Mechanistic insights into polyphenolic constituents from traditional Chinese medicines in inhibiting colorectal cancer metastasis

doi:10.1007/s13659-026-00622-2

Abstract

Abstract: Colorectal cancer (CRC) is the third most predominant cancer caused by genetic, environmental and nutritional factors and is the world’s second most significant cause of cancer-related mortality. During the process of tumor metastasis, firstly, cancer cell increases its proliferative capacity by reducing autophagy and apoptosis, and then the cancer cell capacity is stimulated by increasing the ability of tumors to absorb nutrients from the outside through angiogenesis. Both of the two steps can increase tumor migration and invasion. Finally, the purpose of tumor metastasis is achieved. By inducing autophagy and apoptosis of tumor cells, blocking the angiogenesis and inhibiting EMT outside the tumor can reduce the invasion and migration of cancer, and consequently achieve the purpose of inhibiting tumor metastasis. Traditional Chinese Medicine (TCM) has the characteristics of multiple targets, slight side effects and good therapeutic effects. Research of the anticancer effect of Polyphenolic in TCM has made considerable progress in recent years. This review explores the research achievements of Polyphenolic in TCM on CRC metastasis in the past ten years, summarizes the development direction of Polyphenolic in TCM on CRC metastasis research in the past ten years and makes a prospect for the future.

Key words: Colorectal cancer, Metastasis, TCM, Polyphenolic

摘要： Colorectal cancer (CRC) is the third most predominant cancer caused by genetic, environmental and nutritional factors and is the world’s second most significant cause of cancer-related mortality. During the process of tumor metastasis, firstly, cancer cell increases its proliferative capacity by reducing autophagy and apoptosis, and then the cancer cell capacity is stimulated by increasing the ability of tumors to absorb nutrients from the outside through angiogenesis. Both of the two steps can increase tumor migration and invasion. Finally, the purpose of tumor metastasis is achieved. By inducing autophagy and apoptosis of tumor cells, blocking the angiogenesis and inhibiting EMT outside the tumor can reduce the invasion and migration of cancer, and consequently achieve the purpose of inhibiting tumor metastasis. Traditional Chinese Medicine (TCM) has the characteristics of multiple targets, slight side effects and good therapeutic effects. Research of the anticancer effect of Polyphenolic in TCM has made considerable progress in recent years. This review explores the research achievements of Polyphenolic in TCM on CRC metastasis in the past ten years, summarizes the development direction of Polyphenolic in TCM on CRC metastasis research in the past ten years and makes a prospect for the future.

关键词: Colorectal cancer, Metastasis, TCM, Polyphenolic

Ming-Hong Li, Lu Liu. Mechanistic insights into polyphenolic constituents from traditional Chinese medicines in inhibiting colorectal cancer metastasis[J]. Natural Products and Bioprospecting, 2026, 16(5): 61-61.

Ming-Hong Li, Lu Liu. Mechanistic insights into polyphenolic constituents from traditional Chinese medicines in inhibiting colorectal cancer metastasis[J]. 应用天然产物, 2026, 16(5): 61-61.

References

[1] Islam MR, Akash S, Rahman MM, Nowrin FT, Akter T, Shohag S, et al. Colon cancer and colorectal cancer: prevention and treatment by potential natural products. Chem-Biol Interact. 2022;368:110170. https://doi.org/10.1016/j.cbi.2022.110170.
[2] Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394:1467-80. https://doi.org/10.1016/S0140-6736(19)32319-0.
[3] Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73:233-54. https://doi.org/10.3322/caac.21772.
[4] Fabregas JC, Ramnaraign B, George TJ. Clinical updates for colon cancer care in 2022. Clin Colorectal Cancer. 2022;21:198-203. https://doi.org/10.1016/j.clcc.2022.05.006.
[5] Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12-49. https://doi.org/10.3322/caac.21820.
[6] The GLOBOCAN 2022 cancer estimates: Data sources, methods, and a snapshot of the cancer burden worldwide, (n.d.).
[7] Mierke CT. The matrix environmental and cell mechanical properties regulate cell migration and contribute to the invasive phenotype of cancer cells. Rep Prog Phys. 2019;82:64602. https://doi.org/10.1088/1361-6633/ab1628.
