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Current Molecular Medicine

Author(s): Mohsen Hemmati-Dinarvand, Hossein Mokhtari, Iraj Alipourfard, Elham Beyrami Aghbash, Shahnaz Kheirandish, Ali Khodadadian and Atefeh Seghatoleslam*

DOI: 10.2174/1566524023666220820154623

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Cancer Drug Resistance Reduction via Co-treatment with Oxaliplatin and Nitazoxanide: Targeting the ABC Transporters

Page: [834 - 841] Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Objects: Shortly after cancer is diagnosed, a phenomenon develops in cancer cells called multidrug resistance (MDR), in which cell sensitivity against anti-cancer drugs is significantly reduced. The present investigation aimed to assess the effects of nitazoxanide (NTZ), a safe drug, on LS174T/OXP-resistant cells.

Methods: In the current in vitro research, the effects of NTZ and oxaliplatin (OXP) on the viability of LS174T and LS174T/OXP cell lines were evaluated through MTT assay. Then, the changes in expression levels of MDR1, MRP1, BCRP, and LRP genes and proteins were measured by RT-qPCR and western blotting methods, respectively. Lastly, the apoptosis status was assessed by annexin V–FITC/PI staining flow cytometry assay.

Results: The IC50 values for cells resistant or sensitive to OXP were revealed (11567 nM vs. 1745 nM; p <0.05 for 24 h incubation, and 5161 nM vs. 882.2 nM; p <0.05 for 48 h incubation). Moreover, NTZ plus OXP led to a leftward shift in the cytotoxicity curve (2004 nM; p = 0.007). This co-treatment significantly decreased the expression of all genes and proteins (p <0.05). Finally, the combination of NTZ and OXP induced a significant increase in apoptosis (p <0.001).

Conclusion: The data showed that NTZ treatment could increase the sensitivity of LS174T/OXP cell line to the OXP cytotoxic effects. Thus, NTZ may be efficient in reducing drug resistance in clinics by means of the negative regulation of ATP-binding cassette (ABC) transporters. However, further studies are necessary to explain the exact mechanisms of NTZ.

Keywords: Colorectal cancer, multidrug resistance, oxaliplatin, nitazoxanide, ABC transporters, ATP-binding cassette.

