Vegetal-Derived Bioactive Compounds in Colorectal Cancer: Comparison
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Colorectal cancer is one of the leading causes of morbidity and mortality today. Knowledge of its pathogenesis has made it possible to advance the development of different therapeutic strategies. However, the appearance of drug resistance constitutes one of the main causes of treatment failure. Bioactive compounds of vegetable origin are being studied as a new strategy to improve antitumor treatment, due to their ability to regulate the pathways involved in the development of carcinogenesis or processes that are decisive in its evolution, including multidrug resistance. In vitro and in vivo studies of these substances in combination with cytotoxic drugs have shown that they reduce resistance and increase therapeutic efficacy. The objective of this review is to summarize the knowledge that is described in the scientific literature on the antitumor and chemo-sensitizing capacity of vegetable-derived biomolecules such as polyphenols, flavonoids, and terpenes. These compounds may hold a promising future in improving the treatment of colorectal cancer. 

  • vegetal compounds
  • colorectal cancer
  • cancer
  • vegetal extracts
  • cancer treatment
  • systematic review

 

21. Colorectal Cancer: Resistant Mechanisms

Despite the discovery of new drugs against colorectal cancer (CRC), the emergence of resistance to these agents is inevitable. Drug resistance can be innate (dysregulations of tumor cells before treatment) or acquired (resistance after treatment cycles) [25,26][1][2]. Drug efflux mediated by transmembrane transporters, specifically those of the ATP binding cassette superfamily (ABC), is one of most relevant mechanisms in CRC. These proteins are capable of expelling toxic substances from the inside of cells including different anticancer agents [27][3]. Specifically, p-GP, encoded by the ABCB1 gene, was overexpressed in different CRC cell lines, conferring resistance to treatment. In addition, resistant CRC cells overexpressed CD133, a protein that regulates p-GP expression through the AKT/NF-κB/MDR1 axis [28,29][4][5]. Other members of the ABC family, such as MRP1 and BCRP, are also overexpressed in some CRC cell lines, leading to multiple resistance to chemotherapeutic drugs as 5-FU, doxorubicin, irinotecan, vincristine, among others [30[6][7],31], while MRP2-mediated resistance to oxaliplatin and vincristine in CRC, being Nrf2, signaling is critical for its expression (Figure 1) [32][8]. Drug resistance in CRC can also arise when there are alterations in antitumor drug targets, such as mutations or changes in expression due to epigenetic variations [33][9]. Finally, an increase in the expression of repair protein-DNA, such as MGMT, was detected in some 5-FU-resistant CRC lines [34][10].
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Figure 1. Representative image of modulation of the MDR mechanism of resistance by natural bioactive compounds. (A) Main membrane transporters that are involved in chemoresistance by expelling them into the extracellular medium. (B) Action of natural bioactive compounds in the regulation of MDR by (1) MRP-2 downregulation through the inhibition of the Nrf2/MRP2 pathway, (2) P-glycoprotein and MRP-1 blocking by natural bioactive compounds, and (3) inhibition of glutamine cell intake producing an MRP-1 disfunction.
Apoptosis evasion promotes carcinogenesis and tumor progression, leading to the appearance of pharmacological resistance, especially to drugs that induce this pathway such as doxorubicin and cisplatin. Several apoptosis-resistant tumors were associated with the increased or decreased expression of antiapoptotic (BCL-2, MCL-1, and BCL-XL) and proapoptotic (p53, BAX, and BIM) genes, respectively [35][11]. In addition, modulation of DNA methylation, histones and chromatin remodeling can alter the expression of genes that are involved in the metabolism and activity of chemotherapeutic drugs, inducing resistance [33][9]. Moreover, tumor heterogeneity also plays a role in this phenomenon, as it makes treatment more difficult because of the presence of cancer stem cells which are more resistant to drugs. These cells have a self-healing and differentiation capacity and are associated with greater tumorigenicity. These cells are also capable of acquiring mesenchymal characteristics, which is related to the cell migration process and metastasis and a worse prognosis in patients [36,37][12][13]. On the other hand, it is known that the most resistant cells within the tumor sinus can transfer small miRNAs to their environment, inducing resistance in neighboring cells [38][14]. Finally, another important factor to highlight is the tumor microenvironment, including the extracellular matrix, blood vessels, fibroblast, and immune system cells. This microenvironment will be an additional layer of protection against drugs, making the entry of chemotherapeutics into the tumor sinus more limited [39][15].