[8] Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther. 2020;5:28. https://doi.org/10.1038/s41392-020-0134-x.
[9] Suresh DS, Guruvayoorappan C. Molecular principles of tissue invasion and metastasis. Am J Physiol Cell Physiol. 2023;324:C971-91. https://doi.org/10.1152/ajpcell.00348.2022.
[10] Wang K, Chen Q, Shao Y, Yin S, Liu C, Liu Y, et al. Anticancer activities of TCM and their active components against tumor metastasis. Biomed Pharmacother. 2021;133:111044. https://doi.org/10.1016/j.biopha.2020.111044.
[11] Tumor angiogenesis: therapeutic implications—PubMed (n.d.). https://pubmed.ncbi.nlm.nih.gov/4938153/ (accessed February 11, 2025).
[12] Tumor angiogenesis: causes, consequences, challenges and opportunities | cellular and molecular life sciences, (n.d.). https://doi.org/10.1007/s00018-019-03351-7 (accessed February 11, 2025).
[13] Li X, Zhou J, Wang X, Li C, Ma Z, Wan Q, et al. New advances in the research of clinical treatment and novel anticancer agents in tumor angiogenesis. Biomed Pharmacother. 2023;163:114806. https://doi.org/10.1016/j.biopha.2023.114806.
[14] Karlsson MC, Gonzalez SF, Welin J, Fuxe J. Epithelial-mesenchymal transition in cancer metastasis through the lymphatic system. Mol Oncol. 2017;11:781-91. https://doi.org/10.1002/1878-0261.12092.
[15] Ribatti D, Tamma R, Annese T. Epithelial-mesenchymal transition in cancer: a historical overview. Transl Oncol. 2020;13:100773. https://doi.org/10.1016/j.tranon.2020.100773.
[16] Jheng H-F, Tsai P-J, Guo S-M, Kuo L-H, Chang C-S, Su I-J, et al. Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol. 2012;32:309-19. https://doi.org/10.1128/MCB.05603-11.
[17] Simula L, Nazio F, Campello S. The mitochondrial dynamics in cancer and immune-surveillance. Semin Cancer Biol. 2017;47:29-42. https://doi.org/10.1016/j.semcancer.2017.06.007.
[18] Shin AE, Giancotti FG, Rustgi AK. Metastatic colorectal cancer: Mechanisms and emerging therapeutics. Trends Pharmacol Sci. 2023;44:222-36. https://doi.org/10.1016/j.tips.2023.01.003.
[19] Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 2015;13:45. https://doi.org/10.1186/s12916-015-0278-7.
[20] Wang M, Zhao J, Zhang L, Wei F, Lian Y, Wu Y, et al. Role of tumor microenvironment in tumorigenesis. J Cancer. 2017;8:761-73. https://doi.org/10.7150/jca.17648.
[21] Han L, Lam EW-F, Sun Y. Extracellular vesicles in the tumor microenvironment: Old stories, but new tales. Mol Cancer. 2019;18:59. https://doi.org/10.1186/s12943-019-0980-8.
[22] Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin Y-T, Togashi Y, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022;40:201-218.e9. https://doi.org/10.1016/j.ccell.2022.01.001.
[23] Zhong X, He X, Wang Y, Hu Z, Huang H, Zhao S, et al. Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications. J Hematol Oncol. 2022;15:160. https://doi.org/10.1186/s13045-022-01358-5.
[24] A framework for advancing our understanding of cancer-associated fibroblasts | nature reviews cancer (n.d.). https://www.nature.com/articles/s41568-019-0238-1 (accessed March 1, 2026).
[25] Traditional chinese medicine in the prevention and treatment of cancer and cancer metastasis (review) (n.d.). https://www.spandidos-publications.com/https://doi.org/10.3892/ol.2015.3459 (accessed February 11, 2025).
[26] Ma Z, Fan Y, Wu Y, Kebebe D, Zhang B, Lu P, et al. Traditional Chinese medicine-combination therapies utilizing nanotechnology-based targeted delivery systems: a new strategy for antitumor treatment. IJN. 2019;14:2029-53. https://doi.org/10.2147/IJN.S197889.
[27] Gezici S, Şekeroğlu N. Current perspectives in the application of medicinal plants against cancer: novel therapeutic agents. ACAMC. 2019;19:101-11. https://doi.org/10.2174/1871520619666181224121004.