[1]
Zielińska A, Włodarczyk M, Makaro A, Sałaga M, Fichna J. Management of pain in colorectal cancer patients. Crit Rev Oncol Hematol 2021; 157: 103122.
[http://dx.doi.org/10.1016/j.critrevonc.2020.103122] [PMID: 33171427]
[2]
Zhai Z, Yu X, Yang B, et al. Colorectal cancer heterogeneity and targeted therapy: Clinical implications, challenges and solutions for treatment resistance. Semin Cell Dev Biol 2017; 64: 107-15.
[http://dx.doi.org/10.1016/j.semcdb.2016.08.033] [PMID: 27578007]
[3]
Ceballos MP, Rigalli JP, Ceré LI, Semeniuk M, Catania VA, Ruiz ML. ABC transporters: Regulation and association with multidrug resistance in hepatocellular carcinoma and colorectal carcinoma. Curr Med Chem 2019; 26(7): 1224-50.
[http://dx.doi.org/10.2174/0929867325666180105103637] [PMID: 29303075]
[4]
Gao Q, Li XX, Xu YM, et al. IRE1α-targeting downregulates ABC transporters and overcomes drug resistance of colon cancer cells. Cancer Lett 2020; 476: 67-74.
[http://dx.doi.org/10.1016/j.canlet.2020.02.007] [PMID: 32061752]
[5]
Hsu HH, Chen MC, Baskaran R, et al. Oxaliplatin resistance in colorectal cancer cells is mediated via activation of ABCG2 to alleviate ER stress induced apoptosis. J Cell Physiol 2018; 233(7): 5458-67.
[http://dx.doi.org/10.1002/jcp.26406] [PMID: 29247488]
[6]
Lin H, Yang G, Yu J, et al. KDM5c inhibits multidrug resistance of colon cancer cell line by down-regulating ABCC1. Biomed Pharmacother 2018; 107: 1205-9.
[http://dx.doi.org/10.1016/j.biopha.2018.08.041] [PMID: 30257334]
[7]
De Vera AA, Gupta P, Lei Z, et al. Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1) mediated multidrug resistance (MDR) in cancer: In vitro and in vivo. Cancer Lett 2019; 442: 91-103.
[http://dx.doi.org/10.1016/j.canlet.2018.10.020] [PMID: 30391357]
[8]
Xiao H, Zheng Y, Ma L, Tian L, Sun Q. Clinically relevant ABC transporter for anti-cancer drug resistance. Front Pharmacol 2021; 12: 648407.
[http://dx.doi.org/10.3389/fphar.2021.648407] [PMID: 33953682]
[9]
Kitazono M, Sumizawa T, Takebayashi Y, et al. Multidrug resistance and the lung resistance-related protein in human colon carcinoma SW-620 cells. J Natl Cancer Inst 1999; 91(19): 1647-53.
[http://dx.doi.org/10.1093/jnci/91.19.1647] [PMID: 10511592]
[10]
Hsu HH, Kuo WW, Shih HN, et al. FOXC1 regulation of miR-31-5p confers oxaliplatin resistance by targeting LATS2 in colorectal cancer. Cancers 2019; 11(10): 1576.
[http://dx.doi.org/10.3390/cancers11101576] [PMID: 31623173]
[11]
Pirpour Tazehkand A, Akbarzadeh M, Velaie K, Sadeghi MR, Samadi N. The role of Her2-NRF2 axis in induction of oxaliplatin resistance in colon cancer cells. Biomed Pharmacother 2018; 103: 755-66.
[http://dx.doi.org/10.1016/j.biopha.2018.04.105] [PMID: 29684854]
[12]
Rossignol JF. Nitazoxanide: A first in class broad spectrum antiviral agent. Antiviral Res 2014; 110: 94-103.
[http://dx.doi.org/10.1016/j.antiviral.2014.07.014] [PMID: 25108173]
[13]
Yu J, Yang K, Zheng J, Zhao W, Sun X. Synergistic tumor inhibition of colon cancer cells by nitazoxanide and obeticholic acid, a farnesoid X receptor ligand. Cancer Gene Ther 2021; 28(6): 590-601.
[http://dx.doi.org/10.1038/s41417-020-00239-8] [PMID: 33046820]
[14]
Behrouj H, Seghatoleslam A, Mokarram P, Ghavami S. Effect of casein kinase 1α inhibition on autophagy flux and the AKT/phospho-β-catenin (S552) axis in HCT116, a RAS-mutated colorectal cancer cell line. Can J Physiol Pharmacol 2021; 99(3): 284-93.
[http://dx.doi.org/10.1139/cjpp-2020-0449] [PMID: 33635146]
[15]
Rio DC, Ares M Jr, Hannon GJ, Nilsen TW. Purification of RNA using trizol (TRI reagent). Cold Spring Harb Protoc 2010; 2010(6): prot5439.
[http://dx.doi.org/10.1101/pdb.prot5439] [PMID: 20516177]
[16]
Hirano S. Western blot analysis. Methods Mol Biol 2012; 926: 87-97.
[http://dx.doi.org/10.1007/978-1-62703-002-1_6] [PMID: 22975958]
[17]
