Compounds with various pharmacological properties can be found in abundance in nature (1). The unique perspective on nature is attributable to the availability of anticarcinogenic medicines with minimal harmfulness and the ability to inhibit a large range of tumors (2). In addition, natural products are less costly and more specific than synthetic medications (3,4). As a result, finding unique phytonutrients, and their therapeutic impact, and releasing them into the market may be regarded as a novel approach to cancer treatment. A number of effective anticancer medicines are either obtained from botanical sources or are molecular modifications of natural compounds (5,6).

Polyphenols found in fruits and vegetables have been shown to attenuate the progression of cancer (4,7-9). Polyphenols such as curcumin, genistein, resveratrol, apigenin, fisetin, luteolin etc., have demonstrated anti-neoplastic activity in a variety of malignancies such as leukemia, breast, cervical, skin, colon etc. by targeting different hallmarks of cancer (10-13). In particular, flavonoids are the most common type of plant secondary metabolites with beneficial health effects, such as antioxidant, anti-inflammatory, anti-allergic and anti-viral properties (8,14). They are ubiquitous polyphenolic phytochemicals, which have been extensively investigated in recent years for their cytotoxic and anticancer properties (6,7). Antioxidant activity, antitumor action, cell cycle halting, the stimulation of self-programmed cell death, the manipulation of signaling pathways, the suppression of cancer cell movement and the increasing efficiency of chemotherapeutics are among the anticancer properties of these agents (11,13,14). Experiments reported recently have revealed the efficacy of flavonoids in cancer treatment. The treatment with natural antitumor substances inhibits the growth of cancer cells with minimal toxicity (1,2,13,15,16). Since these critical molecules operate through numerous physiological pathways and affect a wide variety of communication networks (6,7), there has been a surge of interest in flavonoids. Flavonoids are predicted to be consumed between 50 and 800 mg per day in the diet (8). The present review discusses the anticancer properties of chrysin, a flavonoid, in various types of cancer as stand-alone candidate and in combination with chemotherapeutics.

Chrysin (5,7-dihydroxyflavone) found in honey and passion flower is a cost-effective and potent anticancer agent. Chrysin possesses numerous biological properties, such as anti-inflammatory, anti-viral, antioxidant and anti-diabetic properties (3,4) (Fig. 1). The most appealing characteristic of chrysin is its anticancer potential, which has been demonstrated through investigations on a wide range of cancer cell lines and animal tumor models. Thus, knowledge of the molecular processes triggered by chrysin in tumor cells may lead to the development of novel cancer treatment approaches with fewer side effects (10). The present review focuses on the anticancer effects of chrysin on various types of cancer and the molecular mechanisms involved.

Chrysin (5,7-dihydroxy flavone) is a flavone and has a natural 15-carbon structure (Fig. 2). Chrysin is ubiquitously found in passion flower, honey and propolis (3,17,18). Chrysin produced from propolis and honey offers boundless curiosity to researchers (7). Chrysin has two benzene rings (A and B) and one oxygen-containing heterocyclic ring in its structure. It has 2-3 double-bound carbons, with a carbonyl group on the fourth carbon, but no 3-carbon hydroxyl group. Chrysin is classified as a flavone based on its structural categorization. It has -OH groups on the fifth and seventh carbon atoms. Unlike other flavonoids, chrysin has no oxygenation in ring-B. Diverse ring-A oxygenation is primarily responsible for numerous chrysin derivatives, such as wogonin (18,19). The biological actions of chrysin are linked to a lack of oxygenation in the B and C rings, which is associated with anti-inflammatory and antitoxic properties. Flavones show different levels of oxidative potential which is reliant on their difference in structure. The antioxidant property of chrysin is dependent on carbonyl group on C4 and double bond between C2 and C3. At lower doses, flavones are beneficial; however, they can be toxic at higher doses and the recommended dose for chrysin is <3 g/day (18,20).

Chrysin has an extremely low bioavailability in humans due to rapid quick metabolism, removal and restricted assimilation. The bioavailability of chrysin when taken orally has been estimated to be between 0.003 to 0.02% (21). In intestinal and hepatic cells, chrysin undergoes metabolism primarily by conjugation processes (glucuronidation and sulfation) and less by oxidation (22). The highest concentrations of chrysin sulfate and glucuronide have been found in the bile in studies on chrysin metabolism in mice (23). As a result, excretion through feces is the main recommended method for the elimination of chrysin and its metabolites (22,23). Chrysin sulfonate and glucuronide have been found in the urine and plasma at low concentrations (22). The poor bioavailability of chrysin has been best addressed by encapsulating it in nanoparticles (24). One of the optimal methods with which to obtain a therapeutic drug delivery platform to treat recurrent oral ulcers and increase chrysin bioavailability is to entrap the drug in niosomal oromuco-adhesive films (25). The release kinetics and cytotoxicity of chrysin are also regulated by encasing it in poly (d, l-lactic-coglycolic acid) poly (ethylene glycol) (PLGA-PEG) nanoparticles (26). Notably, chrysin has been proven to be safe and effective in various studies where volunteers have taken oral doses ranging from 300 to 625 mg without experiencing any documented effect (10,27).

