Open Access

Potential proapoptotic phytochemical agents for the treatment and prevention of colorectal cancer (Review)

  • Authors:
    • Kanwal Ahmed
    • Syed Faisal Zaidi
    • Zheng‑Guo Cui
    • Dejun Zhou
    • Sheikh Abdul Saeed
    • Hidekuni Inadera
  • View Affiliations

  • Published online on: May 13, 2019     https://doi.org/10.3892/ol.2019.10349
  • Pages: 487-498
  • Copyright: © Ahmed et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer (CRC) is one of the leading causes of mortality among men and women. Chemo‑resistance, adverse effects and disease recurrence are major challenges in the development of effective cancer therapeutics. Substantial literature on this subject highlights that populations consuming diets rich in fibers, fruits and vegetables have a significantly reduced incidence rate of CRC. This chemo‑preventive effect is primarily associated with the presence of phytochemicals in the dietary components. Plant‑derived chemical agents act as a prominent source of novel compounds for drug discovery. Phytochemicals have been the focus of an increasing number of studies due to their ability to modulate carcinogenic processes through the alteration of multiple cancer cell survival pathways. Despite promising results from experimental studies, only a limited number of phytochemicals have entered into clinical trials. The purpose of the current review is to compile previously published pre‑clinical and clinical evidence of phytochemicals in cases of CRC. A PubMed, Google Scholar and Science Direct search was performed for relevant articles published between 2008‑2018 using the following key terms: ‘Phytochemicals with colorectal cancers’, ‘apoptosis’, ‘cell cycle’, ‘reactive oxygen species’ and ‘clinical anticancer activities’. The present review may aid in identifying the most investigated phytochemicals in CRC cells, and due to the limited number of studies that make it from the laboratory bench to clinical trial stage, may provide a novel foundation for future research.

Introduction

Colorectal cancer (CRC) is the third most common cancer diagnosed in men and women and is the fourth leading cause of cancer-associated mortality worldwide (1). In 2018, >30,000 CRC-associated mortalities were reported in the USA (2). According to the World Health Organization, in 2008, 1.2 million new CRC cases were reported globally (3). Annually >0.6 million patients succumb due to CRC (4), and a family history of CRC or chronic inflammatory bowel disease is a contributing factor for disease progression (5). Additionally, a sedentary lifestyle, low physical activity and unhealthy dietary patterns, including diets with low fiber and a high content of red meat or fat, cigarette smoking and alcohol abuse, are the major causes of CRC development. The majority of CRC cases are diagnosed at the advanced stages of disease, which makes curative treatment impossible (6).

Understanding the developmental pathways in tumor cells that promote the growth and metastasis of tumors is important in order to identify the molecular targets of cancer therapeutics. The majority of CRC cases occur as a result of genetic and epigenetic modifications (79). Studies investigating human cancer, including CRC, have demonstrated a central role of p53 in tumor suppression (10). Almost 50% of CRC cases are reported to have a mutation in p53 (9), which promotes cell proliferation, invasion, metastasis and resistance to a variety of anticancer drugs, such as 5 fluorouracil (11,12). Mutations in the KRAS, BRAF and neuroblastoma RAS viral oncogene genes have also been reported in CRC (13). Additionally, mutations of the adenomatous polyposis coli gene in CRC promotes the dysfunction of β-catenin and activates the Wnt pathway, which is an activator of the key cell cycle regulatory genes cyclin D1 and c-Myc, which provide suitable conditions for cellular proliferation (13). In CRC, the activation of NF-κB upregulates a number of genes responsible for the generation of pro-inflammatory mediators and cytokines, which are essential for CRC cell propagation (14). Additionally, the PI3K/Akt pathway promotes tumor proliferation via inhibition of apoptosis and stimulation of the cell cycle (15).

High levels of reactive oxygen species (ROS) have been detected in almost all types of cancer and been demonstrated to potentiate numerous aspects of tumor development and progression. Under physiological conditions, the intracellular ROS levels are not high enough to induce cell damage. However, any imbalance in the redox status of the cell results in oxidative stress, which exerts an important function in the initiation, promotion and progression of carcinogenesis (16). Physical agents, chemical agents, inflammation and infection potentiate oxidative stress, which directly damages DNA and promotes tumorigenesis (17). Under mild oxidative stress, wild-type p53 is reported to induce the expression of antioxidant enzymes, and stimulates cell repair and survival mechanisms (18,19). However, upon acute oxidative stress, p53 reduces the expression of detoxifying enzymes and stimulates apoptosis (20). By contrast, mutated p53 exhibited in cancer cells cannot induce the expression of antioxidant enzymes to detoxify higher levels of ROS, whereas it upregulates cell proliferative gene expression, which promotes the propagation of DNA damage (21).

Apoptosis is a tightly regulated mechanism of cell death and a stress response to toxic stimuli that is required to maintain intestinal epithelial cell homeostasis. Spontaneous apoptosis continuously occurs in the normal, unstressed intestine and stress-induced apoptosis occurs following genotoxic insult, including exposure to DNA-damaging agents. In cancer cells, dysregulation of the apoptotic process results in disturbance of tissue homeostasis, which then results in uncontrolled proliferation of cells (22). Caspases function as initiators and executors of apoptosis. Initiator caspases, including caspase-8 and −9, which are involved in the extrinsic and intrinsic apoptotic pathways, activate effector caspases, including caspase-3 and −7, which cleave several proteins, including poly(ADP ribose) polymerase-1 (PARP-1) in cells (23,24). PARP-1 is a nuclear enzyme involved in DNA repair, DNA stability and transcriptional regulation. PARP-1 cleavage prevents recruitment of enzymes to the site of DNA damage and is considered to be a hallmark of apoptosis (Fig. 1) (25).

The endoplasmic reticulum (ER) is responsible for the synthesis, folding and maturation of proteins (26). Conditions that result in ER stress can activate cell protective mechanisms; however, if the stress is excessive or prolonged then it will eliminate cells via the intrinsic apoptosis pathway (26). This switch between pro-survival and pro-apoptotic pathways is due to the induction of a transcriptional factor C/EBP homologous protein (CHOP) (27), which has been reported to downregulate the anti-apoptotic protein Bcl-2 (28). Additionally, ER stress increases intracellular calcium (Ca2+) levels, which activates calpain-induced cleavage of anti-apoptotic B-cell lymphoma-extra large (Bcl-xl) and increases caspase-12 activity, which then activates caspase-9 independent of apoptotic protease activating factor 1 (Apaf-1), followed by the activation of caspase-3 (Fig. 1) (29,30).

The activation of apoptosis is an important mechanism for CRC prevention and treatment (3133). Dietary phytochemicals are known to prevent the initiation of carcinogenesis via the induction of antioxidant enzymes and block the progression of carcinogenic cells via the induction of apoptosis and cell cycle arrest (34,35). Almost 50% the approved anticancer drugs are derived from natural products or their derivatives (36,37). To establish novel compounds that can be utilized in combined therapy to potentiate the effect of chemotherapeutic drugs, a number of studies have been performed to identify agents present in diet or herbs that interfere with proliferative cell signaling pathways (3438). The aim of the present study was to compile available literature published between 2008–2018 regarding the mechanisms of apoptosis induced by phytochemicals in CRC cells in preclinical and clinical settings. This may assist in providing a solid foundation for future research options in this field.

Literature review method

The present review is based on a literature search of PubMed (ncbi.nlm.nih.gov/pubmed/), Google Scholar (scholar.google.com/) and Science Direct (sciencedirect.com/) to identify relevant studies published between 2008–2018. The search was performed with the following key terms: ‘Phytochemicals with colorectal cancers’, ‘apoptosis’, ‘reactive oxygen species (ROS)’ and ‘clinical anticancer activities’. Only studies investigating the effects of phytochemicals on patients with CRC in preclinical and clinical trials were included in the present review.

Apoptosis-inducing phytochemicals in CRC

Phytochemicals are a non-nutritive group of compounds naturally present in fruits, vegetables, spices, grains and herbs, which have health promoting and disease preventing characteristics (39). In preclinical and clinical studies of different types of tumor, the consumption of fruits and vegetables has been reported to exert beneficial health effects (39,40). CRC is strongly associated with dietary factors and the association of phytochemicals with CRC prevention has been reported in several studies (4143). Numerous phytochemicals exhibit chemo-preventive effects in CRC due to their antioxidative and ROS scavenging activities. However, various phytochemicals are also known to induce apoptosis by promoting ROS generation (4462). Table I details a list of ROS-inducing phytochemicals in CRC.

Table I.

Reactive oxygen species-inducing phytochemicals.

Table I.

Reactive oxygen species-inducing phytochemicals.

