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분자활성 촉매반응 연구단
분자활성 촉매반응 연구단
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HS-543 induces apoptosis of imatinib-resistant chronic myelogenous leukemia with T315I mutation

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Title
HS-543 induces apoptosis of imatinib-resistant chronic myelogenous leukemia with T315I mutation
Author(s)
Kim S.J.; Jung K.H.; Yan H.H.; Son M.K.; Fang Z.; Ryu Y.-L.; Lee H.; Lim J.H.; Suh J.; Jinhee Kim; Soyoung Lee; Sungwoo Hong; Hong S.-S.
Publication Date
2015-01
Journal
ONCOTARGET, v.6, no.3, pp.1507 - 1518
Publisher
IMPACT JOURNALS LLC
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 T315Imutated 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.
URI
https://pr.ibs.re.kr/handle/8788114/2145
ISSN
1949-2553
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Center for Catalytic Hydrocarbon Functionalizations(분자활성 촉매반응 연구단) > Journal Papers (저널논문)
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