2. Antitumor Potential of Natural Products for Colorectal Cancer 

Chemotherapeutic treatment of colon cancer has been compromised mainly by the appearance of resistance, which reduces therapeutic efficacy and leads to a lower cure rate and worse prognosis. These can be produced by the existence of previous mutations in genes that are involved in resistance, by the activation of cellular pathways that are involved in cellular detoxification, and the existence of transmembrane transporters that expel the drugs to the exterior (such as p-glycoprotein) [128][16]. In addition to this protein, other members of the transmembrane protein family such as MRP1 and BCRP are also overexpressed in CRC, and a relationship has been observed between their expression and resistance phenomena against drugs that are frequently used in this type of tumor, such as 5-FU and doxorubicin [30,31][6][7]. It has long been shown that plant compounds can be used as a therapy for different types of cancer. Thus, a plant-derived compound such as taxol has been used for years as a chemotherapeutic agent and is currently used as a therapy in non-small cell lung cancer (NSCLC), breast, pancreatic, and cervical cancer [129][17]. These types of compounds can exert their actions at the molecular level through processes such as the regulation of oxidative stress or epigenetic modification in cells [130][18]. It has been shown that the most studied compounds of plant origin in CRC are polyphenols, specifically resveratrol and curcumin (Table 1). Resveratrol belongs to the stilbenes group and has been shown to possess high antioxidant and antitumor activity, causing cell death through the induction of apoptosis and autophagy. Similar to resveratrol, the other polyphenols that were studied induce death through these pathways [48,67,73,83][19][20][21][22].
Table 1.
Summary of the in vitro and in vivo effects that were exerted by the bioactive natural compounds that were analyzed.
Fam. Comp. Sinergy In Vitro In Vivo Clinical Trials Refs.
Polyphenols Resveratrol 5-FU, OXA Apoptosis and decreased AC (VEGF inhibition). IC50 of 10 mg/mL in HT-29 (72 h). 150 or 300 ppm doses prevented cancerous lesions and induced apoptosis via BAX Safe intake up to a 1g/day dose. Limited BAV (2–29%). [20,47,49,2350,52,][2454,][2555,]57,58][[26][27][28][29][30][31]
Curcumin DOX, 5-FU, OXA G1-CCA and apoptosis at 20 µM. Reduced cell migration and invasion. 300 mg/kg dose prevented precancerous lesions and decreased tumor size. Low absorption and BAV. Increased tumor apoptosis. [69,]70,71,[72,73,32][33][34]74,75,76,81][21[35][36][37][38][39]
Kaempferol DOX, 5-FU, OXA G1 and G2/M-CCA and apoptosis induction. Decreased AC at 0.1 µM in MDA cell line. Decreased AC and MC. Low toxicity and BAV (2%). [82,83,84,85,[86,87,40][88,41][89,90][22]42][43][44][45][46][47]
Flavonoids Quercetin DOX CCA, apoptosis and decreased AC and MC. CYT in up to 300 µM doses in HCT-15, RKO, CT26, MC38, and HT29 cells 10 and 50 mg/kg reduced precancerous lesions and tumor size. Decreased MC and CHR. Not performed. [24,92,93,94,95,96,97][48][49][50][51][52][53][54]
EGCG 5-FU, IRI, CPT, OXA S and G2-CCA, apoptosis, CYT IC50 between 74.6 and 112.1 in CRC cell lines SW480, SW620, and LS411N. Decreased MC. 30 mg/kg for 2 weeks decreased MC, tumor growth and induced apoptosis 150 mg twice a day of green tea extract did not show any effect in CRC development risk [18,99,100,101,102,103,104,105,106,107][55][56][57][58][59][60][61][62][63][64]
Terpenes Geraniol 5-FU S-CCA. CYT IC30 of 200 µM for 7 days treatment in Caco-2 cell line. 250 mg/kg for 4 weeks prevented CRC precancerous lesions. Reduced tumor growth and apoptosis induction. Not performed. [116,117,118][65][66][67]
Panaxadiol 5-FU, IRI CYT IC50 lower than 10 µM in HCT116 cell line (72 h). Decreased AC (VEGF inhibition) 30 mg/kg for 3 weeks reduced tumor growth and AC. Not performed. [119,123,124,125][68][69][70][71]
Rg3 5-FU CYT IC50 100–200 µM in HT-29 cell line (48 h). Induction of apoptosis and AC via AMPK dysregulation. 25 mg/kg for 12 days reduced tumor vascularization and decreased CHR to 5-FU and OXA. Not performed. [121,122,125][71][72][73]
AC (antiangiogenic capacity); BAV (bioavailability); CCA (cell cycle arrest), Comp. (Compound); CPT (cisplatin); CHR (chemoresistance); CRC (colorectal cancer); CYT (cytotoxicity); DOX (doxorubicin); EGCG (epigallocatechin gallate); EMT (epithelial-mesenchymal transition); Fam. (Family); 5-FU (5-fluorouracil); IRI (irinotecan); MC (metastatic capacity); OXA (oxaliplatin); Refs. (references); VEGF (vascular endothelial growth factor).
Polyphenols have been classified as chemopreventives and chemotherapeutics, although their sensitizing effect has also been observed in in vitro and in vivo models. These compounds can modulate drug resistance by increasing drug internalization into the cell, decreasing enzymes that are responsible for drug degradation (such as glutathione-S-transferases and cytochromes) and reducing the expression of transmembrane detoxifying proteins in the cell. In addition, they can induce apoptosis, oxidative stress damage, and inhibit metastasis-triggering processes such as EMT [131][74]. The alteration of all these resistance mechanisms implies that these polyphenols have been shown to be effective in combination with traditional drugs such as 5-FU or oxaliplatin [56,73,75,87,88,89][21][37][44][45][46][75]. This effect is also observed in foods with high polyphenol contents such as the strawberry tree honey, that chemosensitizes the drug 5-FU in colon cancer lines such as HCT116 and LoVo [132][76]. In addition to this, it has been observed that curcumin and resveratrol had the capacity to inhibit tumor proliferation in in vivo models and prevented the formation of tumor precursor lesions, with an increase in apoptosis of induced tumor tissues [47,53,76][24][38][77]. Pharmacokinetic studies have been carried out in humans, where low bioavailability has been observed [47,52,54,71,75][24][27][28][34][37]. Given the low bioavailability of these compounds, the use of nanotechnology for their encapsulation could help stabilize the compound and prevent its degradation in blood. In addition, the use of nanotechnology allows specific targeting of tumor cells through their functionalization with antibodies or peptides [14,15][78][79]. On the other hand, it has been observed that flavonoid compounds also have anticarcinogenic potential. Among them, the most investigated in CRC have been quercetin and EGCG. These compounds exerted their cytotoxic effect by producing cycle arrest, inhibiting key pathways in tumor development such as PI3K/AKT/mTOR and the MAPK pathway, and inhibiting processes that are linked to tumor progression such as cell migration [93,99,100][50][56][57]. In addition, they showed a great chemosensitizing capacity in combination with traditional drugs such as doxorubicin, irinotecan, 5-FU, cisplatin, and oxaliplatin under in vitro and in vivo conditions. A study that was conducted by Hassanein et al. [133][80] showed the chemopreventive effect of EGCG administration together with sulindac, a non-steroidal anti-inflammatory drug, showing that it was able to decrease the production of neoplastic lesions in in vivo models of CRC. As polyphenols, these compounds have a low bioavailability, which is a limitation for their use in humans [18,24,87,88,89,97,101,102,103,105][44][45][46][48][54][55][58][59][60][62]. In this context, the synthesis of gold NPs encapsulating EGCG has been shown to be an effective therapy against tumor cells while it has been shown that the co-encapsulation of EGCG and 5-FU in NPs allows an increase in the effect of both compounds separately, producing an anti-angiogenic and pro-apoptotic effect [106,134][63][81]. The encapsulation of this compound in nanoformulations would increase the half-life of the compound in serum, increasing its bioavailability and increasing its antitumor effect [135][82]. The bibliographic analysis showed that terpenes are the least studied bioactive compounds as chemosensitizers in this type of cancer. Among this family, geraniol and ginsenosides have been the most studied compounds with sensitizing properties in CRC [114,117,118][66][67][83]. Due to the small number of studies that have been conducted on these compounds, it is complicated for these results to be transferred to clinical studies at present. These compounds exert their antiproliferative activity by producing cell cycle arrest and inducing apoptotic pathways. In addition, it has been observed that they suppress pathways essential for tumor development such as PI3K/AKT/mTOR [115,119,120][68][84][85]. Results in in vivo models showed that geraniol sensitized tumors that were induced in mice from a 5-FU-resistant CRC line to the drug, while the major ginsenoside (Rg3) showed synergy with 5-FU in tumors that were generated from the SW620 and LoVo cell lines. However, it has been shown that these compounds have clear preventive and therapeutic properties in CRC [115,116,123][65][69][84].

References

  1. Bukowski, K.; Kciuk, M.; Kontek, R. Mechanisms of Multidrug Resistance in Cancer Chemotherapy. Int. J. Mol. Sci. 2020, 21, 3233.
  2. Wang, X.; Zhang, H.; Chen, X. Drug Resistance and Combating Drug Resistance in Cancer. Cancer Drug Resist. 2019, 2, 141–160.
  3. Housman, G.; Byler, S.; Heerboth, S.; Lapinska, K.; Longacre, M.; Snyder, N.; Sarkar, S. Drug Resistance in Cancer: An Overview. Cancers 2014, 6, 1769–1792.
  4. Linn, S.C.; Giaccone, G. MDR1/P-Glycoprotein Expression in Colorectal Cancer. Eur. J. Cancer 1995, 31A, 1291–1294.
  5. Yuan, Z.; Liang, X.; Zhan, Y.; Wang, Z.; Xu, J.; Qiu, Y.; Wang, J.; Cao, Y.; Le, V.-M.; Ly, H.-T.; et al. Targeting CD133 Reverses Drug-Resistance via the AKT/NF-ΚB/MDR1 Pathway in Colorectal Cancer. Br. J. Cancer 2020, 122, 1342–1353.
  6. Cao, D.; Qin, S.; Mu, Y.; Zhong, M. The Role of MRP1 in the Multidrug Resistance of Colorectal Cancer. Oncol. Lett. 2017, 13, 2471–2476.
  7. Hu, T.; Li, Z.; Gao, C.-Y.; Cho, C.H. Mechanisms of Drug Resistance in Colon Cancer and Its Therapeutic Strategies. World J. Gastroenterol. 2016, 22, 6876–6889.
