Nrf2 is a key factor in the reversal effect of curcumin on multidrug resistance in the HCT‑8/5‑Fu human colorectal cancer cell line

Zhang,Chao; He,Lian‑Jun; Ye,Hai‑Zhu; Liu,Ding‑Feng; Zhu,Yi‑Bao; Miao,Dong‑Dong; Zhang,Sheng‑Peng; Chen,Yun‑Yu; Jia,Yuan‑Wei; Shen,Jie; Liu,Xiao‑Ping

doi:10.3892/mmr.2018.9589

Nrf2 is a key factor in the reversal effect of curcumin on multidrug resistance in the HCT‑8/5‑Fu human colorectal cancer cell line

Authors:
- Chao Zhang
- Lian‑Jun He
- Hai‑Zhu Ye
- Ding‑Feng Liu
- Yi‑Bao Zhu
- Dong‑Dong Miao
- Sheng‑Peng Zhang
- Yun‑Yu Chen
- Yuan‑Wei Jia
- Jie Shen
- Xiao‑Ping Liu
View Affiliations

Affiliations: Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui 241000, P.R. China, School of Clinical Medicine, Wannan Medical College, Wuhu, Anhui 241000, P.R. China, School of Pharmacy, Wannan Medical College, Wuhu, Anhui 241000, P.R. China
Published online on: October 24, 2018 https://doi.org/10.3892/mmr.2018.9589
Pages: 5409-5416
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Multidrug resistance (MDR) is a major concern when using chemotherapy for the treatment of patients with colorectal cancer. MDR modulators are agents that can reverse MDR and, thus, enhance the chemosensitivity of tumor cells. The development of MDR modulators can improve the therapeutic efficacies of MDR in cancer. However, few effective MDR modulators have been identified so far. Curcumin has been reported to be an effective compound in the reversal of MDR in colorectal cancer cells. However, the mechanisms associated with the reversal effect of curcumin on MDR and its regulation of target factors in MDR cells remain to be fully elucidated. 3‑(4,5‑dimethyl‑2‑thiazol)‑2,5‑diphenyltetrazolium bromide assays, flow cytometer apoptosis assays as well as mRNA and protein expression assays were performed in the present study, and the results confirmed the reversal effect of curcumin on HCT‑8/5‑Fu cells and provided evidence that activated nuclear factor erythroid 2‑related factor (Nrf2) deficiency induced by the curcumin altered the B‑cell lymphoma 2 (Bcl‑2) associated X protein/Bcl‑2 expression ratio, which led to the induction of apoptosis in HCT‑8/5‑Fu cells. These results indicated that Nrf2 may have a functional in the reversal effect of curcumin and contribute, at least in part, to the outcomes of chemotherapy in patients with MDR.