CompoundOriginCell line(s) investigated(Ref.)
p-Methoxycinnamic acidRice bran, turmeric, Kaemperfia galangal and brown riceHCT-116(44)
PiperinePiper nigrum and Piper longumHRT-18(45)
ApigeninFruits and vegetables, including parsley, onions, oranges, tea, chamomile, wheat sprouts and certain seasoningsHT-29 and HCT-15(46)
CurcuminCurcuma longHCT-116(47)
CurcuminCurcuma longHT-29(48)
EmodinNatural herbs, including Rheum palmatum and PolygonamSW480 and SW620(49)
QuercetinFruits, vegetables, nuts and red wineHT-29(50)
PatulinMolds, apple, peaches, pears and grainsHCT-116(51)
ResveratrolGrapes, mulberries, peanuts and red wineHCT29 and COLO201(52)
SalinomycinSanguinaria Canadensis root and species containing poppy-fumaria alkaloidsHCT-116(53)
BigelovinInula helianthus-aquaticaHT-29 and HCT 116(54)
CasticinFructus Viticiscolo 205(55)
MorinLeaves of common guava, onion, almond and members of the Moraceae family, including mulberry, figs and Chinese herbsSW480(56)
SesamolSesame seedsHCT116(57)
Gallic acidOak, Drosera, golden root, stinging nettle, Chinese mahogany and dietary substances, including bearberry, blackberry, chocolate and walnutHCT15(58)
HispidinPhellinus linteusCMT-93 and HCT116(59)
ClausenidinClausenidin excavata Burm. f.HT-29(60)
ColchicineColchicum autumnale and Gloriosa superbaHT-29(61)
XylopineXylopia laevigataHCT116(62)

The induction of apoptosis and inhibition of tumor cell proliferation by cell cycle arrest are markers for the evaluation of phytochemical anticancer activities. Table II details a list of phytochemicals that can induce CRC cell cycle arrest at different phases of the cell cycle (45,48,51,54,55,57,59,60,6384). Phytochemicals are classified according to their chemical structure, for example, carotenoids, alkaloids and phenolic compounds such as flavonoids, phenolic acid, stilbenes (resveratrol), curcuminoids, tannins and cumarins (85). The following sections discuss the apoptotic mechanisms of different classes in detail.

Table II.

Cell cycle-arresting phytochemicals.

Table II.

Cell cycle-arresting phytochemicals.

CompoundOriginCell line(s) investigatedCell cycle phase(s)(Ref.)
ArtocarpinArtocarpus heterophyllusHT-29G1(63)
SilibininSilybum marianumLoVoG1 and G2/M(64)
PiperinePiper nigrum and Piper longumHRT-18 G0/G1(45)
PiperinePiper nigrum and Piper longumHT-29G1(65)
Vicenin-2Ocimum sanctum Linn and Moringa oleiferaHT-29 G2/M(66)
CurcuminCurcuma longaCOLO G0/G1(67)
CurcuminCurcuma longa320DMS(68)
CurcuminCurcuma longaHT-29 G2/M(48)
PatulinMolds, apple, peaches, pears and grainHCT116 G2/M(51)
ResveratrolGrapes, mulberries, peanuts and red wineHCT-116 and Caco2 G1/S(69)
BigelovinInula helianthus-aquaticaHT-29 and HCT 116 G2/M(54)
PlumbaginPlumbago zeylinicaHCT116G1(70)
Cucurbitacin-ICucurbitaceae speciesSW480 G2/M(71)
CrocinCrocus sativus L. (Saffron)HCT116 wild-type G0/G1(72)
CrocinCrocus sativus L. (Saffron)HCT116 p53(−/-) G2/M(72)
CrocetinCrocus sativus L. (Saffron)SW480S(73)
GinkgetinGinkgo biloba and DioonHCT116 G2/M(74)
CasticinFructus Viticiscolo 205 G2/M(55)
6-GingerolGingerSW480 G2/M(75)
QuercetinFruits, vegetables, nuts and red wineHT-29 G0/G1(76)
KaempferolFruits and vegetablesHT-29G1 and G2/M(77)
SesamolSesame seedsHCT116S(57)
HispidinPhellinus linteusCMT-93 and HCT116Sub G1(59)
HydroxytyrosolVirgin olive oilCaco2 and HT29G1(78)
HydroxyphenylpropionicVirgin olive oilCaco2 and HT29 G2/M(78)
PhenylaceticVirgin olive oil Caco2 G2/M(78)
CatecholVirgin olive oil Caco2S(78)
ClausenidinClausenidin excavata Burm. f.HT29 G0/G1(60)
XylopineXylopia laevigataHCT116 G2/M(62)
CapsaicinRed hot pepperHCT116 G0/G1(79)
CapsaicinRed hot pepperLoVo G0/G1(80)
BerberineBerberis and CoptisSW480 G0/G1(81)
BerberineBerberis and CoptisHCT-8S(82)
BerberineBerberis and CoptisLoVo G2/M(83)
HarminePeganum HarmalaSW620S and G2/M(84)

Carotenoids

Carotenoids are colored lipid soluble pigments present in plants, fungi, bacteria and algae, and also have been identified in numerous foods, including fruit, vegetables and fish. Carotenoids are responsible for providing bright coloration to plants and animal. There are >600 carotenoids with natural structural variations, which are divided into lycopenes, β-carotenes, luteins and zeaxanthins (86).

Carotenoids are the most characteristic and important components present in saffron (Crocus sativus L.) stigmas. In ancient times, the Arabs, Indians and Chinese used carotenoids for the treatment of various diseases, including cancer. Crocetin is the most potent carotenoid in saffron (86,87). Crocetin can induce different apoptotic mechanisms in colon cancer cells with varying p53 statuses. The presence of wild-type p53 in HCT 116 cells trans-activates Bax along with upregulation of p53-induced death domain protein, which cleaves and activates Bid via caspase-2 (88). However, in functional p53-impaired cells (HCT 116 p53-/-), augmentation of the p53-paralogue p73 was observed, which upregulates Fas to cleave Bid through the Fas-associated death domain (FADD)-caspase-8-pathway (88).

Phenolic compounds

6-Gingerol

Ginger contains numerous phenolic compounds, including 6-gingerol, 6-shagol, 6-paradol and zingerone (89). Among these compounds, 6-gingerol has been extensively investigated for its cytotoxic effects in various types of cancer, including colon cancer (83,84). 6-gingerol inhibits the proliferation of SW480 colon cancer cells by arresting them at the G2/M phase and induces apoptosis via activation of caspase-8, −9, −3 and −7 and PARP cleavage (75).

Flavonoids

Flavonoids are one of the largest groups of naturally-occurring phenols, including flavones, flavanols, isoflavones, flavonols, flavanones and flavanonols (90). Flavonoids are present in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. Along with carotenoids, they are responsible for the vivid colors in fruits and vegetables (91). Flavonoids are known for their anti-oxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties (91).

Casticin, a flavonoid derived from the natural plant Fructus Viticis, has been demonstrated to exert its apoptotic effect in colo 201 cells by arresting cells at the G2/M phase. Casticin increases ROS production, decreases the expression of matrix metalloproteinases, increases the release of cytochrome c from the mitochondria and triggers the activation of caspase-8, −9 and −3. Additionally, increases in tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), Fas, Fas ligand (FasL) and FADD have been observed following treatment with casticin (55). Furthermore, casticin upregulates the pro-apoptotic proteins Bax, BH3 interacting domain death agonist (Bid) and Bcl-2 antagonist/killer, and downregulates Bcl-2 and Bcl-xl, which induces apoptosis via the extrinsic and intrinsic apoptotic pathways (55).

Quercetin is a major dietary flavonoid that has been identified in a wide range of fruits, vegetables and beverages, including tea and wine. Quercetin is known for its antioxidant, anti-inflammatory and anti-proliferative properties (50). In HT-29 colon cancer cells quercetin treatment decreases cell viability, arrests the cell cycle at the G1 phase and induces apoptosis (76,92). Quercetin inhibits the PI3K-mediated cell survival signaling pathway via phosphorylation of its downstream target Akt (92). Additionally, quercetin decreases the expression of COP9 signalosome subunit 6 (CSN6), a subunit of the constitutive photomorphogenesis 9 multiprotein complex (76). Akt is a known regulator of CSN6, which promotes carcinogenesis by stabilizing the viral oncogene homolog Myc (76). Furthermore, quercetin-treatment targets CSN6 genes to induce apoptosis, as it downregulates Myc and Bcl-2 expression, and increases the expression of p53 and Bax (76,92). Quercetin has also been demonstrated to suppress the Wnt/β-catenin and NF-κB pathways in CRC cells (93,94). Additionally, treatment of HT-29 cells with quercetin upregulates AMP-activated protein kinase, a physiological cellular energy sensor, which markedly suppresses cell proliferation (92).

Luteolin (3,4,5,7-tetrahydroxyflavone) is a common flavonoid that exists in numerous types of plants including fruits, vegetables and medicinal herbs (95). Plants rich in luteolin have been used in Chinese traditional medicine for the treatment of various diseases, including hypertension, inflammatory disorders and cancer (95). Luteolin decreases the cell viability of HT-29 cells without affecting normal colon cells and it has been observed to induce apoptosis of HT-29 cells by activating the mitochondria-mediated caspase pathway (96). Treatment of HT-29 cells with luteolin results in a loss of the mitochondrial membrane potential, an increase in mitochondrial Ca2+ level, upregulation of Bax, downregulation of Bcl-2, release of cytochrome c from the mitochondria to the cytosol and an increase in the levels of the active forms of caspase-9 and caspase-3 (96).

Morin is a flavonoid primarily identified in the leaves of common guava, onion and almonds, and in members of the Moraceae family, including mulberry, figs and Chinese herbs. The pro-oxidative effect of morin in SW480 cells results in a disturbance of the mitochondrial function, which results in the activation of the intrinsic and the extrinsic apoptosis pathways (56). Additionally, morin induces a significant reduction in glucose transporter-1 expression, which results in a decline in cellular glucose uptake, resulting in an impaired mitochondrial function, which further sensitizes cells to undergo apoptosis via the intrinsic apoptosis pathway (56).

Scutellarin is a flavonoid isolated from a medicinal herb Scutellaria barbata D. Don. Scutellarin is widely used in Korea and South China to treat cardiovascular, neurological and inflammatory diseases (97). In colon cancer cells, scutellarin downregulates the anti-apoptotic protein Bcl-2 and induces apoptosis by activating p53, which upregulates Bax to activate caspase 3 via the mitochondrial pathway (97).

Myricetin is a flavonoid present in fruits, vegetables, tea, berries and medicinal plants (98). Myricetin has been reported to exhibit anticancer activity in the colon cancer HCT-115 cells via activation of nucleoside diphosphate kinase, which has been reported to induce apoptosis and inhibit metastasis in various types of cancer, such as hepatocellular carcinoma and pancreatic cancer (99,100). Additionally, myricetin activates caspase-3,- 8 and −9, and PARP, and downregulates the anti-apoptotic Bcl-2 protein to induce apoptosis in colon cancer cells (98).

Apigenin is a common flavonoid present in numerous plants, fruits and vegetables. The primary source of its consumption is chamomile tea, which is prepared from dried flowers of Matricaria chamomilla (101). Apigenin has been reported to exert anti-proliferative and anti-metastatic effects in a variety of CRC cell lines, such as those for lung cancer and osteosarcoma (102,103). Additionally, apigenin has been demonstarted to inhibit the Wnt/β-catenin signaling pathway (101,103) and suppress the phosphorylation of STAT3 (104), which in turn results in the downregulation of the anti-apoptotic proteins Bcl-xl and myeloid cell leukemia sequence-1 (Mcl-1), which stimulates the cleavage of PARP and the apoptosis of colon cancer cells (104). Furthermore, an in vivo study revealed that apigenin increases the apoptotic index of SW480 colon cancer cells via an upregulation of FADD (101).

Kaempferol is a flavonol present in fruits and vegetables, including apples, onions, and green and black tea (105). A high intake of kaempferol has been reported to reduce the risk of colon cancer (105). Kaempferol induces apoptosis of HT-29 colon cancer cells via activation of the extrinsic and intrinsic apoptosis pathways. Kaempferol initiates the extrinsic apoptosis pathway by increasing the level of FasL, which binds with the Fas receptor and activates caspase-8. Caspase-8 then cleaves Bid and interacts with the intrinsic apoptosis pathway via translocation of t-Bid to the mitochondria, as evident by the release of cytochrome c, activation of caspase-9, −7 and −3, and PARP cleavage (106). Additionally, kaempferol decreases the expression of the anti-apoptotic protein Bcl-xl and reduces Akt activity (106).

Curcuminoids

Curcumin, a derivative of turmeric (Curcuma longum), is a widely investigated phenolic compound that possesses potent anti-inflammatory, antioxidant and anticancer properties (107). It has previously been reported that curcumin induces apoptosis in human colon cancer HT29 cells via the calpain/caspase-12 apoptotic pathway (48). A previous study demonstrated that curcumin induces ROS generation in p53 mutated HT-29 cells, which results in cell cycle arrest and apoptosis via activation of the ROS-mediated mitochondrial pathway (47). Furthermore, curcumin induces caspase-3-mediated PARP cleavage in p53+/+ and p53−/− HCT116 cells, which indicates that the p53 status does not interfere with the ability of curcumin to induce apoptosis (47). In recent in vitro and in vivo studies, co-treatment of curcumin with TRAIL increased TRAIL-induced apoptosis via an upregulation of death receptor 4 and 5 (108). Additionally, in chemo-resistant CRC cells curcumin enhanced the potential of conventional chemotherapeutic drugs via inhibition of drug induced proliferative targets, including cyclin D1, NF-κB, PI3K and Src (109,110).

Sesamol

Sesamol is a phenolic compound present in sesame seeds that has been extensively investigated in different types of cancer, such as hepatocellular carcinoma and skin tumors (111,112). However, to the best of our knowledge, only a single study has been performed with CRC cells (57). Sesamol acts as an antioxidant at lower concentrations, while at higher concentrations it exhibits pro-oxidant effects, which decrease the viability of colon cancer HCT116 cells via interruption of the cell cycle at the S-phase and induces apoptosis via mitochondrial dysfunction (57).

Phenolic acid

Gallic acid is a type of phenolic acid that is present in dietary substances, including blackberries, chocolate, walnuts, raspberries, clove, vinegar, wine, green tea and herbs, including oak, drosera, golden root, stinging nettle and Chinese mahogany (58,113). Gallic acid is associated with oxidative stress and arrests HCT-15 cells at the sub G1 phase (58). Additionally, gallic acid has been reported to activate p53 upregulated modulator of apoptosis, which is a pro-apoptotic protein that potentiates the release of cytochrome c from the mitochondria via disruption of the mitochondrial membrane potential (MMP), which demonstrates the involvement of the intrinsic apoptosis pathway (114).

Hispidin

Hispidin is a phenolic compound isolated from Phellinus linteus, a medicinal mushroom that is cultivated in Korea, Japan and China, and is well known for its antioxidant activity (59). Hispidin induces apoptosis and ROS generation in colon cancer cells (59). Additionally, hispidin increases the p53 level and promotes the expression of its downstream protein Bax, while decreasing the expression of the anti-apoptotic protein Bcl-2, which contributes to the intrinsic apoptosis pathway. Furthermore, increased expression of death receptor 3 and cleavage of caspase-8, caspase-1 and PARP indicates the involvement of the extrinsic pathway in hispidin-induced apoptosis (59).

Hydroxytyrosol (HT)

HT is an important phenolic compound present in virgin olive oil (77). HT is transformed into several metabolites, including phenylacetic (PA), phenylpropionic acid (PP), hydroxyphenylpropionic (HPP), dihydroxyphenylpropionic (diHPP) acids and catechol, via phase II metabolism or by intestinal microbials (115117). HT, PA and HPP exhibit anti-proliferative and pro-apoptotic activities in colon cancer Caco2 and HT-29 cells. Whereas, PP and diHPP are only associated with apoptosis in HT-29 cells (78). HT-induced mitochondrial dysfunction and caspase-3 activation in CRC cells indicates an involvement of the intrinsic apoptosis pathway (78,118).

Resveratrol

Trans-resveratrol, a natural stilbene present in wine and grapes, has been extensively investigated for its anti-inflammatory and anticancer activities (119). It has been reported to inhibit cell proliferation signaling pathways in a number of studies (120123). In SW-620 and LoVo cells it has been reported to induce apoptosis via the mitochondria-dependent and -independent pathways via an upregulation of pro-apoptotic proteins and downregulation of anti-apoptotic proteins (121,122).

Resveratrol has also been investigated in combination with etoposide in CRC cell lines (120122). Synergistic effects have been observed on cell growth inhibition via downregulation of mitogen-activated protein kinase signaling pathways and an increase in apoptosis via activation of p53 (124126). Additionally, a combination of resveratrol and grape seed extract has been reported to suppress Wnt/β-catenin signaling and increase mitochondria-dependent apoptosis in in vitro and in vivo models (126).

Cumarins

Clausenidin is a natural pyranocoumarin obtained from Clausenidin excavate, which is a wild shrub of the Rutaceae family that is commonly used in Asian folk medicine. Clausenidin induces cell cycle arrest at the G0/G1 phase and apoptosis of HT29 cells, which is demonstrated by DNA fragmentation, MMP loss, increased expression of the pro-apoptotic protein Bax, cytochrome c release, Apaf-1 gene expression and capsase-9 and caspase-3 activities. ROS generation also serves a role in Clausenidin-induced apoptosis (60). In summary, these events indicate an activation of the mitochondria-mediated intrinsic apoptosis pathway following treatment with Clausenidin.

Alkaloids

Piperine

Piperine is an amide alkaloid extracted from the fruits of black and long pepper plants (Piper nigrum Linn. and Piper longum Linn.) (45). Piperine arrests the cell cycle and inhibits CRC cell proliferation independent of p53 status (45,65). Piperine induces apoptosis by inhibiting the cell survival PI3K/Akt signaling pathway and upregulating ER stress response proteins, including inositol-requiring enzyme-1α, CHOP and binding immunoglobulin protein, which results in MMP loss, cytochrome c release and PARP cleavage, which indicates a role of the intrinsic pathway in piperine-induced apoptosis (65).

Colchicine

Colchicine is an alkaloid isolated from Colchicum autumnale (meadow saffron) or Gloriosa superba (glory lily) (127). Colchicine is understood to halt cancer cell growth by its antimitotic activity (128). In colon cancer HT-29 cells, colchicine induces apoptosis via MMP loss, ROS production, caspase-3 activation, upregulation of pro-apoptotic Bax, downregulation of anti-apoptotic Bcl-2 and phosphorylation of p38, which indicates an involvement of p38-regulated intrinsic apoptosis pathway (61).

Xylopine

Xylopine is an aporphine alkaloid present in the stem of Xylopia laevigata (62); however, few studies have investigated this compound. Xylopine has been reported to arrest HCT116 cells at the G2/M phase and activate ROS-dependent intrinsic apoptosis independent of the p53 pathway (62).

Capsaicin

Capsaicin is a major pungent component in hot red pepper (79). Capsaicin induces apoptosis in colon cancer cells by arresting the cell cycle at the G0/G1 phase and is associated with an upregulation of the pro-apoptotic protein Bax in conjunction with PARP cleavage (79,80). Capsaicin alters important cell cycle proteins, including decreasing the expression of cyclin D1 (129) and increasing the expression of p21 (80). Both p21 and Bax are downstream targets of p53 (80). Capsaicin also increases the expression of p53 and decreased apoptosis is observed in p53-knockdown cells, which indicates a key role of p53 in capsaicin-induced apoptosis (80).