Chrysin has been observed to be beneficial in various metabolic disorders, such as diabetes, cardiac disease, neurodegenerative diseases and above all, cancer (28). In both human and animal cancer models, it has been shown that tumors release cytokines, immunological mediators, classical neurotransmitters, pituitary and hypothalamus hormones, melatonin and glucocorticoids. The body and brain activities can be impacted by catecholamines, serotonin, melatonin, neuropeptides and other neurotransmitters generated from tumors. Cancers can take over the immunological and neuroendocrine systems, resetting the body's equilibrium to favor their growth at the expense of the host (29). Chrysin has been shown to exert neuroprotective effects via a variety of mechanisms, such as gamma-aminobutyric acid mimetic properties, monoamine oxidase inhibition, antioxidant, anti-inflammatory and anti-apoptotic activities (30).

Elevated glucose levels have been shown to cause self-programmed death in glomerular specialized cells, and this process can be minimized following treatment with chrysin (18). The main mechanism involved in the effects of chrysin is the decrease in the splitting of DNA and the repair of ratio of Bax and Bcl-2, as well as the inhibition of cytochrome c and apoptotic protease activating factor 1 in glomerular cells subjected to a higher concentration of glucose (18,31). Chrysin therapy has been shown to reduce NF-κB p65 unit, TNF-α, IL-1, IL-6 and caspase-3 levels in the cerebral cortex and hippocampus, resulting in the antidiabetic protection of cognitive decline (32). The use of chrysin also results in reduced blood sugar and insulin signaling molecules and glucose tolerance inhibition (33). Another study revealed that treatment with chrysin between 20-80 mg/kg/day decreased the levels of low-density lipoprotein cholesterol, triglycerides and cholesterol, and at the same time increased the levels of high-density lipoprotein cholesterol, glutathione S-transferase, superoxide dismutase and catalase (34). Chrysin is a potent antioxidant and this has been reported by various studies. In rats, chrysin has been shown to reduce lipid peroxidation, increase antioxidant enzyme levels, decrease the expression of p53 and intrinsic apoptosis-related proteins, including Bax, Noxa, cytochrome c and caspase-3, increase the activity of Bcl-2, inactivate the MAPK/JNK pathway and suppress the NF-κB pathways, and at the same time upregulate the expression of PTEN, and activate the VEGF/AKT pathway (Fig. 3) (18,35). Chrysin inhibits cytochrome P450 2E1, alcohol dehydrogenase and xanthine oxidase at various dosages (20 and 40 mg/kg body weight) and protects Wistar rats against oxidative stress. It also reduces serum aspartate aminotransferase, alanine aminotransferase and glutamate aminotransferase levels (36).

To identify published research, searches were conducted using databases, such as Medline, PubMed, Scopus, Science Direct and Google Scholar. Of note, two authors conducted a literature search for this purpose using the terms chrysin, anticancer, cancer therapy, chemotherapeutics and their combinations. In addition, an investigation of the references of the article was performed to search for any further research. The search approach was used to filter the article titles and abstracts.

Chrysin demonstrates anticarcinogenic action in a number of leukemias and most solid cancers. Chrysin has been shown to have beneficial effects against numerous types of cancer, including hepatic, breast, lung, cervical and prostate carcinomas (10,37) (Fig. 3). Chrysin reduces cancer growth by selectively modulating various cell signaling pathways associated with inflammation, cancer cell survival, proliferation, angiogenesis, invasion and metastasis. A number of studies have reported the anticancer properties of chrysin in cell lines, as well as animal models, demonstrating different pathways (10,37-39) (Fig. 3). A previous study demonstrated that the chrysin treatment in ovarian cancer led to the augmented generation of reactive oxygen species, a decrease in MMP and an increase in cytoplasmic Ca²⁺, together with the initiation of cell demise (40). Chrysin has been shown to promote the apoptosis of lymphocytic leukemia cells, via the mitochondrial pathway (41). It has been found that chrysin has no cytotoxic effect on normal cells, such as fibroblasts (42). Additionally, chrysin has depicted notable anticancer effects in combination with chemotherapeutic drugs by overcoming resistance (43) (Fig. 4). The present review discusses the anticancer effects of chrysin in various types of cancer alone and in combination (Figs. 1, and Fig. 3, Fig. 4, Fig. 5) with chemotherapeutic agents.