[28] Assanga SBI, Luján LML, McCarty MF. Targetting beta-catenin signaling for prevention of colorectal cancer—nutraceutical, drug, and dietary options. Eur J Pharmacol. 2023;956:175898. https://doi.org/10.1016/j.ejphar.2023.175898.
[29] Chapelle N, Matysiak-Budnik T, Douane F, Metairie S, Rougier P, Touchefeu Y. Hepatic arterial infusion in the management of colorectal cancer liver metastasis: current and future perspectives. Dig Liver Dis. 2018;50:220-5. https://doi.org/10.1016/j.dld.2017.12.004.
[30] Mattar RE. Preoperative selection of patients with colorectal cancer liver metastasis for hepatic resection. World J Gastroenterol. 2016;22:567. https://doi.org/10.3748/wjg.v22.i2.567.
[31] Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18:128-34. https://doi.org/10.1038/nrc.2017.118.
[32] Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871-90. https://doi.org/10.1016/j.cell.2009.11.007.
[33] Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178-96. https://doi.org/10.1038/nrm3758.
[34] Craene BD, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97-110. https://doi.org/10.1038/nrc3447.
[35] Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK. EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol. 2020;30:764-76. https://doi.org/10.1016/j.tcb.2020.07.003.
[36] Aiello NM, Maddipati R, Norgard RJ, Balli D, Li J, Yuan S, et al. EMT subtype influences epithelial plasticity and mode of cell migration. Dev Cell. 2018;45:681-695.e4. https://doi.org/10.1016/j.devcel.2018.05.027.
[37] Zhang N, Ng AS, Cai S, Li Q, Yang L, Kerr D. Novel therapeutic strategies: Targeting epithelial-mesenchymal transition in colorectal cancer. Lancet Oncol. 2021;22:e358-68. https://doi.org/10.1016/S1470-2045(21)00343-0.
[38] Cao Y, Lu K, Xia Y, Wang Y, Wang A, Zhao Y. Danshensu attenuated epithelial-mesenchymal transformation and chemoresistance of colon cancer cells induced by platelets. Front Biosci Landmark. 2022;27:160. https://doi.org/10.31083/j.fbl2705160.
[39] Jin Q, Jin X, Liu T, Lu X, Wang G, He N. A disintegrin and metalloproteinase 8 induced epithelial-mesenchymal transition to promote the invasion of colon cancer cells via TGF-β/Smad2/3 signalling pathway. J Cell Mol Med. 2020;24:13058-69. https://doi.org/10.1111/jcmm.15907.
[40] Cao H-Y, Ding R-L, Li M, Yang M-N, Yang L-L, Wu J-B, et al. Danshensu, a major water-soluble component of Salvia miltiorrhiza, enhances the radioresponse for Lewis lung carcinoma xenografts in mice. Oncol Lett. 2017;13:605-12. https://doi.org/10.3892/ol.2016.5508.
[41] Ji Q, Liu X, Han Z, Zhou L, Sui H, Yan L, et al. Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression. BMC Cancer. 2015;15:97. https://doi.org/10.1186/s12885-015-1119-y.
[42] Chen CR, Tan R, Qu WM, Wu Z, Wang Y, Urade Y, et al. Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, exerts antiepileptic effects via the GABA/benzodiazepine receptor complex in mice. Br J Pharmacol. 2011;164:1534-46. https://doi.org/10.1111/j.1476-5381.2011.01456.x.
[43] Chei S, Oh H-J, Song J-H, Seo Y-J, Lee K, Lee B-Y. Magnolol suppresses TGF-β-induced epithelial-to-mesenchymal transition in human colorectal cancer cells. Front Oncol. 2019;9:752. https://doi.org/10.3389/fonc.2019.00752.
[44] Zhang Z, Chen H, Xu C, Song L, Huang L, Lai Y, et al. Curcumin inhibits tumor epithelial-mesenchymal transition by downregulating the Wnt signaling pathway and upregulating NKD2 expression in colon cancer cells. Oncol Rep. 2016;35:2615-23. https://doi.org/10.3892/or.2016.4669.
[45] Li M, Yue GG-L, Tsui SK-W, Fung K-P, Lau CB-S. Turmeric extract, with absorbable curcumin, has potent anti-metastatic effect in vitro and in vivo. Phytomedicine. 2018;46:131-41. https://doi.org/10.1016/j.phymed.2018.03.065.