Berberine

Berberine is an alkaloid present in numerous medicinal plants, including Hydrastis canadensis, Berberis aristata, Coptis chinensi, C. rhizome, C. japonica, phellodendron amurense and P. chinense Schneid, and other plant species used in traditional medicine (130). Berberine is known for its anticancer properties in several types of cancer, such as prostate cancer, neuroblastoma and osteosarcoma (131133). In colon cancer cells, berberine induces apoptosis via caspase-dependent and -independent mechanisms (130,134,135). In SW480 cells it induces cell cycle arrest at the G0/G1 phase and increases the expression of p21 (130). Furthermore, berberine induces the mitochondria-mediated apoptosis pathway by activating apoptosis-associated proteins, including caspase-3 and caspase-9, induces the cleavage of PARP, upregulates the pro-apoptotic protein Bax and downregulates the anti-apoptotic protein Bcl-2 (135). Additionally, the activation of caspase-8 by berberine in SW480 cells functions as a non-apoptotic inhibitor of angiogenesis by decreasing the release of vascular endothelial cell growth factor (135). In HCT-8 cells, berberine arrests the cell cycle at the S phase, and induces apoptosis via activation of the extrinsic and intrinsic apoptosis pathways via an upregulation of Fas, FasL, TNFα, Bax and caspase-3, and a downregulation of Bcl-2 (83,136).

Harmine

Harmine is a β-carboline alkaloid isolated from the seeds of Peganum harmala (137). Harmine has traditionally been used in medicinal preparations in the Middle East, Central Asia and South America (137). Harmine inhibits SW680 cell proliferation by arresting the cell cycle at the S and G2/M phases, and inhibiting Akt and ERK-mediated cell survival pathways (84). Additionally, harmine activates the mitochondria-mediated intrinsic apoptosis pathway via downregulation of the anti-apoptotic proteins Bcl-2, Mcl-1 and Bcl-xl, and upregulation of Bax (84).

Evidence from clinical trials

As aforementioned, a number of phytochemical groups have been demonstrated to induce apoptosis of CRC cells via multiple pathways in in vitro studies. However, clinical studies have been only performed with a limited number of phytochemicals. A phase I pilot study with resveratrol reported that it downregulates Wnt target gene expression in the normal colonic mucosa of patients with CRC, while it upregulates Wnt target genes, including myc and cyclin D1, in colon cancer (138). The mechanism of this increase remains to be completely elucidated and requires further investigation. The resveratrol-induced downregulation of the Wnt-associated genes in normal colonoic mucosa may exert a protective effect as Wnt and its downstream effectors are known to regulate processes involved in tumor initiation, tumor growth and metastasis (139). Another study that investigated the efficacy of resveratrol in patients with colorectal adenocarcinoma demonstrated a 5% reduction in tumor cell proliferation, which indicates that daily oral doses of resveratrol at 0.5 or 1.0 g are sufficient to induce anti-carcinogenic effects (140). However, further clinical evaluation is required before it may be used as an alternative to non-steroidal anti-inflammatory agents and selective cyclooxygenase inhibitors in CRC chemoprevention (140).

Flavonols are understood to inhibit colorectal carcinogenesis via multiple mechanisms, including attenuation of inflammation (141144). Elevated blood levels of IL-6 have also been observed in colorectal adenoma (145). In a 4-year, randomized, multi-center, nutritional intervention trial study it was demonstrated that a high flavonol intake results in a reduction of serum IL-6 level, which decreases the risk of colorectal adenoma recurrence (146).

An open non-randomized clinical study was performed with curcumin at dose of 4 or 2 g in patients with ≥8 aberrant crypt foci (ACF) in a colonoscopic examination. Curcumin at a 4 g daily dose for 30 days reduced ACF by 40%, while a 2 g dose exhibited no effect (147). Another clinical study demonstrated that administration of curcumin increased the body weight of patients with CRC, reduced serum TNF-α levels, upregulated p53 and increased DNA fragmentation in CRC cells (148).

Conclusions and future directions

Despite significant progress in the diagnosis and treatment of cancer, the incidence of CRC is increasing worldwide and is expected to rise by 60% by 2030 (1). Mutations or alterations in cancer are a major challenge for effective management. Due to the high incidence of resistance and adverse effects-associated with chemotherapeutic drugs, there is an urgent requirement to develop more effective therapeutics (149). Phytochemicals are known sources of various compounds that are currently used as chemotherapeutic drugs (36,37). The current review summarized previously published studies regarding the effect of phytochemicals in CRC. To date, an extensive number of studies have been performed to identify molecular pathways involved in CRC and the effects of specific phytochemicals have been examined, primarily in preclinical trials. However, only a limited number have been performed in clinical settings. Therefore, for the majority of phytochemicals it is too early to conclude their anticancer properties. Further extensive research on phytochemicals is required to promote understanding and elucidate their molecular targets, drug interactions, ideal dosages, long-term safety and adverse effects.

Acknowledgements

Not applicable.

Funding

The present study was supported by JSPS KAKENHI (grant no. 17K09154).

Availability of data and materials

Not applicable.

Authors contributions

KA and SFZ contributed to the planning and design of the study; KA drafted the manuscript; KA, SFZ, ZC, DZ, SAS and HI performed the critical revisions of the manuscript and reviewed the intellectual content.

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.

References

1 

Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global patterns and trends in colorectal cancer incidence and mortality. Gut. 66:683–691. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI

3 

Zhang J, Wang TY and Niu XC: Increased plasma levels of pentraxin 3 are associated with poor prognosis of colorectal carcinoma patients. Tohoku J Exp Med. 240:39–46. 2016. View Article : Google Scholar : PubMed/NCBI

4 

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Terzić J, Grivennikov S, Karin E and Karin M: Inflammation and colon cancer. Gastroenterology. 138:2101–2114.e5. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Hafström L, Johansson H and Ahlberg J: Does diagnostic delay of colorectal cancer result in malpractice claims? A retrospective analysis of the Swedish board of malpractice from 1995–2008. Patient Saf Surg. 6:132012. View Article : Google Scholar : PubMed/NCBI

7 

Boland CR and Goel A: Microsatellite instability in colorectal cancer. Gastroenterology. 138:2073–2087.e3. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Lao VV and Grady WM: Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol. 8:686–700. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Pino MS and Chung DC: The chromosomal instability pathway in colon cancer. Gastroenterology. 138:2059–2072. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Naccarati A, Polakova V, Pardini B, Vodickova L, Hemminki K, Kumar R and Vodicka P: Mutations and polymorphisms in TP53 gene--an overview on the role in colorectal cancer. Mutagenesis. 27:211–218. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Xie Q, Wu MY, Zhang DX, Yang YM, Wang BS, Zhang J, Xu J, Zhong WD and Hu JN: Synergistic anticancer effect of exogenous wild-type p53 gene combined with 5-FU in human colon cancer resistant to 5-FU in vivo. World J Gastroenterol. 22:7342–7352. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Bykov VJN, Eriksson SE, Bianchi J and Wiman KG: Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer. 18:89–102. 2018. View Article : Google Scholar : PubMed/NCBI

13 

Testa U, Pelosi E and Castelli G: Colorectal cancer: Genetic abnormalities, tumor progression, tumor heterogeneity, clonal evolution and tumor-initiating cells. Med Sci (Basel). 6:1–113. 2018.

14 

Wang S, Liu Z, Wang L and Zhang X: NF-kappaB signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 6:327–334. 2009. View Article : Google Scholar : PubMed/NCBI

15 

Vivanco I and Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI

16 

PerŠe M: Oxidative Stress in the Pathogenesis of Colorectal Cancer: Cause or Consequence? BioMed Res Int. 7257102013.PubMed/NCBI

17 

Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, Squadrito F, Altavilla D and Bitto A: Oxidative Stress: Harms and Benefits for Human Health. Oxid Med Cell Longev. 2017:84167632017. View Article : Google Scholar : PubMed/NCBI

18 

Cano CE, Gommeaux J, Pietri S, Culcasi M, Garcia S, Seux M, Barelier S, Vasseur S, Spoto RP, Pébusque MJ, et al: Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function. Cancer Res. 69:219–226. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Flöter J, Kaymak I and Schulze A: Regulation of Metabolic Activity by p53. Metabolites. 7:1–18. 2017. View Article : Google Scholar

20 

Kalo E, Kogan-Sakin I, Solomon H, Bar-Nathan E, Shay M, Shetzer Y, Dekel E, Goldfinger N, Buganim Y, Stambolsky P, et al: Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species. J Cell Sci. 125:5578–5586. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Liu J, Zhang C and Feng Z: Tumor suppressor p53 and its gain-of-function mutants in cancer. Acta Biochim Biophys Sin (Shanghai). 46:170–179. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Ahmed K, Tabuchi Y and Kondo T: Hyperthermia: An effective strategy to induce apoptosis in cancer cells. Apoptosis. 20:1411–1419. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Cao K and Tait SWG: Apoptosis and Cancer: Force Awakens, Phantom Menace, or Both? Int Rev Cell Mol Biol. 337:135–152. 2018. View Article : Google Scholar : PubMed/NCBI

24 

El-Khattouti A, Selimovic D, Haikel Y and Hassan M: Crosstalk between apoptosis and autophagy: Molecular mechanisms and therapeutic strategies in cancer. J Cell Death. 6:37–55. 2013. View Article : Google Scholar : PubMed/NCBI