  8. Wang, Z.; Sun, X.; Feng, Y.; Wang, Y.; Zhang, L.; Wang, Y.; Fang, Z.; Azami, N.L.B.; Sun, M.; Li, Q. Dihydromyricetin Reverses MRP2-Induced Multidrug Resistance by Preventing NF-ΚB-Nrf2 Signaling in Colorectal Cancer Cell. Phytomedicine 2021, 82, 153414.
  9. Asano, T. Drug Resistance in Cancer Therapy and the Role of Epigenetics. J. Nippon. Med. Sch. 2020, 87, 244–251.
  10. Das, P.K.; Islam, F.; Lam, A.K. The Roles of Cancer Stem Cells and Therapy Resistance in Colorectal Carcinoma. Cells 2020, 9, 1392.
  11. Neophytou, C.M.; Trougakos, I.P.; Erin, N.; Papageorgis, P. Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance. Cancers 2021, 13, 4363.
  12. Prasetyanti, P.R.; Medema, J.P. Intra-Tumor Heterogeneity from a Cancer Stem Cell Perspective. Mol. Cancer 2017, 16, 41.
  13. Phi, L.T.H.; Sari, I.N.; Yang, Y.G.; Lee, S.H.; Jun, N.; Kim, K.S.; Lee, Y.K.; Kwon, H.Y. Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment. Stem. Cells Int. 2018, 2018, 5416923.
  14. Burrell, R.A.; Swanton, C. Tumour Heterogeneity and the Evolution of Polyclonal Drug Resistance. Mol. Oncol. 2014, 8, 1095–1111.
  15. Junttila, M.R.; de Sauvage, F.J. Influence of Tumour Micro-Environment Heterogeneity on Therapeutic Response. Nature 2013, 501, 346–354.
  16. Ortíz, R.; Quiñonero, F.; García-Pinel, B.; Fuel, M.; Mesas, C.; Cabeza, L.; Melguizo, C.; Prados, J. Nanomedicine to Overcome Multidrug Resistance Mechanisms in Colon and Pancreatic Cancer: Recent Progress. Cancers 2021, 13, 2058.
  17. Gallego-Jara, J.; Lozano-Terol, G.; Sola-Martínez, R.A.; Cánovas-Díaz, M.; Puente, T.d.D. A Compressive Review about Taxol®: History and Future Challenges. Molecules 2020, 25, 5986.
  18. Yuan, M.; Zhang, G.; Bai, W.; Han, X.; Li, C.; Bian, S. The Role of Bioactive Compounds in Natural Products Extracted from Plants in Cancer Treatment and Their Mechanisms Related to Anticancer Effects. Oxid. Med. Cell Longev. 2022, 2022, 1429869.
  19. Elshaer, M.; Chen, Y.; Wang, X.J.; Tang, X. Resveratrol: An Overview of Its Anti-Cancer Mechanisms. Life Sci. 2018, 207, 340–349.
  20. Weng, W.; Goel, A. Curcumin and Colorectal Cancer: An Update and Current Perspective on This Natural Medicine. Semin. Cancer Biol. 2022, 80, 73–86.
  21. Yin, T.F.; Wang, M.; Qing, Y.; Lin, Y.M.; Wu, D. Research Progress on Chemopreventive Effects of Phytochemicals on Colorectal Cancer and Their Mechanisms. World J. Gastroenterol. 2016, 22, 7068.
  22. Chen, A.Y.; Chen, Y.C. A Review of the Dietary Flavonoid, Kaempferol on Human Health and Cancer Chemoprevention. Food Chem. 2013, 138, 2099–2107.
  23. Huang, L.; Zhang, S.; Zhou, J.; Li, X. Effect of Resveratrol on Drug Resistance in Colon Cancer Chemotherapy. RSC Adv. 2019, 9, 2572–2580.
  24. Ko, J.H.; Sethi, G.; Um, J.Y.; Shanmugam, M.K.; Arfuso, F.; Kumar, A.P.; Bishayee, A.; Ahn, K.S. The Role of Resveratrol in Cancer Therapy. Int. J. Mol. Sci. 2017, 18, 2589.
  25. Fuggetta, M.P.; Lanzilli, G.; Tricarico, M.; Cottarelli, A.; Falchetti, R.; Ravagnan, G.; Bonmassar, E. Effect of Resveratrol on Proliferation and Telomerase Activity of Human Colon Cancer Cells in Vitro. J. Exp. Clin. Cancer Res. 2006, 25, 189–193.
  26. Rotelli, M.T.; Bocale, D.; de Fazio, M.; Ancona, P.; Scalera, I.; Memeo, R.; Travaglio, E.; Zbar, A.P.; Altomare, D.F. IN-VITRO Evidence for the Protective Properties of the Main Components of the Mediterranean Diet against Colorectal Cancer: A Systematic Review. Surg Oncol. 2015, 24, 145–152.
  27. Saud, S.M.; Li, W.; Morris, N.L.; Matter, M.S.; Colburn, N.H.; Kim, Y.S.; Young, M.R. Resveratrol Prevents Tumorigenesis in Mouse Model of Kras Activated Sporadic Colorectal Cancer by Suppressing Oncogenic Kras Expression. Carcinogenesis 2014, 35, 2778–2786.
