MCL-1 or BCL-xL-dependent Resistance to the BCL-2 Antagonist (ABT-199) Can Be Overcome by Specific Inhibitor as Single Agents and in Combination With ABT-199 in Acute Myeloid Leukemia Cells

Qing Wang, Jiangbo Wan, Wenhao Zhang, Siguo Hao

Leuk Lymphoma. 2019 Sep;60(9):2170-2180.

PMID: 30626241

Abstract:

Aberrant over-expression of BCL-2 family proteins (BCL-2, BCL-xL, MCL-1) are associated with hematological malignancies. Antagonists of BCL-2 family proteins include BCL-2-selective inhibitor ABT-199, MCL-1-selective inhibitor A-1210477, BCL-xL-selective inhibitor A-1155463. In this study, we evaluated their potential inhibitory effectiveness. Our data showed that OCI-AML3 cells and U937 cells were resistant to BCL-2-selective inhibitor ABT-199 in vitro and in vivo, however, while OCI-AML3 cells were sensitive to MCL-1-selective inhibitor A-1210477 in vitro and in vivo, indicating that A-1210477 could counteract the resistance of AML cells to ABT-199 as a single agent in MCL-1-dependent AML cells. U-937 cell line and mouse model were resistant to A-1210477 or ABT-199, and expressed high level of BCL-xL, indicating that BCL-xL might play an important role in the resistance of A-1210477 or ABT-199. Besides, this study also showed that ABT-199 could synergize with A-1210477 in vitro or in vivo.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1668553261	A-1210477		1668553-26-1	Price