25 

Chaitanya GV, Steven AJ and Babu PP: PARP-1 cleavage fragments: Signatures of cell-death proteases in neurodegeneration. Cell Commun Signal. 8:312010. View Article : Google Scholar : PubMed/NCBI

26 

Shiraishi H, Okamoto H, Yoshimura A and Yoshida H: ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci. 119:3958–3966. 2006. View Article : Google Scholar : PubMed/NCBI

27 

Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M and Ron D: Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 6:1099–1108. 2000. View Article : Google Scholar : PubMed/NCBI

28 

McCullough KD, Martindale JL, Klotz LO, Aw TY and Holbrook NJ: Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 21:1249–1259. 2001. View Article : Google Scholar : PubMed/NCBI

29 

Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA and Yuan J: Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 403:98–103. 2000. View Article : Google Scholar : PubMed/NCBI

30 

Rao RV, Castro-Obregon S, Frankowski H, Schuler M, Stoka V, del Rio G, Bredesen DE and Ellerby HM: Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J Biol Chem. 277:21836–21842. 2002. View Article : Google Scholar : PubMed/NCBI

31 

Abraha AM and Ketema EB: Apoptotic pathways as a therapeutic target for colorectal cancer treatment. World J Gastrointest Onco. 8:583–591. 2016. View Article : Google Scholar

32 

Stoian M, State N, Stoica V and Radulian G: Apoptosis in colorectal cancer. J Med Life. 7:160–164. 2014.PubMed/NCBI

33 

Zhang B, Fang C, Deng D and Xia L: Research progress on common adverse events caused by targeted therapy for colorectal cancer. Oncol Lett. 16:27–33. 2018.(review). PubMed/NCBI

34 

Lee JH, Khor TO, Shu L, Su ZY, Fuentes F and Kong AN: Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. Pharmacol Ther. 137:153–171. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Zaidi SF, Ahmed K, Saeed SA, Khan U and Sugiyama T: Can diet modulate helicobacter pylori associated gastric pathogenesis? An evidence-based analysis. Nutr Cancer. 69:979–989. 2017. View Article : Google Scholar : PubMed/NCBI

36 

Newman DJ and Cragg GM: Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 75:311–335. 2012. View Article : Google Scholar : PubMed/NCBI

37 

Nobili S, Lippi D, Witort E, Donnini M, Bausi L, Mini E and Capaccioli S: Natural compounds for cancer treatment and prevention. Pharmacol Res. 59:365–378. 2009. View Article : Google Scholar : PubMed/NCBI

38 

Rejhová A, Opattová A, Čumová A, Slíva D and Vodička P: Natural compounds and combination therapy in colorectal cancer treatment. Eur J Med Chem. 144:582–594. 2018. View Article : Google Scholar : PubMed/NCBI

39 

González-Vallinas M, González-Castejón M, Rodríguez-Casado A and Ramírez de Molina A: Dietary phytochemicals in cancer prevention and therapy: A complementary approach with promising perspectives. Nutr Rev. 71:585–599. 2013. View Article : Google Scholar : PubMed/NCBI

40 

Lee KW, Bode AM and Dong Z: Molecular targets of phytochemicals for cancer prevention. Nat Rev Cancer. 11:211–218. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Fung TT, Hu FB, Wu K, Chiuve SE, Fuchs CS and Giovannucci E: The mediterranean and dietary approaches to stop hypertension (DASH) diets and colorectal cancer. Am J Clin Nutr. 92:1429–1435. 2010. View Article : Google Scholar : PubMed/NCBI

42 

Nomura AMY, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Pike MC and Kolonel LN: Association of vegetable, fruit, and grain intakes with colorectal cancer: The Multiethnic Cohort Study. Am J Clin Nutr. 88:730–737. 2008. View Article : Google Scholar : PubMed/NCBI

43 

van Duijnhoven FJ, Bueno-De-Mesquita HB, Ferrari P, Jenab M, Boshuizen HC, Ros MM, Casagrande C, Tjønneland A, Olsen A, Overvad K, et al: Fruit, vegetables, and colorectal cancer risk: The European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr. 89:1441–1452. 2009. View Article : Google Scholar : PubMed/NCBI

44 

Gunasekaran S, Venkatachalam K and Namasivayam N: p-Methoxycinnamic acid, an active phenylpropanoid induces mitochondrial mediated apoptosis in HCT-116 human colon adenocarcinoma cell line. Environ Toxicol Pharmacol. 40:966–974. 2015. View Article : Google Scholar : PubMed/NCBI

45 

Yaffe PB, Doucette CD, Walsh M and Hoskin DW: Piperine impairs cell cycle progression and causes reactive oxygen species-dependent apoptosis in rectal cancer cells. Exp Mol Pathol. 94:109–114. 2013. View Article : Google Scholar : PubMed/NCBI

46 

Banerjee K and Mandal M: Oxidative stress triggered by naturally occurring flavone apigenin results in senescence and chemotherapeutic effect in human colorectal cancer cells. Redox Biol. 5:153–162. 2015. View Article : Google Scholar : PubMed/NCBI

47 

Watson JL, Hill R, Yaffe PB, Greenshields A, Walsh M, Lee PW, Giacomantonio CA and Hoskin DW: Curcumin causes superoxide anion production and p53-independent apoptosis in human colon cancer cells. Cancer Lett. 297:1–8. 2010. View Article : Google Scholar : PubMed/NCBI

48 

Singh N, Shrivastav A and Sharma RK: Curcumin induces caspase and calpain-dependent apoptosis in HT29 human colon cancer cells. Mol Med Rep. 2:627–631. 2009.PubMed/NCBI

49 

Liu B, Yuan B, Zhang L, Mu W and Wang C: ROS/p38/p53/Puma signaling pathway is involved in emodin-induced apoptosis of human colorectal cancer cells. Int J Clin Exp Med. 8:15413–15422. 2015.PubMed/NCBI

50 

Raja SB, Rajendiran V, Kasinathan NK, P A, Venkatabalasubramanian S, Murali MR, Devaraj H and Devaraj SN: Differential cytotoxic activity of Quercetin on colonic cancer cells depends on ROS generation through COX-2 expression. Food Chem Toxicol 106 (Pt A). 92–106. 2017. View Article : Google Scholar

51 

Kwon O, Soung NK, Thimmegowda NR, Jeong SJ, Jang JH, Moon DO, Chung JK, Lee KS, Kwon YT, Erikson RL, et al: Patulin induces colorectal cancer cells apoptosis through EGR-1 dependent ATF3 up-regulation. Cell Signal. 24:943–950. 2012. View Article : Google Scholar : PubMed/NCBI

52 

Miki H, Uehara N, Kimura A, Sasaki T, Yuri T, Yoshizawa K and Tsubura A: Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells. Int J Oncol. 40:1020–1028. 2012. View Article : Google Scholar : PubMed/NCBI

53 

Han MH, Kim GY, Yoo YH and Choi YH: Sanguinarine induces apoptosis in human colorectal cancer HCT-116 cells through ROS-mediated Egr-1 activation and mitochondrial dysfunction. Toxicol Lett. 220:157–166. 2013. View Article : Google Scholar : PubMed/NCBI

54 

Li M, Song LH, Yue GG, Lee JKM, Zhao LM, Li L, Zhou X, Tsui SK, Ng SS, Fung KP, et al: Bigelovin triggered apoptosis in colorectal cancer in vitro and in vivo via upregulating death receptor 5 and reactive oxidative species. Sci Rep. 7:42176–42188. 2017. View Article : Google Scholar : PubMed/NCBI

55 

Shang HS, Liu JY, Lu HF, Chiang HS, Lin CH, Chen A, Lin YF, Chung JG, Ng SS, et al: Casticin induced apoptotic cell death and altered associated gene expression in human colon cancer colo 205 cells. Environ Toxicol. 32:2041–2052. 2017. View Article : Google Scholar : PubMed/NCBI

56 

Sithara T, Arun KB, Syama HP, Reshmitha TR and Nisha P: Morin inhibits proliferation of sw480 colorectal cancer cells by inducing apoptosis mediated by reactive oxygen species formation and uncoupling of Warburg effect. Front Pharmacol. 8:6402017. View Article : Google Scholar : PubMed/NCBI

57 

Khamphio M, Barusrux S and Weerapreeyakul N: Sesamol induces mitochondrial apoptosis pathway in HCT116 human colon cancer cells via pro-oxidant effect. Life Sci. 158:46–56. 2016. View Article : Google Scholar : PubMed/NCBI

58 

Subramanian AP, Jaganathan SK, Mandal M, Supriyanto E and Muhamad II: Gallic acid induced apoptotic events in HCT-15 colon cancer cells. World J Gastroenterol. 22:3952–3961. 2016. View Article : Google Scholar : PubMed/NCBI

59 

Lim JH, Lee YM, Park SR, Kim DH and Lim BO: Anticancer activity of hispidin via reactive oxygen species-mediated apoptosis in colon cancer cells. Anticancer Res. 34:4087–4093. 2014.PubMed/NCBI

60 

Waziri PM, Abdullah R, Yeap SK, Omar AR, Kassim NK, Malami I, How CW, Etti IC and Abu ML: Clausenidin induces caspase-dependent apoptosis in colon cancer. BMC Complement Altern Med. 16:2562016. View Article : Google Scholar : PubMed/NCBI

61 

Huang Z, Xu Y and Peng W: Colchicine induces apoptosis in HT-29 human colon cancer cells via the AKT and c-Jun N-terminal kinase signaling pathways. Mol Med Rep. 12:5939–5944. 2015. View Article : Google Scholar : PubMed/NCBI