View Figures

View References

1	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
2	Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B and Starling N: Colorectal cancer. Lancet. 375:1030–1047. 2010. View Article : Google Scholar : PubMed/NCBI
3	Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G II, Samuel S, Kim MP, Lim SJ and Ellis LM: Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 69:1951–1957. 2009. View Article : Google Scholar : PubMed/NCBI
4	Kim JH, Chung JB, Park IS, Kim BS, Yoo NC, Choi JH, Roh JK, Kim HS, Kwon OH, Lee KS, et al: Combined use of tamoxifen, cyclosporin A, and verapamil for modulating multidrug resistance in human hepatocellular carcinoma cell lines. Yonsei Med J. 34:35–44. 1993. View Article : Google Scholar : PubMed/NCBI
5	Thomas H and Coley HM: Overcoming multidrug resistance in cancer: An update on the clinical strategy of inhibiting p-glycoprotein. Cancer Contr. 10:159–165. 2003. View Article : Google Scholar
6	Ferry DR, Traunecker H and Kerr DJ: Clinical trials of P-glycoprotein reversal in solid tumours. Eur J Cancer. 32A:1070–1081. 1996. View Article : Google Scholar : PubMed/NCBI
7	Lin SS, Lai KC, Hsu SC, Yang JS, Kuo CL, Lin JP, Ma YS, Wu CC and Chung JG: Curcumin inhibits the migration and invasion of human A549 lung cancer cells through the inhibition of matrix metalloproteinase-2 and −9 and Vascular Endothelial Growth Factor (VEGF). Cancer Lett. 285:127–133. 2009. View Article : Google Scholar : PubMed/NCBI
8	Limtrakul P: Curcumin as chemosensitizer. Adv Exp Med Biol. 595:269–300. 2007. View Article : Google Scholar : PubMed/NCBI
9	Sharma RA, Gescher AJ and Steward WP: Curcumin: The story so far. Eur J Cancer. 41:1955–1968. 2005. View Article : Google Scholar : PubMed/NCBI
10	Anand P, Thomas SG, Kunnumakkara AB, Sundaram C, Harikumar KB, Sung B, Tharakan ST, Misra K, Priyadarsini IK, Rajasekharan KN, et al: Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol. 76:1590–1611. 2008. View Article : Google Scholar : PubMed/NCBI
11	Guzzarlamudi S, Singh PK, Pawar VK, Singh Y, Sharma K, Paliwal SK, Chourasia MK, Ramana MV and Chaurasia M: Synergistic Chemotherapeutic Activity of Curcumin Bearing Methoxypolyethylene Glycol-g-Linoleic Acid Based Micelles on Breast Cancer Cells. J Nanosci Nanotechnol. 16:4180–4190. 2016. View Article : Google Scholar : PubMed/NCBI
12	Colacino JA, McDermott SP, Sartor MA, Wicha MS and Rozek LS: Transcriptomic profiling of curcumin-treated human breast stem cells identifies a role for stearoyl-coa desaturase in breast cancer prevention. Breast Cancer Res Treat. 158:29–41. 2016. View Article : Google Scholar : PubMed/NCBI
13	Muddineti OS, Kumari P, Ajjarapu S, Lakhani PM, Bahl R, Ghosh B and Biswas S: Xanthan gum stabilized PEGylated gold nanoparticles for improved delivery of curcumin in cancer. Nanotechnology. 27:3251012016. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
15	Gottesman MM, Fojo T and Bates SE: Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer. 2:48–58. 2002. View Article : Google Scholar : PubMed/NCBI
16	Fernald K and Kurokawa M: Evading apoptosis in cancer. Trends Cell Biol. 23:620–633. 2013. View Article : Google Scholar : PubMed/NCBI
17	Chapman RS, Whetton AD, Chresta CM and Dive C: Characterization of drug resistance mediated via the suppression of apoptosis by Abelson protein tyrosine kinase. Mol Pharmacol. 48:334–343. 1995.PubMed/NCBI
18	Chapman RS, Whetton AD and Dive C: The suppression of drug-induced apoptosis by activation of v-ABL protein tyrosine kinase. Cancer Res. 54:5131–5137. 1994.PubMed/NCBI
19	Niture SK and Jaiswal AK: Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem. 287:9873–9886. 2012. View Article : Google Scholar : PubMed/NCBI
20	Chen Q and Li W, Wan Y, Xia X, Wu Q, Chen Y, Lai Z, Yu C and Li W: Amplified in breast cancer 1 enhances human cholangiocarcinoma growth and chemoresistance by simultaneous activation of Akt and Nrf2 pathways. Hepatology. 55:1820–1829. 2012. View Article : Google Scholar : PubMed/NCBI
21	Yin XM, Oltvai ZN and Korsmeyer SJ: BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature. 369:321–323. 1994. View Article : Google Scholar : PubMed/NCBI
22	Niture SK and Jaiswal AK: Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med. 57:119–131. 2013. View Article : Google Scholar : PubMed/NCBI
23	Zhang C, Wang HJ, Bao QC, Wang L, Guo TK, Chen WL, Xu LL, Zhou HS, Bian JL, Yang YR, et al: NRF2 promotes breast cancer cell proliferation and metastasis by increasing RhoA/ROCK pathway signal transduction. Oncotarget. 7:73593–73606. 2016.PubMed/NCBI
24	Stein A, Atanackovic D and Bokemeyer C: Current standards and new trends in the primary treatment of colorectal cancer. Eur J Cancer. 47 Suppl 3:S312–S314. 2011. View Article : Google Scholar : PubMed/NCBI
25	Robert J and Jarry C: Multidrug resistance reversal agents. J Med Chem. 46:4805–4817. 2003. View Article : Google Scholar : PubMed/NCBI
26	Wang J, Wang F, Li F, Zhang W, Shen Y, Zhou D and Guo S: A multifunctional poly(curcumin) nanomedicine for dual-modal targeted delivery, intracellular responsive release, dual-drug treatment and imaging of multidrug resistant cancer cells. J Mater Chem B Mater Biol Med. 4:2954–2962. 2016. View Article : Google Scholar : PubMed/NCBI
27	Baldwin PR, Reeves AZ, Powell KR, Napier RJ, Swimm AI, Sun A, Giesler K, Bommarius B, Shinnick TM, Snyder JP, et al: Monocarbonyl analogs of curcumin inhibit growth of antibiotic sensitive and resistant strains of Mycobacterium tuberculosis. Eur J Med Chem. 92:693–699. 2015. View Article : Google Scholar : PubMed/NCBI
28	Negi N, Prakash P, Gupta ML and Mohapatra TM: Possible Role of Curcumin as an Efflux Pump Inhibitor in Multi Drug Resistant Clinical Isolates of Pseudomonas aeruginosa. J Clin Diagn Res. 8:DC04–DC07. 2014.PubMed/NCBI
29	Fan YX, Abulimiti P, Zhang HL, Zhou YK and Zhu L: Mechanism of reversal of multidrug resistance by curcumin in human colorectal cancer cell line HCT-8/5-FU. Genet Mol Res. 16:162017. View Article : Google Scholar
30	Seo BR, Min KJ, Cho IJ, Kim SC and Kwon TK: Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability. PLoS One. 9:e955882014. View Article : Google Scholar : PubMed/NCBI
31	Sun Y, Zhang J, Zhou J, Huang Z, Hu H, Qiao M, Zhao X and Chen D: Synergistic effect of cucurbitacin B in combination with curcumin via enhancing apoptosis induction and reversing multidrug resistance in human hepatoma cells. Eur J Pharmacol. 768:28–40. 2015. View Article : Google Scholar : PubMed/NCBI
32	Moghadamtousi SZ, Kadir HA, Hassandarvish P, Tajik H, Abubakar S and Zandi K: A review on antibacterial, antiviral, and antifungal activity of curcumin. Biomed Res Int. 2014:1868642014.PubMed/NCBI
33	Patel BB and Majumdar AP: Synergistic role of curcumin with current therapeutics in colorectal cancer: Minireview. Nutr Cancer. 61:842–846. 2009. View Article : Google Scholar : PubMed/NCBI