  28. Aires, V.; Limagne, E.; Cotte, A.K.; Latruffe, N.; Ghiringhelli, F.; Delmas, D. Resveratrol Metabolites Inhibit Human Metastatic Colon Cancer Cells Progression and Synergize with Chemotherapeutic Drugs to Induce Cell Death. Mol. Nutr. Food Res. 2013, 57, 1170–1181.
  29. Cottart, C.H.; Nivet-Antoine, V.; Laguillier-Morizot, C.; Beaudeux, J.L. Resveratrol Bioavailability and Toxicity in Humans. Mol. Nutr. Food Res. 2010, 54, 7–16.
  30. Abdel Latif, Y.; El-Bana, M.; Hussein, J.; El-Khayat, Z.; Farrag, A.R. Effects of Resveratrol in Combination with 5-Fluorouracil on N-Methylnitrosourea-Induced Colon Cancer in Rats. Comp. Clin. Path 2019, 28, 1351–1362.
  31. Buhrmann, C.; Yazdi, M.; Popper, B.; Shayan, P.; Goel, A.; Aggarwal, B.B.; Shakibaei, M. Resveratrol Chemosensitizes TNF-β-Induced Survival of 5-FU-Treated Colorectal Cancer Cells. Nutrients 2018, 10, 888.
  32. Jaiswal, A.S.; Marlow, B.P.; Gupta, N.; Narayan, S. Beta-Catenin-Mediated Transactivation and Cell-Cell Adhesion Pathways Are Important in Curcumin (Diferuylmethane)-Induced Growth Arrest and Apoptosis in Colon Cancer Cells. Oncogene 2002, 21, 8414–8427.
  33. Basbinar, Y.; Calibasi-Kocal, G.; Pakdemirli, A.; Bayrak, S.; Ozupek, N.M.; Sever, T.; Ellidokuz, H.; Yigitbasi, T. Curcumin Effects on Cell Proliferation, Angiogenesis and Metastasis in Colorectal Cancer. JBUON 2019, 24, 1482–1487.
  34. Pricci, M.; Girardi, B.; Giorgio, F.; Losurdo, G.; Ierardi, E.; di Leo, A. Curcumin and Colorectal Cancer: From Basic to Clinical Evidences. Int. J. Mol. Sci. 2020, 21, 2364.
  35. Tunstall, R.G.; Sharma, R.A.; Perkins, S.; Sale, S.; Singh, R.; Farmer, P.B.; Steward, W.P.; Gescher, A.J. Cyclooxygenase-2 Expression and Oxidative DNA Adducts in Murine Intestinal Adenomas: Modification by Dietary Curcumin and Implications for Clinical Trials. Eur. J. Cancer 2006, 42, 415–421.
  36. Yin, J.; Wang, L.; Wang, Y.; Shen, H.; Wang, X.; Wu, L. Curcumin Reverses Oxaliplatin Resistance in Human Colorectal Cancer via Regulation of TGF-β/Smad2/3 Signaling Pathway. Onco. Targets Ther. 2019, 12, 3893–3903.
  37. Zheng, X.; Yang, X.; Lin, J.; Song, F.; Shao, Y. Low Curcumin Concentration Enhances the Anticancer Effect of 5-Fluorouracil against Colorectal Cancer. Phytomedicine 2021, 85, 153547.
  38. Hosseini, S.A.; Zand, H.; Cheraghpour, M. The Influence of Curcumin on the Downregulation of MYC, Insulin and IGF-1 Receptors: A Possible Mechanism Underlying the Anti-Growth and Anti-Migration in Chemoresistant Colorectal Cancer Cells. Medicina 2019, 55, 90.
  39. Gupta, A.; Sood, A.; Dhiman, A.; Shrimali, N.; Singhmar, R.; Guchhait, P.; Agrawal, G. Redox Responsive Poly(Allylamine)/Eudragit S-100 Nanoparticles for Dual Drug Delivery in Colorectal Cancer. Biomater. Adv. 2022, 143, 213184.
  40. Imran, M.; Salehi, B.; Sharifi-Rad, J.; Gondal, T.A.; Saeed, F.; Imran, A.; Shahbaz, M.; Fokou, P.V.T.; Arshad, M.U.; Khan, H.; et al. Kaempferol: A Key Emphasis to Its Anticancer Potential. Molecules 2019, 24, 2277.
  41. Schindler, R.; Mentlein, R. Flavonoids and Vitamin E Reduce the Release of the Angiogenic Peptide Vascular Endothelial Growth Factor from Human Tumor Cells. J. Nutr. 2006, 136, 1477–1482.
  42. Barve, A.; Chen, C.; Hebbar, V.; Desiderio, J.; Saw, C.L.-L.; Kong, A.-N. Metabolism, Oral Bioavailability and Pharmacokinetics of Chemopreventive Kaempferol in Rats. Biopharm. Drug Dispos. 2009, 30, 356–365.