62 

Santos LS, Silva VR, Menezes LRA, Soares MBP, Costa EV and Bezerra DP: Xylopine induces oxidative stress and causes G2/M phase arrest, triggering caspase-mediated apoptosis by p53-independent pathway in HCT116 cells. Oxid Med Cell Longev. 2017:71268722017. View Article : Google Scholar : PubMed/NCBI

63 

Sun G, Zheng Z, Lee MH, Xu Y, Kang S, Dong Z, Wang M, Gu Z, Li H and Chen W: Chemoprevention of Colorectal Cancer by Artocarpin, a Dietary Phytochemical from Artocarpus heterophyllus. J Agric Food Chem. 65:3474–3480. 2017. View Article : Google Scholar : PubMed/NCBI

64 

Kaur M, Velmurugan B, Tyagi A, Deep G, Katiyar S, Agarwal C and Agarwal R: Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft. Mol Cancer Ther. 8:2366–2374. 2009. View Article : Google Scholar : PubMed/NCBI

65 

Yaffe PB, Power Coombs MR, Doucette CD, Walsh M and Hoskin DW: Piperine, an alkaloid from black pepper, inhibits growth of human colon cancer cells via G1 arrest and apoptosis triggered by endoplasmic reticulum stress. Mol Carcinog. 54:1070–1085. 2015. View Article : Google Scholar : PubMed/NCBI

66 

Yang D, Zhang X, Zhang W and Rengarajan T: Vicenin-2 inhibits Wnt/β-catenin signaling and induces apoptosis in HT-29 human colon cancer cell line. Drug Des Devel Ther. 12:1303–1310. 2018. View Article : Google Scholar : PubMed/NCBI

67 

Dasiram JD, Ganesan R, Kannan J, Kotteeswaran V and Sivalingam N: Curcumin inhibits growth potential by G1 cell cycle arrest and induces apoptosis in p53-mutated COLO 320DM human colon adenocarcinoma cells. Biomed Pharmacother. 86:373–380. 2017. View Article : Google Scholar : PubMed/NCBI

68 

Agarwal A, Kasinathan A, Ganesan R, Balasubramanian A, Bhaskaran J, Suresh S, Srinivasan R, Aravind KB and Sivalingam N: Curcumin induces apoptosis and cell cycle arrest via the activation of reactive oxygen species-independent mitochondrial apoptotic pathway in Smad4 and p53 mutated colon adenocarcinoma HT29 cells. Nutr Res. 51:67–81. 2018. View Article : Google Scholar : PubMed/NCBI

69 

Liu B, Zhou Z, Zhou W, Liu J, Zhang Q, Xia J, Liu J, Chen N, Li M and Zhu R: Resveratrol inhibits proliferation in human colorectal carcinoma cells by inducing G1/S-phase cell cycle arrest and apoptosis through caspase/cyclin-CDK pathways. Mol Med Rep. 10:1697–1702. 2014. View Article : Google Scholar : PubMed/NCBI

70 

Eldhose B, Gunawan M, Rahman M, Latha MS and Notario V: Plumbagin reduces human colon cancer cell survival by inducing cell cycle arrest and mitochondria-mediated apoptosis. Int J Oncol. 45:1913–1920. 2014. View Article : Google Scholar : PubMed/NCBI

71 

Kim HJ, Park JH and Kim JK: Cucurbitacin-I, a natural cell-permeable triterpenoid isolated from Cucurbitaceae, exerts potent anticancer effect in colon cancer. Chem Biol Interact. 219:1–8. 2014. View Article : Google Scholar : PubMed/NCBI

72 

Amin A, Bajbouj K, Koch A, Gandesiri M and Schneider-Stock R: Defective autophagosome formation in p53-null colorectal cancer reinforces crocin-induced apoptosis. Int J Mol Sci. 16:1544–1561. 2015. View Article : Google Scholar : PubMed/NCBI

73 

Li CY, Huang WF, Wang QL, Wang F, Cai E, Hu B, Du JC, Wang J, Chen R, Cai XJ, et al: Crocetin induces cytotoxicity in colon cancer cells via p53-independent mechanisms. Asian Pac J Cancer Prev. 13:3757–3761. 2012. View Article : Google Scholar : PubMed/NCBI

74 

74. Lee YJ, Kang YR, Lee SY, Jin Y, Han DC and Kwon BM: Ginkgetin induces G2-phase arrest in HCT116 colon cancer cells through the modulation of b-Myb and miRNA34a expression. Int J Oncol. 51:1331–1342. 2017. View Article : Google Scholar : PubMed/NCBI

75 

Radhakrishnan EK, Bava SV, Narayanan SS, Nath LR, Thulasidasan AKT, Soniya EV and Anto RJ: [6]-Gingerol induces caspase-dependent apoptosis and prevents PMA-induced proliferation in colon cancer cells by inhibiting MAPK/AP-1 signaling. PLoS One. 9:e1044012014. View Article : Google Scholar : PubMed/NCBI

76 

Yang L, Liu Y, Wang M, Qian Y, Dong X, Gu H, Wang H, Guo S and Hisamitsu T: Quercetin-induced apoptosis of HT-29 colon cancer cells via inhibition of the Akt-CSN6-Myc signaling axis. Mol Med Rep. 14:4559–4566. 2016. View Article : Google Scholar : PubMed/NCBI

77 

Cho HJ and Park JHY: Kaempferol induces cell cycle arrest in HT-29 human colon cancer cells. J Cancer Prev. 18:257–263. 2013. View Article : Google Scholar : PubMed/NCBI

78 

López de Las Hazas MC, Piñol C, Macià A and Motilva MJ: Hydroxytyrosol and the colonic metabolites derived from virgin olive oil intake induce cell cycle arrest and apoptosis in colon cancer cells. J Agric Food Chem. 65:6467–6476. 2017. View Article : Google Scholar : PubMed/NCBI

79 

Lee SH and Clark R: Anti-Tumorigenic Effects of Capsaicin in Colon Cancer. J Food Chem Nanotechnol. 2:162–167. 2016. View Article : Google Scholar

80 

Jin J, Lin G, Huang H, Xu D, Yu H, Ma X, Zhu L, Ma D and Jiang H: Capsaicin mediates cell cycle arrest and apoptosis in human colon cancer cells via stabilizing and activating p53. Int J Biol Sci. 10:285–295. 2014. View Article : Google Scholar : PubMed/NCBI

81 

Chidambara Murthy KN, Jayaprakasha GK and Patil BS: The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells. Eur J Pharmacol. 688:14–21. 2012. View Article : Google Scholar : PubMed/NCBI

82 

Xu LN, Lu BN, Hu MM, Xu YW, Han X, Qi Y and Peng JY: Mechanisms involved in the cytotoxic effects of berberine on human colon cancer HCT-8 cells. Biocell. 36:113–120. 2012.PubMed/NCBI

83 

Cai Y, Xia Q, Luo R, Huang P, Sun Y, Shi Y and Jiang W: Berberine inhibits the growth of human colorectal adenocarcinoma in vitro and in vivo. J Nat Med. 68:53–62. 2014. View Article : Google Scholar : PubMed/NCBI

84 

Liu J, Li Q, Liu Z, Lin L, Zhang X, Cao M and Jiang J: Harmine induces cell cycle arrest and mitochondrial pathway-mediated cellular apoptosis in SW620 cells via inhibition of the Akt and ERK signaling pathways. Oncol Rep. 35:3363–3370. 2016. View Article : Google Scholar : PubMed/NCBI

85 

Tailor D and Singh RP: Dietary and non-dietary phytochemicals in cancer control. Nutrition, Diet and Cancer. Shankar S and Shrivastava RK: Springer. (New York). 585–622. 2012. View Article : Google Scholar

86 

Milani A, Basirnejad M, Shahbazi S and Bolhassani A: Carotenoids: Biochemistry, pharmacology and treatment. Br J Pharmacol. 174:1290–1324. 2017. View Article : Google Scholar : PubMed/NCBI

87 

Gutheil WG, Reed G, Ray A, Anant S and Dhar A: Crocetin: An agent derived from saffron for prevention and therapy for cancer. Curr Pharm Biotechnol. 13:173–179. 2012. View Article : Google Scholar : PubMed/NCBI

88 

Ray P, Guha D, Chakraborty J, Banerjee S, Adhikary A, Chakraborty S, Das T and Sa G: Crocetin exploits p53-induced death domain (PIDD) and FAS-associated death domain (FADD) proteins to induce apoptosis in colorectal cancer. Sci Rep. 6:32979–32989. 2016. View Article : Google Scholar : PubMed/NCBI

89 

Chakraborty D, Bishayee K, Ghosh S, Biswas R, Mandal SK and Khuda-Bukhsh AR: [6]-Gingerol induces caspase 3 dependent apoptosis and autophagy in cancer cells: drug-DNA interaction and expression of certain signal genes in HeLa cells. Eur J Pharmacol. 694:20–29. 2012. View Article : Google Scholar : PubMed/NCBI

90 

Ju SA, Park SM, Lee YS, Bae JH, Yu R, An WG, Suh JH and Kim BS: Administration of 6-gingerol greatly enhances the number of tumor-infiltrating lymphocytes in murine tumors. Int J Cancer. 130:2618–2628. 2012. View Article : Google Scholar : PubMed/NCBI