[46] Katoh M, Katoh M. WNT signaling pathway and stem cell signaling network. Clin Cancer Res. 2007;13:4042-5. https://doi.org/10.1158/1078-0432.CCR-06-2316.
[47] Kim HJ, Park SY, Park OJ, Kim Y-M. Curcumin suppresses migration and proliferation of Hep3B hepatocarcinoma cells through inhibition of the Wnt signaling pathway. Mol Med Rep. 2013;8:282-6. https://doi.org/10.3892/mmr.2013.1497.
[48] Leow P-C, Bahety P, Boon CP, Lee CY, Tan KL, Yang T, et al. Functionalized curcumin analogs as potent modulators of the Wnt/β-catenin signaling pathway. Eur J Med Chem. 2014;71:67-80. https://doi.org/10.1016/j.ejmech.2013.10.073.
[49] Choe Y, Pleasure SJ. Wnt signaling regulates intermediate precursor production in the postnatal Dentate Gyrus by regulating Cxcr4 expression. Dev Neurosci. 2012;34:502-14. https://doi.org/10.1159/000345353.
[50] Zhao S, Wang J, Qin C. Blockade of CXCL12/CXCR4 signaling inhibits intrahepatic cholangiocarcinoma progression and metastasis via inactivation of canonical Wnt pathway. J Exp Clin Cancer Res. 2014;33:103. https://doi.org/10.1186/s13046-014-0103-8.
[51] Buhrmann C, Kraehe P, Lueders C, Shayan P, Goel A, Shakibaei M. Curcumin suppresses crosstalk between colon cancer stem cells and stromal fibroblasts in the tumor microenvironment: potential role of EMT. PLoS ONE. 2014;9:e107514. https://doi.org/10.1371/journal.pone.0107514.
[52] Bahrami A, Majeed M, Sahebkar A. Curcumin: a potent agent to reverse epithelial-to-mesenchymal transition. Cell Oncol. 2019;42:405-21. https://doi.org/10.1007/s13402-019-00442-2.
[53] Toden S, Okugawa Y, Jascur T, Wodarz D, Komarova NL, Buhrmann C, et al. Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis. 2015;36:355-67. https://doi.org/10.1093/carcin/bgv006.
[54] Meng X, Cai J, Liu J, Han B, Gao F, Gao W, Zhang Y, Zhang J, Zhao Z, Jiang C. Curcumin increases efficiency of γ-irradiation in gliomas by inhibiting hedgehog signaling pathway. Cell Cycle (Georget. Tex). 2017;16:1181-92. https://doi.org/10.1080/15384101.2017.1320000.
[55] Lu Y, Zhang R, Zhang X, Zhang B, Yao Q. Curcumin may reverse 5-fluorouracil resistance on colonic cancer cells by regulating TET1-NKD-wnt signal pathway to inhibit the EMT progress. Biomed Pharmacother Biomed Pharmacother. 2020;129:110381. https://doi.org/10.1016/j.biopha.2020.110381.
[56] Gupta A, Singh AK, Kumar R, Ganguly R, Rana HK, Pandey PK, et al. Corilagin in cancer: a critical evaluation of anticancer activities and molecular mechanisms. Molecules. 2019;24:3399. https://doi.org/10.3390/molecules24183399.
[57] Hwang ST, Yang MH, Kumar AP, Sethi G, Ahn KS. Corilagin represses epithelial to mesenchymal transition process through modulating Wnt/β-catenin signaling cascade. Biomolecules. 2020;10:1406. https://doi.org/10.3390/biom10101406.
[58] Liu X-Y, Zhang L, Yang X-W, Zhang Y-B, Xu W, Zhang P, et al. Simultaneous detection and quantification of 57 compounds in Spatholobi caulis applying ultra-fast liquid chromatography with tandem mass spectrometry. J Sep Sci. 2020;43:4247-62. https://doi.org/10.1002/jssc.202000496.
[59] Sun L, Yang L, Du X, Liu L, Ran Q, Yang Q, et al. Ethyl-acetate extract of Spatholobi caulis blocked the pro-metastatic support from the hemato-microenvironment of colon cancer by specific disruption of tumor-platelet adhesion. Phytomedicine. 2024;128:155420. https://doi.org/10.1016/j.phymed.2024.155420.
