A-1210477, a selective MCL-1 inhibitor, overcomes ABT-737 resistance in AML.

ABSTRACT: Acute myeloid leukemia (AML) is one of the most common hematological malignancies. It is difficult to treat since it easily develops resistance to therapeutic drugs. Myeloid cell leukemia 1 (MCL-1), BCL-2 and BCL-XL, which belong to the anti-apoptotic group of proteins in the BCL-2 family, are overexpressed in AML. The effects of inhibitors that target anti-apoptotic proteins of the BCL-2 family in AML were evaluated in the present study. MCL-1 protein levels of HL60, MOLM13, OCI-AML3 and MV4-11 cell lines were investigated. Furthermore, following treatment with MCL-1-selective antagonist A-1210477 and/or BCL-2/BCL-XL antagonist ABT-737, cell viability was detected. The chimera rate of human CD45(+) cells of bone marrow from mouse models was analyzed via flow cytometry and immunohistochemistry using murine tissues (lung, spleen and liver). The data revealed that the HL-60 cell line, which exhibited a low MCL-1 protein level, and MOLM-13 and MV4-11 cell lines, whose MCL level was intermediate, were sensitive to ABT-737, whereas OCI-AML3 cells, which exhibited a high MCL-1 level, were insensitive to ABT-737. However, multiple AML mouse models and AML cell lines were sensitive to the MCL-1-selective antagonist A-1210477. The results of the present study indicated that the MCL-1-selective antagonist could overcome the resistance to the BCL-2/BCL-XL antagonist (ABT-737) in vitro and in vivo.

SUBMITTER: Wang Q 

PROVIDER: S-EPMC6781566 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature