Curcumin resistance induced by hypoxia in HepG2 cells is mediated by multidrug-resistance-associated proteins

Abstract

Background: Tumor hypoxia, a common pathophysiological feature of solid tumors, contributes to drug resistance and treatment failure. Here, we demonstrate that hypoxia in HepG2 cells induces resistance towards cytotoxicity of curcumin, a promising anticancer agent. Materials and Methods: The number of surviving cells after exposure to chemotherapeutic drugs under normoxia (ambient O 2 ) and hypoxia (1% O 2 ) was determined by crystal violet staining. The expression levels of drug transporter genes were analyzed by quantitative real-time reverse transcription-polymerase chain reaction. Results: Increased resistance to curcumin, as well as to etoposide and doxorubicin, was observed in HepG2 cells under hypoxia. Gene expression analysis revealed that hypoxia increased the expression of ATP-binding cassette (ABC) drug transporter genes, sub-family C including ABCC1, ABCC2, and ABCC3, by more than two-fold. While expression of ABC drug transporter genes sub-family B member 1 and sub-family G member 2 (ABCB2/P-gp and ABCG2, respectively) did not change significantly. Both inhibitors of ABCC1/ABCC2 and depletion of intracellular glutathione levels were able to reverse hypoxia-induced curcumin resistance. Conclusion: ABCC1 and ABCC2 play an important role in hypoxia-induced curcumin resistance in human hepatocellular carcinoma.