  43. Cho, H.J.; Park, J.H.Y. Kaempferol Induces Cell Cycle Arrest in HT-29 Human Colon Cancer Cells. J. Cancer Prev. 2013, 18, 257–263.
  44. Riahi-Chebbi, I.; Souid, S.; Othman, H.; Haoues, M.; Karoui, H.; Morel, A.; Srairi-Abid, N.; Essafi, M.; Essafi-Benkhadir, K. The Phenolic Compound Kaempferol Overcomes 5-Fluorouracil Resistance in Human Resistant LS174 Colon Cancer Cells. Sci. Rep. 2019, 9, 195.
  45. Li, Q.; Wei, L.; Lin, S.; Chen, Y.; Lin, J.; Peng, J. Synergistic Effect of Kaempferol and 5-fluorouracil on the Growth of Colorectal Cancer Cells by Regulating the PI3K/Akt Signaling Pathway. Mol. Med. Rep. 2019, 20, 728–734.
  46. Park, J.; Lee, G.E.; An, H.J.; Lee, C.J.; Cho, E.S.; Kang, H.C.; Lee, J.Y.; Lee, H.S.; Choi, J.S.; Kim, D.J.; et al. Kaempferol Sensitizes Cell Proliferation Inhibition in Oxaliplatin-Resistant Colon Cancer Cells. Arch. Pharm. Res. 2021, 44, 1091–1108.
  47. Meena, D.; Vimala, K.; Kannan, S. Combined Delivery of DOX and Kaempferol Using PEGylated Gold Nanoparticles to Target Colon Cancer. J. Clust. Sci. 2022, 33, 173–187.
  48. Zhou, Y.; Zhang, J.; Wang, K.; Han, W.; Wang, X.; Gao, M.; Wang, Z.; Sun, Y.; Yan, H.; Zhang, H.; et al. Quercetin Overcomes Colon Cancer Cells Resistance to Chemotherapy by Inhibiting Solute Carrier Family 1, Member 5 Transporter. Eur. J. Pharmacol. 2020, 881, 173185.
  49. Tang, S.M.; Deng, X.T.; Zhou, J.; Li, Q.P.; Ge, X.X.; Miao, L. Pharmacological Basis and New Insights of Quercetin Action in Respect to Its Anti-Cancer Effects. Biomed Pharm. 2020, 121, 109604.
  50. Reyes-Farias, M.; Carrasco-Pozo, C. The Anti-Cancer Effect of Quercetin: Molecular Implications in Cancer Metabolism. Int. J. Mol. Sci. 2019, 20, 3177.
  51. Kee, J.Y.; Han, Y.H.; Kim, D.S.; Mun, J.G.; Park, J.; Jeong, M.Y.; Um, J.Y.; Hong, S.H. Inhibitory Effect of Quercetin on Colorectal Lung Metastasis through Inducing Apoptosis, and Suppression of Metastatic Ability. Phytomedicine 2016, 23, 1680–1690.
  52. Srivastava, N.S.; Srivastava, R.A.K. Curcumin and Quercetin Synergistically Inhibit Cancer Cell Proliferation in Multiple Cancer Cells and Modulate Wnt/β-Catenin Signaling and Apoptotic Pathways in A375 Cells. Phytomedicine 2019, 52, 117–128.
  53. Neamtu, A.A.; Maghiar, T.A.; Alaya, A.; Olah, N.K.; Turcus, V.; Pelea, D.; Totolici, B.D.; Neamtu, C.; Maghiar, A.M.; Mathe, E. A Comprehensive View on the Quercetin Impact on Colorectal Cancer. Molecules 2022, 27, 1973.
  54. Chang, C.E.; Hsieh, C.M.; Huang, S.C.; Su, C.Y.; Sheu, M.T.; Ho, H.O. Lecithin-Stabilized Polymeric Micelles (LsbPMs) for Delivering Quercetin: Pharmacokinetic Studies and Therapeutic Effects of Quercetin Alone and in Combination with Doxorubicin. Sci. Rep. 2018, 8, 17640.
  55. Wu, W.; Dong, J.; Gou, H.; Geng, R.; Yang, X.; Chen, D.; Xiang, B.; Zhang, Z.; Ren, S.; Chen, L.; et al. EGCG Synergizes the Therapeutic Effect of Irinotecan through Enhanced DNA Damage in Human Colorectal Cancer Cells. J. Cell Mol. Med. 2021, 25, 7913–7921.
  56. Almatrood, S.A.; Almatroudi, A.; Khan, A.A.; Alhumaydh, F.A.; Alsahl, M.A.; Rahmani, A.H. Potential Therapeutic Targets of Epigallocatechin Gallate (EGCG), the Most Abundant Catechin in Green Tea, and Its Role in the Therapy of Various Types of Cancer. Molecules 2020, 25, 3146.
  57. Luo, K.W.; Xia, J.; Cheng, B.H.; Gao, H.C.; Fu, L.W.; Luo, X. le Tea Polyphenol EGCG Inhibited Colorectal-Cancer-Cell Proliferation and Migration via Downregulation of STAT3. Gastroenterol. Rep. 2020, 9, 59–70.