The term ‘cervical cancer’ refers to a malignant tumor that arises from cells in the cervix uteri (44,45). It is a malignancy which frequently affects women and is considered to be one of the chief reasons of cancer-related mortality worldwide (46-48). According to the WHO 2021 report, it is the fourth most frequent type of cancer among women globally, both in regards of prevalence and mortality rates, with an estimated 6 lakhs new cancer cases and 3.5 lakh deaths (49). The primary cause of cervical cancer is manifestation of human papillomavirus (HPV), and virtually all cervical cancers include one or more HPV genotypes (50,51). There are no antiviral therapies available for HPV infection; however, prophylactic vaccination is an excellent primary preventive technique for cervical cancer (52,53). Gardasil 9 has been approved for nine types of HPV types (16 and 18 being most prevalent) and also, these vaccinations provide minimal benefit to those who are previously infested with the virus, and also are unavailable to general populations in developing countries where cervical cancer is prevalent maximum (52-54). There are various chemotherapeutics available for cervical cancer treatment; however, they all have severe side-effects; hence, the search for selective cancer treatment strategies with which to reduce the cervical cancer morbidity and motility continues (3,11).

Various studies have reported the anticancer effects of chrysin on different types of cervical cancer cells (Table I). Chrysin incudes the death of cervical cancer cells via the modulation of various pathways, such as MAPK, AKT/mTOR and genes responsible for tumor growth (Fig. 3) (4). Chrysin also induces apoptosis via PI3K pathway in HeLa cells (55) Chrysin likewise downregulates proliferating cell nuclear antigen (PCNA) expression in cervical carcinoma cells (10). Chrysin at a dose of 30 µM has also been shown to promote nuclear factor kappa-light-chain-enhancer of activated B-cells in HeLa cells (56,57). Additionally chrysin reactivates various TSGs and genes related to apoptosis and migration by decreasing the methylation percentage of these genes, and decreasing the expression of various epigenetic enzymes, such as DNA methyl transferase, histone acetyl transferase, histone deacetyl transferase and histone methyl transferase at the biochemical and transcript level, leading to the modulation of H3 and H4 histone modification marks and decreased DNA methylation following the treatment of Hela cells with chrysin (37). Chrysin encourages TRAIL-induced apoptosis by sensitizing HeLa cells to chrysin (58). Chrysin functions as a dual inhibitor of methylation at the DNA and histone level (59). Chrysin decreases the expression of TWIST 1 and NF-κB and thus suppresses epithelial-mesenchymal transition (EMT) in HeLa cells (60).

In addition to the anticancer effects of chrysin used alone, the use of chrysin in combination with other chemotherapeutics and natural compounds has depicted additional effects. It has been shown that chrysin and capsaicin promote early senescence and programmed cell death via mitochondrial dysfunction and an increase in p53 levels (61). Chrysin and cisplatin have also been shown to exert synergistic effects on induction of apoptosis and the inhibition of migration (62) (Table II).

Breast cancer is the most prevalent and lethal type of cancer affecting women (63). The efficacy of commonly used treatments in breast cancer therapy has been limited by recurrence and chemoresistance (64,65). Natural products, including flavonoids have been shown to exert a potent inhibitory effect on breast cancer growth and metastasis (11,66,67). These natural compounds possess anticancer and anti-cell migration properties, and enhance the efficiency of chemotherapeutic drugs (11). It has been shown that chrysin alone modulates the PI3K/AKT pathway (Table I) and when used in combination (Table II), it exerts anticancer effects on breast cancer cells by modulating human telomerase reverse transcriptase (hTERT) and cyclin D in breast cancer cells (11,68,69).