91 

Panche AN, Diwan AD and Chandra SR: Flavonoids: An overview. J Nutr Sci. 5:e472016. View Article : Google Scholar : PubMed/NCBI

92 

Kim HJ, Kim SK, Kim BS, Lee SH, Park YS, Park BK, Kim SJ, Kim J, Choi C, Kim JS, et al: Apoptotic effect of quercetin on HT-29 colon cancer cells via the AMPK signaling pathway. J Agric Food Chem. 58:8643–8650. 2010. View Article : Google Scholar : PubMed/NCBI

93 

Refolo MG, DAlessandro R, Malerba N, Laezza C, Bifulco M, Messa C, Caruso MG, Notarnicola M and Tutino V: Anti-proliferative and pro apoptotic effects of flavonoid quercetin are mediated by CB1 receptor in human colon cancer cell lines. J Cell Physiol. 230:2973–2980. 2015. View Article : Google Scholar : PubMed/NCBI

94 

Zhang XA, Zhang S, Yin Q and Zhang J: Quercetin induces human colon cancer cells apoptosis by inhibiting the nuclear factor-kappa B Pathway. Pharmacogn Mag. 11:404–409. 2015. View Article : Google Scholar : PubMed/NCBI

95 

Liu Y, Lang T, Jin B, Chen F, Zhang Y, Beuerman RW, Zhou L and Zhang Z: Luteolin inhibits colorectal cancer cell epithelial-to-mesenchymal transition by suppressing CREB1 expression revealed by comparative proteomics study. J Proteomics. 161:1–10. 2017. View Article : Google Scholar : PubMed/NCBI

96 

Kang KA, Piao MJ, Ryu YS, Hyun YJ, Park JE, Shilnikova K, Zhen AX, Kang HK, Koh YS, Jeong YJ, et al: Luteolin induces apoptotic cell death via antioxidant activity in human colon cancer cells. Int J Oncol. 51:1169–1178. 2017. View Article : Google Scholar : PubMed/NCBI

97 

Yang N, Zhao Y, Wang Z, Liu Y and Zhang Y: Scutellarin suppresses growth and causes apoptosis of human colorectal cancer cells by regulating the p53 pathway. Mol Med Rep. 15:929–935. 2017. View Article : Google Scholar : PubMed/NCBI

98 

Lee JH, Choi YJ, Park SH and Nam MJ: Potential role of nucleoside diphosphate kinase in myricetin-induced selective apoptosis in colon cancer HCT-15 cells. Food Chem Toxicol 116 (Pt B). 315–322. 2018. View Article : Google Scholar

99 

Seydi E, Rasekh HR, Salimi A, Mohsenifar Z and Pourahmad J: Myricetin selectively induces apoptosis on cancerous hepatocytes by directly targeting their mitochondria. Basic Clin Pharmacol Toxicol. 119:249–258. 2016. View Article : Google Scholar : PubMed/NCBI

100 

Phillips PA, Sangwan V, Borja-Cacho D, Dudeja V, Vickers SM and Saluja AK: Myricetin induces pancreatic cancer cell death via the induction of apoptosis and inhibition of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Cancer Lett. 308:181–188. 2011. View Article : Google Scholar : PubMed/NCBI

101 

Xu M, Wang S, Song YU, Yao J, Huang K and Zhu X: Apigenin suppresses colorectal cancer cell proliferation, migration and invasion via inhibition of the Wnt/β-catenin signaling pathway. Oncol Lett. 11:3075–3080. 2016. View Article : Google Scholar : PubMed/NCBI

102 

Zhou Z, Tang M, Liu Y, Zhang Z, Lu R and Lu J: Apigenin inhibits cell proliferation, migration, and invasion by targeting Akt in the A549 human lung cancer cell line. Anticancer Drugs. 28:446–456. 2017. View Article : Google Scholar : PubMed/NCBI

103 

Liu X, Li L, Lv L, Chen D, Shen L and Xie Z: Apigenin inhibits the proliferation and invasion of osteosarcoma cells by suppressing the Wnt/β-catenin signaling pathway. Oncol Rep. 34:1035–1041. 2015. View Article : Google Scholar : PubMed/NCBI

104 

Maeda Y, Takahashi H, Nakai N, Yanagita T, Ando N, Okubo T, Saito K, Shiga K, Hirokawa T, Hara M, et al: Apigenin induces apoptosis by suppressing Bcl-xl and Mcl-1 simultaneously via signal transducer and activator of transcription 3 signaling in colon cancer. Int J Oncol. 52:1661–1673. 2018.

105 

Bobe G, Sansbury LB, Albert PS, Cross AJ, Kahle L, Ashby J, Slattery ML, Caan B, Paskett E, Iber F, et al: Dietary flavonoids and colorectal adenoma recurrence in the Polyp Prevention Trial. Cancer Epidemiol Biomarkers Prev. 17:1344–1353. 2008. View Article : Google Scholar : PubMed/NCBI

106 

Lee HS, Cho HJ, Yu R, Lee KW, Chun HS and Park JHY: Mechanisms underlying apoptosis-inducing effects of Kaempferol in HT-29 human colon cancer cells. Int J Mol Sci. 15:2722–2737. 2014. View Article : Google Scholar : PubMed/NCBI

107 

Tong W, Wang Q, Sun D and Suo J: Curcumin suppresses colon cancer cell invasion via AMPK-induced inhibition of NF-κB, uPA activator and MMP9. Oncol Lett. 12:4139–4146. 2016. View Article : Google Scholar : PubMed/NCBI

108 

Yang X, Li Z, Wu Q, Chen S, Yi C and Gong C: TRAIL and curcumin codelivery nanoparticles enhance TRAIL-induced apoptosis through upregulation of death receptors. Drug Deliv. 24:1526–1536. 2017. View Article : Google Scholar : PubMed/NCBI

109 

Shakibaei M, Kraehe P, Popper B, Shayan P, Goel A and Buhrmann C: Curcumin potentiates antitumor activity of 5-fluorouracil in a 3D alginate tumor microenvironment of colorectal cancer. BMC Cancer. 15:2502015. View Article : Google Scholar : PubMed/NCBI

110 

Shakibaei M, Mobasheri A, Lueders C, Busch F, Shayan P and Goel A: Curcumin enhances the effect of chemotherapy against colorectal cancer cells by inhibition of NF-κB and Src protein kinase signaling pathways. PLoS One. 8:e572182013. View Article : Google Scholar : PubMed/NCBI

111 

Liu Z, Ren B, Wang Y, Zou C, Qiao Q, Diao Z, Mi Y, Zhu D and Liu X: Sesamol induces human hepatocellular carcinoma cells apoptosis by impairing mitochondrial function and suppressing autophagy. Sci Rep. 7:457282017. View Article : Google Scholar : PubMed/NCBI

112 

Bhardwaj R, Sanyal SN, Vaiphei K, Kakkar V, Deol PK, Kaur IP and Kaur T: Sesamol induces apoptosis by altering expression of bcl-2 and bax proteins and modifies skin tumor development in Balb/c mice. Anticancer Agents Med Chem. 17:726–733. 2017. View Article : Google Scholar : PubMed/NCBI

113 

Daglia M, Di Lorenzo A, Nabavi SF, Talas ZS and Nabavi SM: Polyphenols: well beyond the antioxidant capacity: gallic acid and related compounds as neuroprotective agents: you are what you eat! Curr Pharm Biotechnol. 15:362–372. 2014. View Article : Google Scholar : PubMed/NCBI

114 

Yang C, Xie X, Tang H, Dong X, Zhang X and Huang F: Transcriptome analysis reveals GA induced apoptosis in HCT116 human colon cancer cells through calcium and p53 signal pathways. RSC Advances. 8:12449–12458. 2018. View Article : Google Scholar

115 

Rubió L, Macià A, Valls RM, Pedret A, Romero MP, Solà R and Motilva MJ: A new hydroxytyrosol metabolite identified in human plasma: Hydroxytyrosol acetate sulphate. Food Chem. 134:1132–1136. 2012. View Article : Google Scholar : PubMed/NCBI

116 

de Las Hazas MCL, Motilva MJ, Piñol C and Macià A: Application of dried blood spot cards to determine olive oil phenols (hydroxytyrosol metabolites) in human blood. Talanta. 159:189–193. 2016. View Article : Google Scholar : PubMed/NCBI

117 

Mosele JI, Martín-Peláez S, Macià A, Farràs M, Valls RM, Catalán Ú and Motilva MJ: Faecal microbial metabolism of olive oil phenolic compounds: In vitro and in vivo approaches. Mol Nutr Food Res. 58:1809–1819. 2014. View Article : Google Scholar : PubMed/NCBI

118 

Sun L, Luo C and Liu J: Hydroxytyrosol induces apoptosis in human colon cancer cells through ROS generation. Food Funct. 5:1909–1914. 2014. View Article : Google Scholar : PubMed/NCBI

119 

Bertelli AA, Ferrara F, Diana G, Fulgenzi A, Corsi M, Ponti W, Ferrero ME and Bertelli A: Resveratrol, a natural stilbene in grapes and wine, enhances intraphagocytosis in human promonocytes: A co-factor in antiinflammatory and anticancer chemopreventive activity. Int J Tissue React. 21:93–104. 1999.PubMed/NCBI

120 

Buhrmann C, Shayan P, Popper B, Goel A and Shakibaei M: Sirt1 is required for resveratrolmediated chemopreventive effects in colorectal cancer cells. Nutrients. 8:1452016. View Article : Google Scholar : PubMed/NCBI

