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J Cell Physiol. 2019 Jan 8. doi: 10.1002/jcp.28091. [Epub ahead of print]

The Bcl-2 inhibitor venetoclax inhibits Nrf2 antioxidant pathway activation induced by hypomethylating agents in AML.

Author information

1
Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope Medical Center, Duarte, California.
2
Department of Medical Biotechnology, Biotechnology Center of Ho Chi Minh City, Ho Chi Minh City, Vietnam.
3
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California.
4
City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, California.

Abstract

Induction of reactive oxygen species (ROS), an important process for the cytotoxicity of various acute myeloid leukemia (AML) therapies including hypomethylating agents (HMAs), concurrently activates the NF-E2-related factor 2 (Nrf2) antioxidant response pathway which in turn results in induction of antioxidant enzymes that neutralize ROS. In this study, we demonstrated that Nrf2 inhibition is an additional mechanism responsible for the marked antileukemic activity in AML seen with the combination of HMAs and venetoclax (ABT-199). HMA and venetoclax combined treatment augmented mitochondrial ROS induction and apoptosis compared with treatment HMA alone. Treatment of AML cell lines as well as primary AML cells with venetoclax disrupted HMA decitabine-increased nuclear translocation of Nrf2 and induction of downstream antioxidant enzymes including heme oxygenase-1 and NADP-quinone oxidoreductase-1. Venetoclax treatment also leads to dissociation of B-cell lymphoma 2 from the Nrf2/Keap-1 complex and targets Nrf2 to ubiquitination and proteasomal degradation. Thus, our results here demonstrated an undiscovered mechanism underlying synergistic effect of decitabine and venetoclax in AML cells, elucidating for impressive results in antileukemic activity against AML in preclinical and early clinical studies by combined treatment of these drugs.

KEYWORDS:

Nrf2; acute myeloid leukemia; antioxidant response; hypomethylating agents; reactive oxygen species; ubiquitination; venetoclax

PMID:
30623427
DOI:
10.1002/jcp.28091

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