Shafiei-Irannejad V, Samadi N, Yousefi B, Salehi R, Velaei K, Zarghami N. Metformin enhances doxorubicin sensitivity via inhibition of doxorubicin efflux in P-gp-overexpressing MCF-7 cells. Chem Biol Drug Des 2018; 91(1): 269-76.
[http://dx.doi.org/10.1111/cbdd.13078] [PMID: 28782285]
[18]
Madigan JP, Robey RW, Poprawski JE, et al. A role for ceramide glycosylation in resistance to oxaliplatin in colorectal cancer. Exp Cell Res 2020; 388(2): 111860.
[http://dx.doi.org/10.1016/j.yexcr.2020.111860] [PMID: 31972222]
[19]
Hemmati-Dinarvand M, Ahmadvand H, Seghatoleslam A. Nitazoxanide and cancer drug resistance: Targeting Wnt/β-catenin signaling pathway. Arch Med Res 2021; 53(3): 263-70.
[PMID: 34937659]
[20]
Kozovska Z, Gabrisova V, Kucerova L. Colon cancer: Cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother 2014; 68(8): 911-6.
[http://dx.doi.org/10.1016/j.biopha.2014.10.019] [PMID: 25458789]
[21]
Shen DY, Zhang W, Zeng X, Liu CQ. Inhibition of Wnt/β-catenin signaling downregulates P-glycoprotein and reverses multi drug resistance of cholangiocarcinoma. Cancer Sci 2013; 104(10): 1303-8.
[http://dx.doi.org/10.1111/cas.12223] [PMID: 23822562]
[22]
Müller J, Sidler D, Nachbur U, Wastling J, Brunner T, Hemphill A. Thiazolides inhibit growth and induce glutathione S transferase Pi (GSTP1) dependent cell death in human colon cancer cells. Int J Cancer 2008; 123(8): 1797-806.
[http://dx.doi.org/10.1002/ijc.23755] [PMID: 18688861]
[23]
Wang X, Shen C, Liu Z, et al. Nitazoxanide, an antiprotozoal drug, inhibits late-stage autophagy and promotes ING1-induced cell cycle arrest in glioblastoma. Cell Death Dis 2018; 9(10): 1032.
[http://dx.doi.org/10.1038/s41419-018-1058-z] [PMID: 30302016]
[24]
Ripani P, Delp J, Bode K, et al. Thiazolides promote G1 cell cycle arrest in colorectal cancer cells by targeting the mitochondrial respiratory chain. Oncogene 2020; 39(11): 2345-57.
[http://dx.doi.org/10.1038/s41388-019-1142-6] [PMID: 31844249]
[25]
Hong SK, Kim HJ, Song CS, Choi IS, Lee JB, Park SY. Nitazoxanide suppresses IL-6 production in LPS stimulated mouse macrophages and TG injected mice. Int Immunopharmacol 2012; 13(1): 23-7.
[http://dx.doi.org/10.1016/j.intimp.2012.03.002] [PMID: 22430099]
[26]
Fan MH, Bodapati S, Solow CD, et al. A c-Myc activation sensor based high throughput drug screening identifies an antineoplastic effect of nitazoxanide. Mol Cancer Ther 2013; 12(9): 1896-905.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-1243] [PMID: 23825064]
[27]
Qu Y, Olsen JR, Yuan X, et al. Small molecule promotes β-catenin citrullination and inhibits Wnt signaling in cancer. Nat Chem Biol 2018; 14(1): 94-101.
[http://dx.doi.org/10.1038/nchembio.2510] [PMID: 29083417]
[28]
Chikazawa N, Tanaka H, Tasaka T, et al. Inhibition of Wnt signaling pathway decreases chemotherapy resistant side population colon cancer cells. Anticancer Res 2010; 30(6): 2041-8.
[PMID: 20651349]
[29]
Stadler SC, Vincent CT, Fedorov VD, et al. Dysregulation of PAD4-mediated citrullination of nuclear GSK3β activates TGF-β signaling and induces epithelial-to-mesenchymal transition in breast cancer cells. Proc Natl Acad Sci USA 2013; 110(29): 11851-6.
[http://dx.doi.org/10.1073/pnas.1308362110] [PMID: 23818587]
[30]
Deplus R, Denis H, Putmans P, et al. Citrullination of DNMT3A by PADI4 regulates its stability and controls DNA methylation. Nucleic Acids Res 2014; 42(13): 8285-96.
[http://dx.doi.org/10.1093/nar/gku522] [PMID: 24957603]
[31]
Li F, Miao L, Xue T, et al. Inhibiting PAD2 enhances the anti-tumor effect of docetaxel in tamoxifen resistant breast cancer cells. J Exp Clin Cancer Res 2019; 38(1): 414.
[http://dx.doi.org/10.1186/s13046-019-1404-8] [PMID: 31601253]
[32]
Qin H, Liu X, Li F, et al. PAD1 promotes epithelial mesenchymal transition and metastasis in triple-negative breast cancer cells by regulating MEK1-ERK1/2-MMP2 signaling. Cancer Lett 2017; 409: 30-41.
[http://dx.doi.org/10.1016/j.canlet.2017.08.019] [PMID: 28844713]