HS-543 induces apoptosis of Imatinib-resistant chronic myelogenous leukemia with T315I mutation

Abstract

Chronic myeloid leukemia (CML) is characterized by a constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl/T315I is the predominant mutation that causes resistance to Imatinib. In the present study, we synthesized a novel Bcr-Abl inhibitor, HS-543, and investigated its effect on cell survival or apoptosis in CML cells bearing Bcr-Abl/T315I (BaF3/T315I) or wild-type Bcr-Abl (BaF3/WT). HS-543 showed anti-proliferative effects in the BaF3/WT cells as well as the BaF3/T315I cells with resistance to Imatinib and strongly inhibited the Bcr-Abl signaling pathway in a dose-dependent manner. Furthermore, it significantly increased the sub G(1) phase associated with early apoptosis, with increased levels of cleaved PARP and cleaved caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we found that HS-543 induced apoptosis with the loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin, together with increasing that of Bax. In BaF3/T315I xenograft models, HS-543 significantly delayed tumor growth, unlike Imatinib. Our results demonstrate that HS-543 exhibits the induction of apoptosis and anti-proliferative effect by blocking the Bcr-Abl signaling pathway in the T315I-mutated Bcr-Abl cells with resistance to Imatinib. We suggest that HS-543 may be a novel promising agent to target Bcr-Abl and overcome Imatinib resistance in CML patients.