[60] Hseu Y-C, Chao Y-H, Lin K-Y, Way T-D, Lin H-Y, Thiyagarajan V, et al. Antrodia camphorata inhibits metastasis and epithelial-to-mesenchymal transition via the modulation of claudin-1 and Wnt/β-catenin signaling pathways in human colon cancer cells. J Ethnopharmacol. 2017;208:72-83. https://doi.org/10.1016/j.jep.2017.07.001.
[61] Qin Y, Zhao D, Zhou H-G, Wang, X-H, Zhong W-L, Chen S, Gu W-G, Wang W, Zhang C-H, Liu Y-R, Liu H-J, Zhang Q, Guo Y-Q, Sun T, Yang C. Apigenin inhibits NF-κB and snail signaling, EMT and metastasis in human hepatocellular carcinoma, Oncotarget. 2016;7:41421-31. https://doi.org/10.18632/oncotarget.9404.
[62] Zhou P, Wang C, Hu Z, Chen W, Qi W, Li A. Genistein induces apoptosis of colon cancer cells by reversal of epithelial-to-mesenchymal via a Notch1/NF-κB/slug/E-cadherin pathway. BMC Cancer. 2017;17:813. https://doi.org/10.1186/s12885-017-3829-9.
[63] Shen Y-A, Lin C-H, Chi W-H, Wang C-Y, Hsieh Y-T, Wei Y-H, et al. Resveratrol impedes the stemness, epithelial-mesenchymal transition, and metabolic reprogramming of cancer stem cells in nasopharyngeal carcinoma through p53 activation. Evidence-Based Complementary Alternative Med. 2013;2013:1-13. https://doi.org/10.1155/2013/590393.
[64] Kim NH, Kim HS, Li X-Y, Lee I, Choi H-S, Kang SE, et al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J Cell Biol. 2011;195:417-33. https://doi.org/10.1083/jcb.201103097.
[65] Yan Z, Yang Q, Xue M, Wang S, Hong W, Gao X. YY1-induced lncRNA ZFPM2-AS1 facilitates cell proliferation and invasion in small cell lung cancer via upregulating of TRAF4. Cancer Cell Int. 2020;20:108. https://doi.org/10.1186/s12935-020-1157-7.
[66] Lin T-A, Lin W-S, Chou Y-C, Nagabhushanam K, Ho C-T, Pan M-H. Oxyresveratrol inhibits human colon cancer cell migration through regulating epithelial-mesenchymal transition and microRNA. Food Funct. 2021;12:9658-68. https://doi.org/10.1039/D1FO01920A.
[67] Yuan L, Zhou M, Huang D, Wasan H, Zhang K, Sun L, et al. Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of epithelial-mesenchymal transition via the AKT/GSK-3β/Snail signaling pathway. Mol Med Rep. 2019. https://doi.org/10.3892/mmr.2019.10528.
[68] Chen H, Ye Y, Yang Y, Zhong M, Gu L, Han Z, et al. TIPE-mediated up-regulation of MMP-9 promotes colorectal cancer invasion and metastasis through MKK-3/p38/NF-κB pro-oncogenic signaling pathway. Signal Transduction Targeted Ther. 2020;5:163. https://doi.org/10.1038/s41392-020-00276-7.
[69] Zhou W, Cao W, Wang M, Yang K, Zhang X, Liu Y, et al. Validation of quercetin in the treatment of colon cancer with diabetes via network pharmacology, molecular dynamics simulations, and in vitro experiments. Mol Divers. 2024;28:2947-65. https://doi.org/10.1007/s11030-023-10725-4.
[70] Kee J-Y, Han Y-H, Kim D-S, Mun J-G, Park J, Jeong M-Y, et al. Inhibitory effect of quercetin on colorectal lung metastasis through inducing apoptosis, and suppression of metastatic ability. Phytomedicine. 2016;23:1680-90. https://doi.org/10.1016/j.phymed.2016.09.011.
[71] Barboura M, Cornebise C, Hermetet F, Guerrache A, Selmi M, Salek A, et al. Tannic acid, a hydrolysable tannin, prevents transforming growth factor-β-induced epithelial-mesenchymal transition to counteract colorectal tumor growth. Cells. 2022;11:3645. https://doi.org/10.3390/cells11223645.
