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

  • Nutr Cancer. 2019;71(6):1007-1018. doi: 10.1080/01635581.2019.1578387.
Yongjun Li  1 ,  Yukai Guo  1 ,  Zhuang Feng  2 ,  Raymond Bergan  3 ,  Bo Li  4 ,  Yongliang Qin  1 ,  Lianmei Zhao  5 ,  Zhenzhen Zhang  3 ,  Min Shi  1
Affiliations
  • 1. a Department of Clinical Laboratory , The Second Hospital of Hebei Medical University , Shijiazhuang , Hebei, China.
  • 2. b Legacy Health and Cascade Pathology Services , Portland , Oregon, USA.
  • 3. c Division of Hematology/Oncology , Knight Cancer Institute, Oregon Health & Science University , Portland , Oregon, USA.
  • 4. d Department of Emergency , Shijiazhuang Center for Disease Control and Prevention , Shijiazhuang , Hebei, China.
  • 5. e Research Center , The Fourth Hospital of Hebei Medical University , Shijiazhuang , Hebei, China.
PMID: 31032633 DOI: 10.1080/01635581.2019.1578387
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.

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