  58. Wubetu, G.Y.; Shimada, M.; Morine, Y.; Ikemoto, T.; Ishikawa, D.; Iwahashi, S.; Yamada, S.; Saito, Y.; Arakawa, Y.; Imura, S. Epigallocatechin Gallate Hinders Human Hepatoma and Colon Cancer Sphere Formation. J. Gastroenterol. Hepatol. 2016, 31, 256–264.
  59. Toden, S.; Tran, H.M.; Tovar-Camargo, O.A.; Okugawa, Y.; Goel, A. Epigallocatechin-3-Gallate Targets Cancer Stem-like Cells and Enhances 5-Fluorouracil Chemosensitivity in Colorectal Cancer. Oncotarget 2016, 7, 16158–16171.
  60. La, X.; Zhang, L.; Li, Z.; Li, H.; Yang, Y. (-)-Epigallocatechin Gallate (EGCG) Enhances the Sensitivity of Colorectal Cancer Cells to 5-FU by Inhibiting GRP78/NF-ΚB/MiR-155-5p/MDR1 Pathway. J. Agric. Food Chem. 2019, 67, 2510–2518.
  61. Maruyama, T.; Murata, S.; Nakayama, K.; Sano, N.; Ogawa, K.; Nowatari, T.; Tamura, T.; Nozaki, R.; Fukunaga, K.; Ohkohchi, N. (-)-Epigallocatechin-3-Gallate Suppresses Liver Metastasis of Human Colorectal Cancer. Oncol. Rep. 2014, 31, 625–633.
  62. Hu, F.; Wei, F.; Wang, Y.; Wu, B.; Fang, Y.; Xiong, B. EGCG Synergizes the Therapeutic Effect of Cisplatin and Oxaliplatin through Autophagic Pathway in Human Colorectal Cancer Cells. J. Pharmacol. Sci. 2015, 128, 27–34.
  63. Wang, R.; Huang, J.; Chen, J.; Yang, M.; Wang, H.; Qiao, H.; Chen, Z.; Hu, L.; Di, L.; Li, J. Enhanced Anti-Colon Cancer Efficacy of 5-Fluorouracil by Epigallocatechin-3- Gallate Co-Loaded in Wheat Germ Agglutinin-Conjugated Nanoparticles. Nanomedicine 2019, 21, 102068.
  64. Seufferlein, T.; Ettrich, T.J.; Menzler, S.; Messmann, H.; Kleber, G.; Zipprich, A.; Frank-Gleich, S.; Algül, H.; Metter, K.; Odemar, F.; et al. Green Tea Extract to Prevent Colorectal Adenomas, Results of a Randomized, Placebo-Controlled Clinical Trial. Am. J. Gastroenterol. 2022, 117, 884–894.
  65. Vieira, A.; Heidor, R.; Cardozo, M.T.; Scolastici, C.; Purgatto, E.; Shiga, T.M.; Barbisan, L.F.; Ong, T.P.; Moreno, F.S. Efficacy of Geraniol but Not of β-Ionone or Their Combination for the Chemoprevention of Rat Colon Carcinogenesis. Braz. J. Med. Biol. Res. 2011, 44, 538–545.
  66. Carnesecchi, S.; Bras-Gonçalves, R.; Bradaia, A.; Zeisel, M.; Gossé, F.; Poupon, M.F.; Raul, F. Geraniol, a Component of Plant Essential Oils, Modulates DNA Synthesis and Potentiates 5-Fluorouracil Efficacy on Human Colon Tumor Xenografts. Cancer Lett. 2004, 215, 53–59.
  67. Carnesecchi, S.; Langley, K.; Exinger, F.; Gosse, F.; Raul, F. Geraniol, a Component of Plant Essential Oils, Sensitizes Human Colonic Cancer Cells to 5-Fluorouracil Treatment. J. Pharmacol. Exp. Ther. 2002, 301, 625–630.
  68. Gao, J.L.; Lv, G.Y.; He, B.C.; Zhang, B.Q.; Zhang, H.; Wang, N.; Wang, C.Z.; Du, W.; Yuan, C.S.; He, T.C. Ginseng Saponin Metabolite 20(S)-Protopanaxadiol Inhibits Tumor Growth by Targeting Multiple Cancer Signaling Pathways. Oncol. Rep. 2013, 30, 292–298.
  69. Wang, C.Z.; Zhang, Z.; Wan, J.Y.; Zhang, C.F.; Anderson, S.; He, X.; Yu, C.; He, T.C.; Qi, L.W.; Yuan, C.S. Protopanaxadiol, an Active Ginseng Metabolite, Significantly Enhances the Effects of Fluorouracil on Colon Cancer. Nutrients 2015, 7, 799–814.
  70. Du, G.-J.; Wang, C.-Z.; Zhang, Z.-Y.; Wen, X.-D.; Somogyi, J.; Calway, T.; He, T.-C.; Du, W.; Yuan, C.-S. Caspase-Mediated pro-Apoptotic Interaction of Panaxadiol and Irinotecan in Human Colorectal Cancer Cells. J. Pharm. Pharmacol. 2012, 64, 727–734.
