Nitazoxanide and Cancer Drug Resistance: Targeting Wnt/ß-catenin Signaling Pathway.

ABSTRACT

OBJECTIVES: One of the most important complications that lead to unsuccessful treatment of cancer is resistance against chemotherapy agents, so called multidrug resistance (MDR). Thus, identification of the novel medications with low side effects and high efficacy to reverse MDR is highly required. Accordingly, the current study was performed to investigate the molecular mechanism of MDR in LS174T and LS174T/Oxaliplatin (OXP) cell lines during treatment with Nitazoxanide (NTZ) in combination with OXP. MATERIALS AND METHODS: In the present in vitro study, we evaluated the effects of NTZ on the cytotoxicity of OXP using Thiazolyl Blue Tetrazolium Blue (MTT) assay in LS174T and LS174T/OXP cell lines when treated with OXP and NTZ, alone or in combination, for 24 and 48 h incubation. Then, we assessed the changes in the expression level of CTNNB1, ABCB1, c-Myc, and cyclin D1 genes in different treated groups. RESULTS: Exposure of LS174T/OXP cells to NTZ led to the elevation of cell sensitivity to OXP and induced caspase-3/7 activity, which results in apoptosis. Furthermore, NTZ downregulated Wnt/ß-catenin signaling pathway through significant decrease of CTNNB1, c-Myc, ABCB1, and cyclin D1 genes and resulted in drug resistance reversal and inhibition of cell proliferation. CONCLUSION: These results indicate that Wnt/ß-catenin pathway is important in developing cancer and MDR. In this regard, NTZ could reverse MDR in colorectal cancer (CRC) cells by downregulation of Wnt/ß-catenin signaling pathway, suggesting that NTZ should be more considered in future studies as a potent adjuvant in CRC chemotherapy.