121 

Chen H, Jin ZL and Xu H: MEK/ERK signaling pathway in apoptosis of SW620 cell line and inhibition effect of resveratrol. Asian Pac J Trop Med. 9:49–53. 2016. View Article : Google Scholar : PubMed/NCBI

122 

Yuan SX, Wang DX, Wu QX, Ren CM, Li Y, Chen QZ, Zeng YH, Shao Y, Yang JQ, Bai Y, et al: BMP9/p38 MAPK is essential for the antiproliferative effect of resveratrol on human colon cancer. Oncol Rep. 35:939–947. 2016. View Article : Google Scholar : PubMed/NCBI

123 

Saud SM, Li W, Morris NL, Matter MS, Colburn NH, Kim YS and Young MR: Resveratrol prevents tumorigenesis in mouse model of Kras activated sporadic colorectal cancer by suppressing oncogenic Kras expression. Carcinogenesis. 35:2778–2786. 2014. View Article : Google Scholar : PubMed/NCBI

124 

De Maria S, Scognamiglio I, Lombardi A, Amodio N, Caraglia M, Cartenì M, Ravagnan G and Stiuso P: Polydatin, a natural precursor of resveratrol, induces cell cycle arrest and differentiation of human colorectal Caco-2 cell. J Transl Med. 11:2642013. View Article : Google Scholar : PubMed/NCBI

125 

Kumazaki M, Noguchi S, Yasui Y, Iwasaki J, Shinohara H, Yamada N and Akao Y: Anti-cancer effects of naturally occurring compounds through modulation of signal transduction and miRNA expression in human colon cancer cells. J Nutr Biochem. 24:1849–1858. 2013. View Article : Google Scholar : PubMed/NCBI

126 

Reddivari L, Charepalli V, Radhakrishnan S, Vadde R, Elias RJ, Lambert JD and Vanamala JKP: Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis. BMC Complement Altern Med. 16:2782016. View Article : Google Scholar : PubMed/NCBI

127 

Sivakumar G: Colchicine semisynthetics: Chemotherapeutics for cancer? Curr Med Chem. 20:892–898. 2013. View Article : Google Scholar : PubMed/NCBI

128 

Risinger AL, Giles FJ and Mooberry SL: Microtubule dynamics as a target in oncology. Cancer Treat Rev. 35:255–261. 2009. View Article : Google Scholar : PubMed/NCBI

129 

Lee SH, Richardson RL, Dashwood RH and Baek SJ: Capsaicin represses transcriptional activity of β-catenin in human colorectal cancer cells. J Nutr Biochem. 23:646–655. 2012. View Article : Google Scholar : PubMed/NCBI

130 

Guamán Ortiz LM, Tillhon M, Parks M, Dutto I, Prosperi E, Savio M, Arcamone AG, Buzzetti F, Lombardi P and Scovassi AI: Multiple effects of berberine derivatives on colon cancer cells. BioMed Res Int. 2014:9245852014. View Article : Google Scholar : PubMed/NCBI

131 

Wang Y, Liu Q, Liu Z, Li B, Sun Z, Zhou H, Zhang X, Gong Y and Shao C: Berberine, a genotoxic alkaloid, induces ATM-Chk1 mediated G2 arrest in prostate cancer cells. Mutat Res. 734:20–29. 2012. View Article : Google Scholar : PubMed/NCBI

132 

Li J, Gu L, Zhang H, Liu T, Tian D, Zhou M and Zhou S: Berberine represses DAXX gene transcription and induces cancer cell apoptosis. Lab Invest. 93:354–364. 2013. View Article : Google Scholar : PubMed/NCBI

133 

Yan K, Zhang C, Feng J, Hou L, Yan L, Zhou Z, Liu Z, Liu C, Fan Y, Zheng B, et al: Induction of G1 cell cycle arrest and apoptosis by berberine in bladder cancer cells. Eur J Pharmacol. 661:1–7. 2011. View Article : Google Scholar : PubMed/NCBI

134 

Tillhon M, Guamán Ortiz LM, Lombardi P and Scovassi AI: Berberine: New perspectives for old remedies. Biochem Pharmacol. 84:1260–1267. 2012. View Article : Google Scholar : PubMed/NCBI

135 

Wang L, Liu L, Shi Y, Cao H, Chaturvedi R, Calcutt MW, Hu T, Ren X, Wilson KT, Polk DB, et al: Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor. PLoS One. 7:e364182012. View Article : Google Scholar : PubMed/NCBI

136 

Xu LN, Lu BN, Hu MM, Xu YW, Han X, Qi Y and Peng JY: Mechanisms involved in the cytotoxic effects of berberine on human colon cancer HCT-8 cells. Biocell. 36:113–20. 2012.PubMed/NCBI

137 

Patel K, Gadewar M, Tripathi R, Prasad SK and Patel DK: A review on medicinal importance, pharmacological activity and bioanalytical aspects of beta-carboline alkaloid ‘Harmine’. Asian Pac J Trop Biomed. 2:660–664. 2012. View Article : Google Scholar : PubMed/NCBI

138 

Nguyen AV, Martinez M, Stamos MJ, Moyer MP, Planutis K, Hope C and Holcombe RF: Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Manag Res. 1:25–37. 2009. View Article : Google Scholar : PubMed/NCBI

139 

Anastas JN and Moon RT: WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 13:11–26. 2013. View Article : Google Scholar : PubMed/NCBI

140 

Patel KR, Brown VA, Jones DJ, Britton RG, Hemingway D, Miller AS, West KP, Booth TD, Perloff M, Crowell JA, et al: Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 70:7392–7399. 2010. View Article : Google Scholar : PubMed/NCBI

141 

Ferguson LR and Philpott M: Cancer prevention by dietary bioactive components that target the immune response. Curr Cancer Drug Targets. 7:459–464. 2007. View Article : Google Scholar : PubMed/NCBI

142 

Camuesco D, Comalada M, Rodríguez-Cabezas ME, Nieto A, Lorente MD, Concha A, Zarzuelo A and Gálvez J: The intestinal anti-inflammatory effect of quercitrin is associated with an inhibition in iNOS expression. Br J Pharmacol. 143:908–918. 2004. View Article : Google Scholar : PubMed/NCBI

143 

Kwon KH, Murakami A, Tanaka T and Ohigashi H: Dietary rutin, but not its aglycone quercetin, ameliorates dextran sulfate sodium-induced experimental colitis in mice: Attenuation of pro-inflammatory gene expression. Biochem Pharmacol. 69:395–406. 2005. View Article : Google Scholar : PubMed/NCBI

144 

Camuesco D, Comalada M, Concha A, Nieto A, Sierra S, Xaus J, Zarzuelo A and Gálvez J: Intestinal anti-inflammatory activity of combined quercitrin and dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated fatty acids, in rats with DSS-induced colitis. Clin Nutr. 25:466–476. 2006. View Article : Google Scholar : PubMed/NCBI

145 

Kim S, Keku TO, Martin C, Galanko J, Woosley JT, Schroeder JC, Satia JA, Halabi S and Sandler RS: Circulating levels of inflammatory cytokines and risk of colorectal adenomas. Cancer Res. 68:323–328. 2008. View Article : Google Scholar : PubMed/NCBI

146 

Bobe G, Albert PS, Sansbury LB, Lanza E, Schatzkin A, Colburn NH and Cross AJ: Interleukin-6 as a potential indicator for prevention of high-risk adenoma recurrence by dietary flavonols in the polyp prevention trial. Cancer Prev Res (Phila). 3:764–775. 2010. View Article : Google Scholar : PubMed/NCBI

147 

Carroll RE, Benya RV, Turgeon DK, Vareed S, Neuman M, Rodriguez L, Kakarala M, Carpenter PM, McLaren C, Meyskens FL Jr, et al: Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila). 4:354–364. 2011. View Article : Google Scholar : PubMed/NCBI

148 

He ZY, Shi CB, Wen H, Li FL, Wang BL and Wang J: Upregulation of p53 expression in patients with colorectal cancer by administration of curcumin. Cancer Invest. 29:208–213. 2011. View Article : Google Scholar : PubMed/NCBI

149 

Chakraborty S and Rahman T: The difficulties in cancer treatment. Ecancermedicalscience. 6:ed162012.PubMed/NCBI

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July-2019
Volume 18 Issue 1

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Copy and paste a formatted citation
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Spandidos Publications style
Ahmed K, Zaidi SF, Cui ZG, Zhou D, Saeed SA and Inadera H: Potential proapoptotic phytochemical agents for the treatment and prevention of colorectal cancer (Review). Oncol Lett 18: 487-498, 2019.
APA
Ahmed, K., Zaidi, S.F., Cui, Z., Zhou, D., Saeed, S.A., & Inadera, H. (2019). Potential proapoptotic phytochemical agents for the treatment and prevention of colorectal cancer (Review). Oncology Letters, 18, 487-498. https://doi.org/10.3892/ol.2019.10349
MLA
Ahmed, K., Zaidi, S. F., Cui, Z., Zhou, D., Saeed, S. A., Inadera, H."Potential proapoptotic phytochemical agents for the treatment and prevention of colorectal cancer (Review)". Oncology Letters 18.1 (2019): 487-498.
Chicago
Ahmed, K., Zaidi, S. F., Cui, Z., Zhou, D., Saeed, S. A., Inadera, H."Potential proapoptotic phytochemical agents for the treatment and prevention of colorectal cancer (Review)". Oncology Letters 18, no. 1 (2019): 487-498. https://doi.org/10.3892/ol.2019.10349