Research Papers:
HS-543 induces apoptosis of Imatinib-resistant chronic myelogenous leukemia with T315I mutation
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Abstract
Soo Jung Kim1,*, Kyung Hee Jung1,*, Hong Hua Yan1, Mi Kwon Son1, Zhenghuan Fang1, Ye-Lim Ryu1, Hyunseung Lee1, Joo Han Lim1, Jun-Kyu Suh2, JinHee Kim3,4, Soyoung Lee3,4, Sungwoo Hong3,4 and Soon-Sun Hong1
1 College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea
2 National Research Center for Sexual Medicine, College of Medicine, Inha University, Sinheung-dong, Jung-gu, Incheon, Republic of Korea
3 Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Republic of Korea
4 Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
* These authors contributed equally to this work
Correspondence:
Soon-Sun Hong, email:
Sungwoo Hong, email:
Keywords: HS-543, Bcr-Abl, T315I, Chronic Myeloid Leukemia
Received: August 04, 2014 Accepted: December 01, 2014 Published: December 02, 2014
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 G1 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.
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