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.
Highlights
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that is characterized by high levels of immature white blood cells, which is one of the most understood neoplasms
In 95% of CML cases, the product of a reciprocal translocation between chromosomes 9 and 22, the Philadelphia chromosome, is detected, which is characterized by the presence of Bcr–Abl fusion gene, representing a subtype of leukemia with poor prognosis, rapidly acquiring resistance to the Imatinib treatment during therapy [12, 13]
Imatinib resistance often occurs in patients especially in CML accelerated phase and blast crisis, and almost unrelievedly occurs in patients with the BcrAbl expression, showing shortcomings of the therapy
Summary
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that is characterized by high levels of immature white blood cells, which is one of the most understood neoplasms. The Bcr–Abl aberrant tyrosine kinase is mainly responsible for malignant transformation by activating multiple signal transduction pathways including Stats, MAPK/ Erk, and PI3K/Akt, which lead to increased www.impactjournals.com/oncotarget survival, proliferation, and escape from apoptosis [3, 4]. For this reason, Bcr–Abl tyrosine kinase has been considered as an important target for CML therapeutics. These compounds do not show therapeutic activities against all Imatinib-resistant mutants of Bcr-Abl, and a long-term tolerablility problem has emerged
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