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

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.