Previous research has demonstrated that chrysin suppresses the proliferation in the MCF-7 breast cancer model in a dose and time-dependent manner with IC50 values of 19.5 and 9.2 M for 48 and 72 h, respectively (34,70). This anti-proliferative action is credited to its capability to induce the apoptosis of these cancer cell lines. Chrysin significantly inhibits histone deacetylase (HDAC)8 activity with an IC50 of 40.2 µM that significantly decreased the progression of breast cancer (MDA-MB-231). It was previously shown that the oral administration of 90 mg/kg/day of chrysin for 6 weeks evidently decreased tumor size in the MDA-MB-231 xenograft model. Chrysin administration led to the upregulation of CDKN1 at the transcript and protein level (71). Chrysin decreased the viability of 4T1 breast cancer cells by suppressing hypoxia-induced phosphorylation of STAT3 and suppressed hypoxia-induced VEGF gene expression. A similar effect was observed in animal models implanted with 4T1 cells (42,72). Chrysin also obstructs the migratory capacity of metastatic human triple-negative breast cancer cells by modifying MMP10, EMT transition, and PI3K/AKT pathway (68) (Table I). Another study demonstrated that chrysin-loaded PGLA/PEG nanoparticles modulated TIMPS and MMP2 and 9, and PI3K expression in a mouse 4T1 breast tumor model (73).

In addition to its stand-alone anticancer properties, chrysin has been shown to enhance the efficiency of chemotherapeutic drugs. Nano technology has further increased the efficiency of drugs (74). Chrysin and metformin in combination have been found to exert anti-proliferative effects against T47D breast cancer cells. Chrysin used alone and as an adjuvant with metformin has been found to downregulate cyclin D and hTERT expression in the breast cancer cell line (69). Similar results were obtained with the combination of chrysin and silibinin in T47D breast cancer (75). Another study demonstrated that chrysin ruthenium complex promoted the apoptosis of MCF-7 cancer cells via the modulation of Bcl-2, p53 and Bax (76). It has been shown that nano-chrysin inhibits the proliferation of SKOV-3 and MCF-7 cells in a concentration-dependent manner. Nano-chrysin had a much lower IC50 value than pure chrysin and triggers the apoptosis of cancer cells (77). Polymeric micelles have also been created to administer chrysin and methotrexate to breast cancer cells during chemotherapy (78). It has been found that PLGA-PEG loaded with chrysin increases the solubility of the drug and decreases the disputatious effects of chrysin. Chrysin proficiently collects in the T47D cancer cells and augments the cytotoxicity of chrysin on breast cancer cells (79). The combination of chrysin and silibinin decreases the expression hTERT and cyclin D1 in T47D breast cancer cells (75) (Fig. 5). Curcumin and chrysin have been shown to exert significant cooperative cytotoxicity, halt the cell cycle at the G2/M stage and promote apoptosis through the upregulation of expression of miR-321 and miR-502c in comparison to the drugs used alone (80) (Table II).

Lung cancer is one of the principal causes of cancer-related mortality (81,82). In spite of the major advances being made in diagnosis and therapy, the overall 5-year survival rate of patients with lung cancer remains <20% (83). Resistance to chemotherapy and radiation has been identified as the key impediments to effective treatment, and novel adjuvants are urgently required. As a result, it is critical to investigate new targeted agents for lung cancer (81). Flavonoids are phenolic chemicals found in plants that have antibacterial, antiviral, anti-inflammatory, anti-allergic, anti-thrombotic, anti-mutagenic and anti-neoplastic effects (84).

Chrysin (5,7-dihydroxyflavone) is a naturally occurring flavonoid found in several therapeutic plants (4,28). The anti-proliferative abilities of chrysin against human lung cancer cells have been established by a number of research groups (28,81) (Table III). Treatment with chrysin has been shown to lead to the activation of AMPKA and the suppression of AKT, the induction of apoptosis and the growth inhibition of A549 lung cancer cells (81).

CLDN1 and CLDN11 expression have been found to be higher in human lung squamous cell carcinoma. Treatment with chrysin treatment reduces both the mRNA and protein expression of these claudin genes (85) (Fig. 3). Chrysin exerts cytotoxic effects on and promotes the death of human lung cancer and lymphoma cells from mice at doses ranging from 25 to 75 g/ml, with no overt damage to normal cells. Chrysin induces G1/S phase arrest at specific doses. Treatment with chrysin treatment (1.3 mg/kg body weight) significantly decreases tumor volume, resulting in a 52.6% increase in mouse survival (86).

Chrysin restores the cellular equilibrium of cells subjected to benzopyrene by downregulating the expression of elevated proteins, such as PCNA, NF-κB and COX-2 (7,42). Chrysin promotes the apoptosis of lung adenocarcinoma cells via the modulation of caspases, Bax and Bcl-2(87). Chrysin, together with doxorubicin, promote the activation of AMPK to induce A549 programmed cell death which is attributed to AKT inhibition (81). It has also been shown that chrysin can prevent the constitutive activation of STAT3, leading to the decreased expression of myeloid cell leukemia-1 (Mcl-1); this action motivates the deactivating TRAIL resistance of A549 human lung cancer cells by chrysin (58). A previous study demonstrated that quercetin and chrysin together decreased the levels of pro-inflammatory molecules, such as IL-6, -1 and -10, and the levels of TNF via the NF-κB pathway. In addition, chrysin and quercetin downregulated the expression of Myd88 and Toll-like receptor 4, as well as MMP9(88). Chrysin has been shown to increase the efficacy of docetaxel in non-small cell lung cancer by inducing cytotoxicity, suppressing cell proliferation and promoting apoptosis (89) (Fig. 5). A previous study demonstrated that in A549 lung cancer cells, curcumin- and chrysin-loaded nanoparticles led to the downregulation of hTERT and MMPs (90). Another study demonstrated that the combination of chrysin and doxorubicin decreased the IC50 value of four cell lines, namely H460, A549, H157 and H1975(91). Chrysin at concentrations between 5 and 30 µM and doxorubicin at concentrations between 0.025 and 3.0 µM in combination functioned synergistically in lung cancer cells to induce cell death and reduce the toxicity of doxorubicin (91) (Table II). However, despite the numerous biological properties of chrysin, its limited bioavailability is the primary barrier to its use in pharmaceuticals. Chrysin-loaded nanoparticles have depicted improved therapeutic activity in animal models and may serve as a useful formulation for pharmacological intervention (89).

Skin cancer is a common disease that affects numerous individuals worldwide. The increase in the number of skin cancer cases over the past few decades may be due to multiple factors. These could include individual and collective habits, as well as changes in the climate, particularly in the ozone layer. The most common types of skin cancer encountered by physicians are melanomas and non-melanomas. More specifically, there are two forms of non-melanoma cancer: Squamous cell carcinoma and basal cell carcinoma (92). The prognosis of patients with this type of cancer is typically very poor (93). Of note, 80% of skin malignancies that are not melanomas are caused by basal cell carcinoma. UV radiation exposure is the main factor that may result in basal cell carcinoma. Aggressive melanomas account for 60% of skin cancer-related mortality, despite representing only 1% of all cases of skin cancer cases (94). Chrysin has been shown to inhibit squamous cell carcinoma via the modulation of Rb and by decreasing the expression of CDK2 and CDK4(95).

Melanoma is an extremely resistant and aggressive skin tumor that accounts for >2-3% of all cancer occurrences. Melanoma incidence has risen dramatically in recent decades and is responsible for more than 75% of all skin cancer fatalities due to its aggressiveness (96,97). Melanoma can be treated with surgery in its early stages; however, treatment is impossible after it metastasizes to other areas (97). As melanin synthesis occurs inside the specialized membrane-bound organelles known as melanosomes, it is a highly regulated process in normal melanocytes. Under these circumstances, the synthesis of melanin serves as a defense against attacks from the environment and UVR-induced malignancies. However, melanin pigment appears to have a function in the malignant transformation of melanocytes despite its protective effect against UVR (98). This process can become dysregulated in melanoma cells when melanogenesis intermediates seep outside of melanosomes, influencing the behavior of the cells or the environment around them (99). Thus, unchecked melanogenesis plays a role, perhaps a crucial one, in the development of melanotic melanoma and, in conjunction with melanin pigment, it can reduce the effects of chemo- and radiotherapy. The protective properties of melanin pigment under normal circumstances and its destructive properties under pathological ones represent the yin and yang of melanogenesis (98).

Bioactive compounds, including chrysin derived from plants, are able to induce apoptosis, as well as hinder migration; they have been evaluated as possible medications in melanoma treatment (100,101). In vitro, it has been shown that chrysin selectively exhibits toxicity and induces the self-programed death of human uveal melanoma cells (M17 and SP6.5) without having any effect on normal cells (101). In vitro and in vivo, chrysin has been shown to exert profound toxicity against melanoma cells (Table III) by encouraging self-programed death along with halting the cell cycle at the G2/M or G1/S phases. In animal models, 2 and 3 weeks of treatment with chrysin was found to decrease the tumor volume by >55 and >65%, respectively (96,101) O note, chrysin promotes the toxicity of natural killer cells, T-cells and macrophages, towards cancer cells) (96). MMPs, such as MMP2 and MMP9 play a prominent role in cancer cell migration via the degradation of the extracellular matrix (102). Chrysin inhibits the migration of melanoma cells and HeLa cells via the downregulation of MMP2, and the upregulation of E-cadherin and the downregulation of cadherin (37,103). The AKT/PI3K and NF-κB pathways play a role in cancer cells and chrysin is associated with the inhiation of the PI3K/Akt and NF-κB pathways in melanoma. Chrysin decreases melanoma cell migration via the downregulation of the EMT-related proteins, E-cadherin, Snail and Smad; WNT/β-catenin target proteins, such as MMP2, MMP9, and VEGF have also been found to be downregulated by chrysin in melanoma cells (104) (Table III and Fig. 3). To overcome drug resistance in melanoma cells, nano-chrysin and nano-curcumin previous research used for the treatment of C57B16 mice bearing B16F10 melanoma tumors. It was observed that the combination of the two in an encapsulated form decreased the migration of these highly metastatic cancer cells via the downregulation of MMPs, tissue inhibitor of metalloproteases and hTERT gene expression, more so in the mouse B16F10 melanoma tumor model (3,105) (Table II).

Bladder cancer is another main type of cancer found in progressive countries. Its incidence rate is 6 lakh and >2 lakh deaths yearly according to the GLOBOCAN report in 2020(106). As all conventional therapies are toxic and bladder cancer has exhibited resistance to chemotherapeutics, research is being conducted to discover and develop new strategies (107). Plant-derived bioactive compounds are being used for the treatment and prevention of different types of cancer, including bladder cancer (4,9,107). Notably, bladder cell cancer development is aided by the activation of AKT/ERK/PI3K and STAT (108-110). Chrysin has been shown to modulate the AKT pathway in bladder fibrosis (111) (Fig. 3). Chrysin is a phytochemical found in honey and bee propolis and it causes increase in ROS leading to upregulation of caspases, downregulation of Bcl2, Bcl-xL and inhibition of STAT3 and Mcl-1(112). Chrysin promotes the apoptosis of bladder cancer cells (T-24 and 5637) via the upregulation of caspase-9 and -3, and the downregulation of Bcl-xL, Mcl-1 and Bcl-2 and the intrinsic pathway (112) (Table IV).

The mutation of TP53 is the main reason for the poor survival rates of patients with bladder cell cancer. Chrysin inhibits the propagation of bladder cancer cells having mutated and wild-type TP53. Chrysin increases in reactive oxygen species, halts the cell cycle, and promotes the downregulation of SRC, PLK1 and HOXB3 in cells having mutated. Chrysin also promotes DNA hypermethylation in grade 2 cells, and downregulates mTOR and c-MYC in grade 3 cells. It has been proven that chrysin activity is related to the TP53 status (113,114). The combined use of chrysin with other chemotherapeutics exerts a synergistic effect. A previous study demonstrates that the combination of TRAIL and chrysin led to a decrease in the resistance of bladder cells to treatment and increased cell death (115).

The effects of chrysin in hepatocellular carcinoma have been reported by various studies (Table IV). Among the different factors that affect cancer cell metabolism, namely the change from oxidative phosphorylation to aerobic glycolysis, hexokonase2 is a key protein (116). Chrysin revokes the initial development of hepatic cancer and encourages programmed cell death in N-nitroso-diethylamine-created early neoplastic lumps in rats (117). In a previous study, Chrysin decreased expression of HK-2 in mitochondria, and the interaction between HK-2 and VDAC 2 was disrupted, which resulted in a marked increase in membrane permeability and the release of pro-apoptotic enzymes, such as cytochrome c and the release of Bax in hepatocellular carcinoma cells and animal models (118). As previously demonstrated, by decreasing the expression of specified hexokinase2, chrysin decreased glucose absorption and lactate generation in hepatocellular carcinoma cells and apoptosis was induced by chrysin due to the translocation of Bax from the cytoplasm to the mitochondria. Furthermore, in hepatocellular carcinoma xenograft models, Chrysin resulted in a promising decrease in tumor development via hexokinase-2 downregulation (118). Chrysin exerted its effect on propagation and programmed cell death in diethyl nitrosamine-induced early hepatocarcinogenesis in male Wistar rats. COX-2, NF-κB p65 and BcL-xL downregulation was observed, and Bax, p53 and caspase-3 exhibited an amplified expression (117).

The emergence of chemoresistance has been linked to the constitutive activation of the Nrf2-mediated signaling pathway. Gao et al (119) examined whether Nrf2 expression was connected to drug resistance in BEL-7402 (BEL-7402/ADM) cells that were resistant to doxorubicin, and whether chrysin could reverse drug resistance in BEL-7402/ADM cells. It was observed that chrysin markedly decreased Nrf2 expression at both the mRNA and protein level via the downregulation of the PI3K-Akt and ERK pathways (119). In another study, the combination of chrysin and curcumin led to the apoptosis of HepG2 cells via the p53 pathway (120) (Table II).

Gastric cancer is placed fifth for frequency and fourth for mortality globally, and an estimated 769,000 deaths have been recorded according to the GLOBOCAN report in 2020) (106). Conventional therapies are unable to entirely cure cancer or considerably enhance the quality of life of patients with cancer metastasis due to cancer cell migration. As a result, innovative medicines that target the abnormal pathways that contribute to cancer invasion or metastasis are being developed (121). Chrysin has been shown to exert significant effects in gastric cancer (Table V). Chrysin has been shown to suppress both endogenous and inducible recepteur d'origine nantais (RON), expression dose-dependently. The transcription factors, Egr-1 and NF-κB, have a significant function in RON activity. Furthermore, by inhibiting Egr-1 and NF-κB in AGS cells, chrysin reduces RON expression at both levels (121) (Fig. 3). Chrysin instigated the movement of gastric cancer cells via the downregulation of MMP9 and the downregulation of JNK and ERK pathways (122). In gastric cancer (MKN45) cells, the effect of chrysin on the expression profile of TET proteins (TET1-3) was recently investigated. TET enzymes play a role in DNA demethylation and, as a result, alter gene expression via epigenetic mechanisms. It was found that TET1 expression in gastric cancer cells was enhanced by chrysin exposure at both the transcript and protein levels. Chrysin, a HDAC inhibitor, caused cytotoxicity, and also inhibited migration and invasion. These effects were discovered to be mediated by TET1 overexpression induced by chrysin. TET1 overexpression in gastric cancer cells replicated Chrysin-induced actions, leading to this result. Notably, chrysin treatment induced apoptosis via the modulation of Bax/Bcl-2, caused cell cycle detention at the sub G1 phase and repressed the metastasis of MKN-45 cells. In animal experiments, chrysin decreased cancer development and increased TET1 expression. Chrysin administration (20 mg/kg) for 14 days significantly attenuated tumor development in a nude mouse xenograft model of gastric cancer (123). These results demonstrate that chrysin promotes programmed cell death in gastric cancer cells initiated by the epigenetic player, TET1(42). Furthermore, dysregulation in miRNA expression leads to the appearance of pathological circumstances, particularly cancer (124,125). Mohammadian et al (126) reported that chrysin upregulated miR-9 and miR 22, and decreased miR-18, miR-21 and miR-221 expression in the AGS cell line (Table V). The use of chrysin and PLGA-PEG nanoparticles has been shown to lead to the greater promotion of miR-34a, miR-126 and miR-22 gene expression, in comparison with free chrysin (127). In another study, the greater decrease of miR-18a, miR-21 and miR-221 was attained by chrysin-loaded PLGA-PEG nanoparticles (128). A previous study demonstrated that chrysin upregulated miR-9 and Let-7a as onco-suppressor aspects in cancer to hinder the propagation of gastric cancer cells. Nanoparticles suggestively encourage the aptitude of chrysin in upregulating miR-9 expression (129). It has been found that chrysin with other chemotherapeutic agents enhances the anticancer effect. The synergistic effect of chrysin and 5-fluorouracil (5-FU) (Table II) was observed in AGS/5-FU-resistant AGS cells with an enhanced p53-p21 activity, with the arrest of the cell cycle at the G2/M phase (43). Chrysin and cisplatin used concomitantly have been shown to lead to the self-programmed death of HepG2 cells via both extracellular signals and mitochondrial pathways by the activation of respective caspases) (120) (Table II). Chrysin has also been shown to enhance the sensitivity of BEL-7402/ADM cells to doxorubicin (121).

Colorectal cancer (CRC) is ranked third in terms of frequency, but second in terms of cancer-related mortality. The incidence rates are ~4-fold greater in developed countries than in developing ones. The colon cancer incidence rates vary by ~9-fold throughout the globe, with the highest rates observed in Europe, New Zealand and North America, with a higher incidence in the male population. However, Norway and Hungary also exhibit the highest rates, although the incidence here among males and females is equal (106). Previously, in in vitro and in vivo experiments, the cytotoxic effects of chrysin (Table V) and its line of action were verified in colon cancer cells (CT26) (38). Chrysin exerted cytotoxic effects and induced the apoptosis of CT26 cells in a concentration-dependent manner (IC50, 80 µg/ml). Furthermore, Chrysin-treated mice exhibited a considerable reduction in tumor volume (38). A marked reduction in the colon tumor volume in treated mice (8 and 10 mg/kg) was observed as compared to the untreated mice. RT-PCR elucidated that chrysin attenuated the tumor volume through the downregulation of the Sall4 and the upregulation of Bax. Thus, the downregulation of Sall4 and the increased expression of Bax were linked to a decreased tumor volume (38). The anticancer activity of chrysin has also been investigated in studies involving the colon cancer cell lines, HT-55, HCA-7 and LoVo. The IC50 values of chrysin against these cell lines ranged from 0.4 to 0.8 mM with the modulation of various molecules, such as ERK and AKT (42,130). Another study found that irradiated chrysin induced the intrinsic apoptosis of H29 colon cancer cells (131).