[72] He M, Min J-W, Kong W-L, He X-H, Li J-X, Peng B-W. A review on the pharmacological effects of vitexin and isovitexin. Fitoterapia. 2016;115:74-85. https://doi.org/10.1016/j.fitote.2016.09.011.
[73] Zhu H, Zhao N, Jiang M. Isovitexin attenuates tumor growth in human colon cancer cells through the modulation of apoptosis and epithelial-mesenchymal transition via PI3K/akt/mTOR signaling pathway. Biochem Cell Biol. 2021;99:741-9. https://doi.org/10.1139/bcb-2021-0045.
[74] Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowitz S, Willson JK, et al. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 1990;50:7717-22.
[75] Korinek V, Barker N, Morin PJ, Van Wichen D, De Weger R, Kinzler KW, et al. Constitutive transcriptional activation by a β-catenin-tcf complex in APC-/- colon carcinoma. Science. 1997;275:1784-7. https://doi.org/10.1126/science.275.5307.1784.
[76] Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta-catenin-tcf signaling in colon cancer by mutations in beta-catenin or APC. Sci. 1997;275:1787-90. https://doi.org/10.1126/science.275.5307.1787.
[77] Parsons DW, Wang T-L, Samuels Y, Bardelli A, Cummins JM, DeLong L, et al. Colorectal cancer: mutations in a signalling pathway. Nature. 2005;436:792. https://doi.org/10.1038/436792a.
[78] Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 2000;14:2501-14. https://doi.org/10.1101/gad.836800.
[79] Kunac N, Filipović N, Kostić S, Vukojević K. The expression pattern of bcl-2 and bax in the tumor and stromal cells in colorectal carcinoma. Med (Kaunas Lith). 2022;58:1135. https://doi.org/10.3390/medicina58081135.
[80] Sträter J, Hinz U, Walczak H, Mechtersheimer G, Koretz K, Herfarth C, Möller P, Lehnert T. Expression of TRAIL and TRAIL receptors in colon carcinoma: TRAIL-R1 is an independent prognostic parameter. Clin Cancer Res Off J Am Assoc Cancer Res. 2002;8:3734-40.
[81] Zhao G, Guo J, Li D, Jia C, Yin W, Sun R, et al. MicroRNA-34a suppresses cell proliferation by targeting LMTK3 in human breast cancer mcf-7 cell line. DNA Cell Biol. 2013;32:699-707. https://doi.org/10.1089/dna.2013.2130.
[82] Asangani IA, Rasheed SAK, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27:2128-36. https://doi.org/10.1038/sj.onc.1210856.
[83] Zang S, Liu T, Shi J, Qiao L. Curcumin: a promising agent targeting cancer stem cells. Anti-Cancer Agents Med Chem. 2014;14:787-92. https://doi.org/10.2174/1871520614666140521114735.
[84] Moustapha A, Pérétout PA, Rainey NE, Sureau F, Geze M, Petit J-M, et al. Curcumin induces crosstalk between autophagy and apoptosis mediated by calcium release from the endoplasmic reticulum, lysosomal destabilization and mitochondrial events. Cell Death Discovery. 2015;1:15017. https://doi.org/10.1038/cddiscovery.2015.17.
[85] Weng W, Goel A. Curcumin and colorectal cancer: an update and current perspective on this natural medicine. Semin Cancer Biol. 2022;80:73-86. https://doi.org/10.1016/j.semcancer.2020.02.011.
[86] Khaket TP, Singh MP, Khan I, Kang SC. In vitro and in vivo studies on potentiation of curcumin-induced lysosomal-dependent apoptosis upon silencing of cathepsin C in colorectal cancer cells. Pharmacol Res. 2020;161:105156. https://doi.org/10.1016/j.phrs.2020.105156.
[87] Murtaza G, Karim S, Akram MR, Khan SA, Azhar S, Mumtaz A, Bin Asad MHH. Caffeic acid phenethyl ester and therapeutic potentials. Biomed Res Int. 2014;2014:145342. https://doi.org/10.1155/2014/145342.
[88] Yahya S, Sulaiman MK, Sudhandiran G. Caffeic acid phenethyl ester mediates apoptosis in serum-starved HT29 colon cancer cells through modulation of heat shock proteins and MAPK pathways. Cell Biochem Funct. 2024;42:e3942. https://doi.org/10.1002/cbf.3942.