  71. Hong, S.; Cai, W.; Huang, Z.; Wang, Y.; Mi, X.; Huang, Y.; Lin, Z.; Chen, X. Ginsenoside Rg3 Enhances the Anticancer Effect of 5-FU in Colon Cancer Cells via the PI3K/AKTpathway. Oncol. Rep. 2020, 44, 1333–1342.
  72. Yuan, H.D.; Quan, H.Y.; Zhang, Y.; Kim, S.H.; Chung, S.H. 20(S)-Ginsenoside Rg3-Induced Apoptosis in HT-29 Colon Cancer Cells Is Associated with AMPK Signaling Pathway. Mol. Med. Rep. 2010, 3, 825–831.
  73. Tang, Y.C.; Zhang, Y.; Zhou, J.; Zhi, Q.; Wu, M.Y.; Gong, F.R.; Shen, M.; Liu, L.; Tao, M.; Shen, B.; et al. Ginsenoside Rg3 Targets Cancer Stem Cells and Tumor Angiogenesis to Inhibit Colorectal Cancer Progression in Vivo. Int. J. Oncol. 2018, 52, 127–138.
  74. Maleki Dana, P.; Sadoughi, F.; Asemi, Z.; Yousefi, B. The Role of Polyphenols in Overcoming Cancer Drug Resistance: A Comprehensive Review. Cell Mol. Biol. Lett. 2022, 27, 1.
  75. Huang, X.M.; Yang, Z.J.; Xie, Q.; Zhang, Z.K.; Zhang, H.; Ma, J.Y. Natural Products for Treating Colorectal Cancer: A Mechanistic Review. Biomed Pharm. 2019, 117, 109142.
  76. Afrin, S.; Giampieri, F.; Cianciosi, D.; Alvarez-Suarez, J.M.; Bullon, B.; Amici, A.; Quiles, J.L.; Forbes-Hernández, T.Y.; Battino, M. Strawberry Tree Honey in Combination with 5-Fluorouracil Enhances Chemosensitivity in Human Colon Adenocarcinoma Cells. Food Chem. Toxicol. 2021, 156, 112484.
  77. Carter, L.G.; D’Orazio, J.A.; Pearson, K.J. Resveratrol and Cancer: Focus on in Vivo Evidence. Endocr. Relat. Cancer 2014, 21, R209–R225.
  78. Guo, Y.; Sun, Q.; Wu, F.-G.; Dai, Y.; Chen, X.; Guo, Y.; Sun, Q.; Wu, F.; Dai, Y.; Chen Yong Loo, X. Polyphenol-Containing Nanoparticles: Synthesis, Properties, and Therapeutic Delivery. Adv. Mater. 2021, 33, 2007356.
  79. Mitchell, M.J.; Billingsley, M.M.; Haley, R.M.; Wechsler, M.E.; Peppas, N.A.; Langer, R. Engineering Precision Nanoparticles for Drug Delivery. Nat. Rev. Drug Discov. 2020, 20, 101–124.
  80. Hassanein, N.M.A.; Hassan, E.S.G.; Hegab, A.M.; Elahl, H.M.S. Chemopreventive Effect of Sulindac in Combination with Epigallocatechin Gallate or Kaempferol against 1,2-Dimethyl Hydrazine-Induced Preneoplastic Lesions in Rats: A Comparative Study. J. Biochem. Mol. Toxicol. 2018, 32, e22198.
  81. Chavva, S.R.; Deshmukh, S.K.; Kanchanapally, R.; Tyagi, N.; Coym, J.W.; Singh, A.P.; Singh, S. Epigallocatechin Gallate-Gold Nanoparticles Exhibit Superior Antitumor Activity Compared to Conventional Gold Nanoparticles: Potential Synergistic Interactions. Nanomaterials 2019, 9, 396.
  82. Li, Z.; Jiang, H.; Xu, C.; Gu, L. A Review: Using Nanoparticles to Enhance Absorption and Bioavailability of Phenolic Phytochemicals. Food Hydrocoll 2015, 43, 153–164.
  83. De Cássia Da Silveira, E.; Sá, R.; Andrade, L.N.; de Sousa, D.P. A Review on Anti-Inflammatory Activity of Monoterpenes. Molecules 2013, 18, 1227–1254.
  84. Cho, M.; So, I.; Chun, J.N.; Jeon, J.H. The Antitumor Effects of Geraniol: Modulation of Cancer Hallmark Pathways (Review). Int. J. Oncol. 2016, 48, 1772–1782.
  85. Wang, Z.; Li, M.Y.; Zhang, Z.H.; Zuo, H.X.; Wang, J.Y.; Xing, Y.; Ri, M.H.; Jin, H.L.; Jin, C.H.; Xu, G.H.; et al. Panaxadiol Inhibits Programmed Cell Death-Ligand 1 Expression and Tumour Proliferation via Hypoxia-Inducible Factor (HIF)-1α and STAT3 in Human Colon Cancer Cells. Pharmacol. Res. 2020, 155, 104727.
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