Chrysin in combination with other chemotherapeutic agents has exhibited notable results. Drug resistance and adverse effects have limited the use of 5-FU in the treatment of patients with CRC (132,133). In the treatment of CRC, chrysin has recently been proposed as a substitute for 5-FU. The use of chrysin (5-50 M) has been linked to a considerable reduction in the viability of CRC cells (134). Autophagy is influenced by chrysin in the treatment if CRC, according to a study of the molecular processes. Autophagy is a ‘self-digestion’ process that is triggered by stressful situations, such endoplasmic reticulum stress, mitochondrial injury, malnutrition, etc. (135). Curcumin- and chrysin-loaded PLGA-PEG nanoparticles have been shown to exert a collaborative effect and improve the cell death effects of these bioactive agents against colorectal cancer cells (136). A previous study demonstrated that apigenin used in combination with chrysin suppressed the development and migration of CRC cells by reducing p38-MAPK/AKT activity; however, at higher doses of chrysin (50 and 100 µM), the effect was antagonistic (137) (Table II).

Nanoparticle-based combinatorial chemotherapy has been proposed as a potential technique for increasing intracellular drug concentrations and achieving synergistic effects in anticancer therapy. It has been shown that chrysin and curcumin alone exert a dose-dependent cytotoxic effect on Caco-2 cells (138). However, curcumin-chrysin-loaded nanoparticles, on the other hand, exert a significant inhibitory effect on proliferation in comparison to the drugs used alone, leading to a marked decrease in hTERT expression (138). Nano-encapsulated chrysin and curcumin exert have been shown to exert a high synergistic effect on SW480 cells cancer cells, as compared to their free versions. The SW480 CRC cells subjected to a combination of chrysin and curcumin in a nano-encapsulated form were found to exhibit a significant inhibition of hTERT expression (136) (Fig. 5).

Ovarian cancer is not often detected, but is a very fatal cancer and is the principal cause of mortality due to gynecological cancers (139). Ovarian cancer is divided into epithelial, germ cell, or stromal tumors, based upon their location within the ovary (140), with the most common being the epithelial type; this can be categorized into the benign, low malignant and malignant type (141). The treatment regimen for ovarian cancer is surgery followed by chemotherapy using carboplatin or cisplatin or a combination of the two (140). However, due to the side-effects associated with conventional therapies, it appears that plant-derived agents are probable candidates for the treatment and prevention ovarian cancer (40,142). Treatment with chrysin has been shown to lead to the induction of cell death and the intrinsic apoptosis of A2780cp cisplatin-resistant human ovarian cancer cells (143). Another study demonstrated that the treatment of ovarian cancer cells with chrysin led to an upsurge in the concentration of ROS and cytoplasmic Ca²⁺ and the activation of the MAPK/PI3K pathways, that resulted in the induction of self-programed cell death (40). However, by contrast, a number of studies have demonstrated that the activation of the PI3K/AKT pathway contributes to cell proliferation and metastasis, and the inhibition of this pathway is a potential pathway for targeted cancer therapy (4,56,144). Thus, aforementioned study has depicted that chrysin suppresses ovarian cancer via the activation of PI3K/AKT and MAPK (40). Hence, further research is warranted in order to fully understand the exact modes of action of chrysin.

Additionally, it has been reported that there is an association between the incidence of cancer and diabetes (145); chrysin targets various disorders, including diabetes and cancer. However, o date, to the best of our knowledge, there are no data available demonstrating that the anti-diabetic action of chrysin has prevented the occurrence of cancer.

In conclusion, researchers are currently focusing on finding the impact of various plant-derived agents on cancers with the aim of developing cancer therapies. The results of this research are aiding in the more in-depth understanding of the causes and development of cancer. Although the effects of chrysin have been shown in various types of cancer, the exact molecular mechanisms through which chrysin controls the progression of different types of cancer have not yet been fully eludicated. Nevertheless, the majority of the data presented to date validate the effects of chrysin on various types of cancer in vitro and in animal models. However, the use of chrysin as a therapeutic agent in clinical setups is still far from being realized, until trials on humans are not performed and validated. In addition, experiments to confirm its effects in combination with conventional treatment agents and to enhance the treatment efficacy are required.