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 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.

• Authors: Soo Jung Kim, Kyung Hee Jung, Hong Hua Yan, Mi Kwon Son, Zhenghuan Fang, Ye-Lim Ryu, Hyunseung Lee, Joo Han Lim, Jun-Kyu Suh, JinHee Kim, Soyoung Lee, Sungwoo Hong, Soon-Sun Hong
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 3 Pg. 1507-18 (Jan 30 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25483100 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BCR-ABL1 fusion protein, human
• Piperazines
• Imatinib Mesylate
• Urea
• Fusion Proteins, bcr-abl

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics, metabolism)
• Humans
• Imatinib Mesylate (pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Models, Molecular
• Mutation
• Piperazines (pharmacology)
• Random Allocation
• Signal Transduction
• Urea (analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays