https://doi.org/10.4081/ejh.2023.3719
Quercetin reverses 5-fluorouracil resistance in colon cancer cells by modulating the NRF2/HO-1 pathway
Submitted: 21 March 2023
Accepted: 28 June 2023
Published: 7 August 2023
Accepted: 28 June 2023
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Quercetin (Que) has been proven to enhance the chemosensitivity of multiple cancers, including colon cancer (CC). However, whether the combination of Que and 5-fluorouracil (5-FU) has a synergistic effect on drug-resistant CC cells has not previously been reported. The effect of Que (5 and 10 μg/mL) on cell vitality and apoptosis of CC and CC drug-resistant cells was examined using a cell counting kit-8 (CCK-8) and flow cytometry. After cells were treated with 5-FU (10, 40 μg/mL), Que (10 μM, 40 μM), or 5-FU in combination with Que, cell proliferation, apoptosis, oxidative stress-related factors, reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway-related factors were examined by colony formation assay, flow cytometry, ELISA, ROS kit, immunofluorescence assay, and Western blot. The results showed that 5-FU reduced cell viability and induced apoptosis of CC as well as 5-FU-resistant CC cells. Que further restrained the proliferation, oxidative stress-related factors (SOD, CAT, GPx, and GR), ROS production, and induced apoptosis in CC cells and 5-FU-resistant CC cells induced by 5-FU. Moreover, the combination of Que and 5-FU attenuated the Nrf2/HO-1 pathway-related marker levels in CC cells and 5-FU-resistant CC cells. Therefore, our results suggest that Que reverses 5-FU resistance in CC cells via modulating the Nrf2/HO-1 pathway.
Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017;66:683-91.
DOI: https://doi.org/10.1136/gutjnl-2015-310912
Endo H, Hosono K, Fujisawa T, Takahashi H, Sugiyama M, Yoneda K, et al. Involvement of JNK pathway in the promotion of the early stage of colorectal carcinogenesis under high-fat dietary conditions. Gut 2009;58:1637-43.
DOI: https://doi.org/10.1136/gut.2009.183624
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin 2014;64:104-17.
DOI: https://doi.org/10.3322/caac.21220
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374-403.
DOI: https://doi.org/10.1016/j.ejca.2012.12.027
Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, et al. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 2002;20:1996-2004.
DOI: https://doi.org/10.1200/JCO.2002.08.105
Manoochehri M, Karbasi A, Bandehpour M, Kazemi B. Down-regulation of BAX gene during carcinogenesis and acquisition of resistance to 5-FU in colorectal cancer. Pathol Oncol Res 2014;20:301-7.
DOI: https://doi.org/10.1007/s12253-013-9695-0
Sultana B, Anwar F. Flavonols (kaempeferol, quercetin, myricetin) contents of selected fruits, vegetables and medicinal plants. Food Chem 2008;108:879-84.
DOI: https://doi.org/10.1016/j.foodchem.2007.11.053
Baran I, Ganea C, Scordino A, Musumeci F, Barresi V, Tudisco S, et al. Effects of menadione, hydrogen peroxide, and quercetin on apoptosis and delayed luminescence of human leukemia Jurkat T-cells. Cell Biochem Biophys 2010;58:169-79.
DOI: https://doi.org/10.1007/s12013-010-9104-1
Russo M, Spagnuolo C, Tedesco I, Bilotto S, Russo GL. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem Pharmacol 2012;83:6-15.
DOI: https://doi.org/10.1016/j.bcp.2011.08.010
Tang SM, Deng XT, Zhou J, Li QP, Ge XX, Miao L. Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects. Biomed Pharmacother 2020;121:109604.
DOI: https://doi.org/10.1016/j.biopha.2019.109604
Boersma HH, Woerdenbag HJ, Bauer J, Scheithauer W, Kampinga HH, Konings AW. Interaction between the cytostatic effects of quercetin and 5-fluorouracil in two human colorectal cancer cell lines. Phytomedicine 1994;239-44.
DOI: https://doi.org/10.1016/S0944-7113(11)80071-1
Kim HS, Wannatung T, Lee S, Yang WK, Chung SH, Lim JS, et al. Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer. Apoptosis 2012;17:938-49.
DOI: https://doi.org/10.1007/s10495-012-0719-0
Dihal AA, Woutersen RA, van Ommen B, Rietjens IM, Stierum RH. Modulatory effects of quercetin on proliferation and differentiation of the human colorectal cell line Caco-2. Cancer Lett 2006;238:248-59.
DOI: https://doi.org/10.1016/j.canlet.2005.07.007
Zhang H, Zhang M, Yu L, Zhao Y, He N, Yang X. Antitumor activities of quercetin and quercetin-5',8-disulfonate in human colon and breast cancer cell lines. Food Chem Toxicol 2012;50:1589-99.
DOI: https://doi.org/10.1016/j.fct.2012.01.025
Shan BE, Wang MX, Li RQ. Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/beta-catenin signaling pathway. Cancer Invest 2009;27:604-12.
DOI: https://doi.org/10.1080/07357900802337191
Zhou Y, Zhang J, Wang K, Han W, Wang X, Gao M, 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.
DOI: https://doi.org/10.1016/j.ejphar.2020.173185
Rani Inala MS, Pamidimukkala K. Amalgamation of quercetin with anastrozole and capecitabine: A novel combination to treat breast and colon cancers - an in vitro study. J Cancer Res Ther 2023;19:S93-S105.
DOI: https://doi.org/10.4103/jcrt.JCRT_599_20
Li T, Li Y. Quercetin acts as a novel anti-cancer drug to suppress cancer aggressiveness and cisplatin-resistance in nasopharyngeal carcinoma (NPC) through regulating the yes-associated protein/Hippo signaling pathway. Immunobiology 2023;228:152324.
DOI: https://doi.org/10.1016/j.imbio.2022.152324
Chen C, Zhou J, Ji C. Quercetin: a potential drug to reverse multidrug resistance. Life Sci 2010;87:333-8.
DOI: https://doi.org/10.1016/j.lfs.2010.07.004
Riahi-Chebbi I, Souid S, Othman H, Haoues M, Karoui H, Morel A, et al. The phenolic compound Kaempferol overcomes 5-fluorouracil resistance in human resistant LS174 colon cancer cells. Sci Rep 2019;9:195.
DOI: https://doi.org/10.1038/s41598-018-36808-z
Saini A, Norman AR, Cunningham D, Chau I, Hill M, Tait D, et al. Twelve weeks of protracted venous infusion of fluorouracil (5-FU) is as effective as 6 months of bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer. Br J Cancer 2003;88:1859-65.
DOI: https://doi.org/10.1038/sj.bjc.6600995
Lan CY, Chen SY, Kuo CW, Lu CC, Yen GC. Quercetin facilitates cell death and chemosensitivity through RAGE/PI3K/AKT/mTOR axis in human pancreatic cancer cells. J Food Drug Anal 2019;27:887-96.
DOI: https://doi.org/10.1016/j.jfda.2019.07.001
Wang H, Tao L, Qi K, Zhang H, Feng D, Wei W, et al. Quercetin reverses tamoxifen resistance in breast cancer cells. J BUON 2015;20:707-13.
Shu Y, Xie B, Liang Z, Chen J. Quercetin reverses the doxorubicin resistance of prostate cancer cells by downregulating the expression of c-met. Oncol Lett 2018;15:2252-8.
DOI: https://doi.org/10.3892/ol.2017.7561
Terana GT, Abd-Alhaseeb MM, Omran GA, Okda TM. Quercetin potentiates 5-fluorouracil effects in human colon cancer cells through targeting the Wnt/β-catenin signalling pathway: the role of miR-27a. Contemp Oncol (Pozn) 2022;26:229-38.
DOI: https://doi.org/10.5114/wo.2022.120361
Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy: a brief review. Cardiovasc Toxicol 2001;1:181-93.
DOI: https://doi.org/10.1385/CT:1:3:181
Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 1991;51:794-8.
Pan H, Kim E, Rankin GO, Rojanasakul Y, Tu Y, Chen YC. Theaflavin-3,3'-digallate enhances the inhibitory effect of cisplatin by regulating the copper transporter 1 and glutathione in human ovarian cancer cells. Int J Mol Sci 2018;19:1-12.
DOI: https://doi.org/10.3390/ijms19010117
Godwin AK, Meister A, O'Dwyer PJ, Huang CS, Hamilton TC, Anderson ME. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci USA 1992;89:3070-4.
DOI: https://doi.org/10.1073/pnas.89.7.3070
Bansal A, Simon MC. Glutathione metabolism in cancer progression and treatment resistance. J Cell Biol 2018;217:2291-8.
DOI: https://doi.org/10.1083/jcb.201804161
Cho HY, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal 2006;8:76-87.
DOI: https://doi.org/10.1089/ars.2006.8.76
Syu JP, Chi JT, Kung HN. Nrf2 is the key to chemotherapy resistance in MCF7 breast cancer cells under hypoxia. Oncotarget 2016;7:14659-72.
DOI: https://doi.org/10.18632/oncotarget.7406
Shibata T, Kokubu A, Saito S, Narisawa-Saito M, Sasaki H, Aoyagi K, et al. NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer. Neoplasia 2011;13:864-73.
DOI: https://doi.org/10.1593/neo.11750
Zhang M, Zhang C, Zhang L, Yang Q, Zhou S, Wen Q, et al. Nrf2 is a potential prognostic marker and promotes proliferation and invasion in human hepatocellular carcinoma. BMC Cancer 2015;15:531.
DOI: https://doi.org/10.1186/s12885-015-1541-1
Joung EJ, Li MH, Lee HG, Somparn N, Jung YS, Na HK, et al. Capsaicin induces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potential target. Antioxid Redox Signal 2007;9:2087-98.
DOI: https://doi.org/10.1089/ars.2007.1827
Shen G, Kong AN. Nrf2 plays an important role in coordinated regulation of Phase II drug metabolism enzymes and Phase III drug transporters. Biopharm Drug Dispos 2009;30:345-55.
DOI: https://doi.org/10.1002/bdd.680
Abbasi A, Mostafavi-Pour Z, Amiri A, Keshavarzi F, Nejabat N, Ramezani F, et al. Chemoprevention of prostate cancer cells by vitamin C plus quercetin: role of Nrf2 in inducing oxidative stress. Nutr Cancer 2021;73:2003-13.
DOI: https://doi.org/10.1080/01635581.2020.1819346
Darband SG, Sadighparvar S, Yousefi B, Kaviani M, Ghaderi-Pakdel F, Mihanfar A, et al. Quercetin attenuated oxidative DNA damage through NRF2 signaling pathway in rats with DMH induced colon carcinogenesis. Life Sci 2020;253:117584.
DOI: https://doi.org/10.1016/j.lfs.2020.117584
How to Cite
Tang, Z., Wang, L., Chen, Y., Zheng, X., Wang, R., Liu, B., Zhang, S., & Wang, H. (2023). Quercetin reverses 5-fluorouracil resistance in colon cancer cells by modulating the NRF2/HO-1 pathway. European Journal of Histochemistry, 67(3). https://doi.org/10.4081/ejh.2023.3719
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