The role of hydrogen sulfide in doxorubicin-induced drug resistance in hepatocellular carcinoma cells

Abstract

Doxorubicin is one of the most common chemical agents used in the treatment of cancers. Doxorubicin-treated cancer cells often develop drug resistance due to alterations in the trafficking and metabolism of the drug, which severely limits the drug’s effectiveness. This is seen at especially high rates in human hepatocellular carcinoma (HCC), the most common form of liver cancer. H2S is an important gasotransmitter and is involved in a variety of cellular functions and pathophysiologic processes. The role of H2S in drug resistance in cancer cells is still unclear. In this study, by using a human hepatocellular carcinoma cell line (HepG2), we found that NaHS (an H2S donor) was able to reduce cancer cell viability and colony formation in a doxorubicin dose dependent manner, while H2S alone did not show any effect. The expression of H2S-generating enzyme cystathionine gamma-lyase (CSE) but not cystathionine beta-synthase (CBS) was reduced by doxorubicin treatment. In addition, H2S promoted cellular retention of doxorubicin in HepG2 cells, possibly by suppressing the expression of ABCA1 and ABCG8, two drug efflux proteins. LXRα acts as a transcription factor for ABCA1 and ABCG8, however our findings showed that H2S had no effect on the protein expression and S-sulfhydration of LXRα, suggesting LXRα is not involved in H2S-regulated expressions of ABCA1 and ABCG8. In comparison with the parental cells, CSE expression was also reduced in doxorubicin-resistant cells. Exogenously applied NaHS reversed the drug resistance in doxorubicin-resistant cells. In conclusion, our study provides a novel solution for reversing drug resistance by targeting H2S signaling.