[89] 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. Phytomed Int J Phytother Phytopharm. 2016;23:1680-90. https://doi.org/10.1016/j.phymed.2016.09.011.
[90] Liang S, Deng X, Lei L, Zheng Y, Ai J, Chen L, et al. The comparative study of the therapeutic effects and mechanism of baicalin, baicalein, and their combination on ulcerative colitis rat. Front Pharmacol. 2019;10:1466. https://doi.org/10.3389/fphar.2019.01466.
[91] Miao Y, Ishfaq M, Liu Y, Wu Z, Wang J, Li R, et al. Baicalin attenuates endometritis in a rabbit model induced by infection with Escherichia coli and Staphylococcus aureus via NF-κB and JNK signaling pathways. Domest Anim Endocrinol. 2021;74:106508. https://doi.org/10.1016/j.domaniend.2020.106508.
[92] Zeng A, Liang X, Zhu S, Liu C, Luo X, Zhang Q, et al. Baicalin, a potent inhibitor of NF-κB signaling pathway, enhances chemosensitivity of breast cancer cells to docetaxel and inhibits tumor growth and metastasis both in vitro and in vivo. Front Pharmacol. 2020;11:879. https://doi.org/10.3389/fphar.2020.00879.
[93] Song L, Zhu S, Liu C, Zhang Q, Liang X. Baicalin triggers apoptosis, inhibits migration, and enhances anti-tumor immunity in colorectal cancer via TLR4/NF-κB signaling pathway. J Food Biochem. 2022;46:e13703. https://doi.org/10.1111/jfbc.13703.
[94] Zhao P, Ning J, Huang J, Huang X. Mechanism of resveratrol on LPS/ATP-induced pyroptosis and inflammatory response in HT29 cells. Autoimmunity. 2024;57:2427094. https://doi.org/10.1080/08916934.2024.2427094.
[95] Liu M, Du Y, Gao D. Licochalcone a: a review of its pharmacology activities and molecular mechanisms. Front Pharmacol. 2024;15:1453426. https://doi.org/10.3389/fphar.2024.1453426.
[96] Liu X, Xing Y, Li M, Zhang Z, Wang J, Ri M, et al. Licochalcone A inhibits proliferation and promotes apoptosis of colon cancer cell by targeting programmed cell death-ligand 1 via the NF-κB and Ras/Raf/MEK pathways. J Ethnopharmacol. 2021;273:113989. https://doi.org/10.1016/j.jep.2021.113989.
[97] Fang C-Y, Wu C-C, Hsu H-Y, Chuang H-Y, Huang S-Y, Tsai C-H, et al. EGCG inhibits proliferation, invasiveness and tumor growth by up-regulation of adhesion molecules, suppression of gelatinases activity, and induction of apoptosis in nasopharyngeal carcinoma cells. Int J Mol Sci. 2015;16:2530-58. https://doi.org/10.3390/ijms16022530.
[98] Ding F, Yang S. Epigallocatechin-3-gallate inhibits proliferation and triggers apoptosis in colon cancer via the hedgehog/phosphoinositide 3-kinase pathways. Can J Physiol Pharmacol. 2021;99:910-20. https://doi.org/10.1139/cjpp-2020-0588.
[99] Zeng Y-H, Zhou L-Y, Chen Q-Z, Li Y, Shao Y, Ren W-Y, et al. Resveratrol inactivates PI3K/akt signaling through upregulating BMP7 in human colon cancer cells. Oncol Rep. 2017;38:456-64. https://doi.org/10.3892/or.2017.5662.
[100] Lu G, Wang X, Cheng M, Wang S, Ma K. The multifaceted mechanisms of ellagic acid in the treatment of tumors: state-of-the-art. Biomed Pharmacother Biomed Pharmacother. 2023;165:115132. https://doi.org/10.1016/j.biopha.2023.115132.
[101] Zhao J, Li G, Wei J, Dang S, Yu X, Ding L, et al. Ellagic acid induces cell cycle arrest and apoptosis via the TGF-β1/Smad3 signaling pathway in human colon cancer HCT-116 cells. Oncol Rep. 2020;44:768-76. https://doi.org/10.3892/or.2020.7617.