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

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 vitroresearch, 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.