. Biomolecules. 10(1268)2020.PubMed/NCBI View Article : Google Scholar


Sun T, Zhang YS, Pang B, Hyun DC, Yang M and Xia Y: Engineered nanoparticles for drug delivery in cancer therapy. Angew Chem Int Ed Engl. 53:12320–12364. 2014.PubMed/NCBI View Article : Google Scholar


Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B, et al: PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res. 49(D1):D1388–D1395. 2021.PubMed/NCBI View Article : Google Scholar


Patil M, Pabla N and Dong Z: Checkpoint kinase 1 in DNA damage response and cell cycle regulation. Cell Mol Life Sci. 70:4009–4021. 2013.PubMed/NCBI View Article : Google Scholar


Schmitt E, Paquet C, Beauchemin M and Bertrand R: DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis. J Zhejiang Univ Sci B. 8:377–397. 2007.PubMed/NCBI View Article : Google Scholar


Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, Zhang G, Wang X, Dong Z, Chen F and Cui H: Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 5(8)2020.PubMed/NCBI View Article : Google Scholar

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Lv Y, Liu Z, Jia H, Xiu Y, Liu Z and Deng L: Properties of flavonoids in the treatment of bladder cancer (Review). Exp Ther Med 24: 676, 2022
Lv, Y., Liu, Z., Jia, H., Xiu, Y., Liu, Z., & Deng, L. (2022). Properties of flavonoids in the treatment of bladder cancer (Review). Experimental and Therapeutic Medicine, 24, 676.
Lv, Y., Liu, Z., Jia, H., Xiu, Y., Liu, Z., Deng, L."Properties of flavonoids in the treatment of bladder cancer (Review)". Experimental and Therapeutic Medicine 24.5 (2022): 676.
Lv, Y., Liu, Z., Jia, H., Xiu, Y., Liu, Z., Deng, L."Properties of flavonoids in the treatment of bladder cancer (Review)". Experimental and Therapeutic Medicine 24, no. 5 (2022): 676.