Involvement of the PI3K/Akt/Nrf2 Signaling Pathway in Resveratrol-Mediated Reversal of Drug Resistance in HL-60/ADR Cells

Abstract

Resistance to chemotherapy drugs, such as adriamycin (ADR), is a common problem in acute myeloid leukemia (AML) patients. We hypothesized that the natural compound resveratrol (Res) may reverse AML drug resistance through the PI3K/Akt/Nrf2 pathway. We investigated the in vitro effect of Res using human promyelocytic leukemia cells (HL-60) and the ADR-resistant cell line (HL-60/ADR) and treated with either Res or ADR + Res. Cellular proliferation inhibition rate, auto-fluorescence intensity of ADR in HL-60/ADR cells and HL-60 cells, mRNA expression of Nrf2 and the drug-resistant gene MRP1, and protein expression of PI3K, Akt, p-Akt, Nrf2, and MRP1 were measured. Results showed ADR + Res had a more significant inhibitory effect than ADR alone on HL-60/ADR cells. Auto-fluorescence intensity of ADR in HL-60/ADR cells treated with ADR + Res significantly increased. No difference of the auto-fluorescence intensity of ADR was observed in HL-60 cells treated with ADR and ADR + Res. mRNA expression of Nrf2 and MRP1 significantly decreased in HL-60/ADR cells treated with both Res and ADR + Res; protein expression of PI3K, p-Akt, Nrf2, and MRP1 significantly decreased in HL-60/ADR cells treated with PI3K inhibitor, Res and ADR + Res. In conclusion, Res reverses the drug resistance of AML HL-60/ADR cells through regulation of the PI3K/Akt/Nrf2 signaling pathway and MRP1 expression.

Acknowledgments

The authors would like to thank Dr. Guang Fan and Zhenhua Jia for their technical support.

Disclosure Statement

None of the authors had any personal or financial conflict of interests.

Additional information

Funding

This work was supported by the Project of Science and Technology, Department of Hebei Province under Grant No. 16277734D; the Medical Science Research Foundation of Hebei Province Health Bureau, China under Grant Nos. 20130159 and 20130176.

Notes on contributors

Yongjun Li

Y.L. and M.S. designed the research study; Y.G., Y.Q., and B.L. performed the experiments; Y.G. and Z.Z. wrote the manuscript, Z.F. and R.B. critically reviewed and interpreted the results. All authors reviewed and approved the manuscript.

Yukai Guo

Y.L. and M.S. designed the research study; Y.G., Y.Q., and B.L. performed the experiments; Y.G. and Z.Z. wrote the manuscript, Z.F. and R.B. critically reviewed and interpreted the results. All authors reviewed and approved the manuscript.

Zhuang Feng

Y.L. and M.S. designed the research study; Y.G., Y.Q., and B.L. performed the experiments; Y.G. and Z.Z. wrote the manuscript, Z.F. and R.B. critically reviewed and interpreted the results. All authors reviewed and approved the manuscript.

Raymond Bergan

Y.L. and M.S. designed the research study; Y.G., Y.Q., and B.L. performed the experiments; Y.G. and Z.Z. wrote the manuscript, Z.F. and R.B. critically reviewed and interpreted the results. All authors reviewed and approved the manuscript.

Bo Li

Y.L. and M.S. designed the research study; Y.G., Y.Q., and B.L. performed the experiments; Y.G. and Z.Z. wrote the manuscript, Z.F. and R.B. critically reviewed and interpreted the results. All authors reviewed and approved the manuscript.

Yongliang Qin

Y.L. and M.S. designed the research study; Y.G., Y.Q., and B.L. performed the experiments; Y.G. and Z.Z. wrote the manuscript, Z.F. and R.B. critically reviewed and interpreted the results. All authors reviewed and approved the manuscript.

Lianmei Zhao

Y.L. and M.S. designed the research study; Y.G., Y.Q., and B.L. performed the experiments; Y.G. and Z.Z. wrote the manuscript, Z.F. and R.B. critically reviewed and interpreted the results. All authors reviewed and approved the manuscript.

Zhenzhen Zhang

Y.L. and M.S. designed the research study; Y.G., Y.Q., and B.L. performed the experiments; Y.G. and Z.Z. wrote the manuscript, Z.F. and R.B. critically reviewed and interpreted the results. All authors reviewed and approved the manuscript.

Min Shi

Y.L. and M.S. designed the research study; Y.G., Y.Q., and B.L. performed the experiments; Y.G. and Z.Z. wrote the manuscript, Z.F. and R.B. critically reviewed and interpreted the results. All authors reviewed and approved the manuscript.