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Indexed by:期刊论文

Date of Publication:2015-04-05

Journal:EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES

Included Journals:SCIE、PubMed、Scopus

Volume:70

Page Number:64-71

ISSN No.:0928-0987

Key Words:CML; Paclitaxel; BH3 mimetics; Synergism

Abstract:Paclitaxel is an alternative chemotherapeutic agent for chronic myelogenous leukemia (CML) when primary or secondary resistance of tyrosine kinase inhibitors (TKI) is emerging, because paclitaxel could bypass the apoptotic deficiencies linked to p53 and fas ligand pathways in CML. However, high levels of Bcl-2 family proteins in CML could resist paclitaxel-induced apoptosis. Herein, we utilized two BH3 mimetics ABT-737 and Si to study the potential of BH3 mimetics in combination with paclitaxel in treatment of CML cells and illustrated the mechanism by which BH3 mimetics synergize with paclitaxel. As a single agent, S1 could induce apoptosis in CML-derived cell line K562, whereas ABT-737 was largely ineffective. However, both of the two agents could efficiently synergize with paclitaxel through intrinsic apoptosis pathway. By using Bcl-2 siRNA, Bcl-XL siRNA or Mcl-1 siRNA, we found although each of the three members exhibited activities to block paclitaxel-induced apoptosis, Mcl-1 was the determinant for the synergistic effect between paclitaxel and ABT-737 or Si. Furthermore, paclitaxel/ABT737 synergized to drastically upregulate Bim to displace Bak from Mcl-1, whereas Si directly binds Mcl-1 to release both Bim and Bak. As such, ABT-737 and S1 sensitized CML to paclitaxel by Mcl-1 inhibition, indirect inhibition through Bim antagonizing Mcl-1, or direct inhibition through binding to Mcl-1 itself. Finally, activation of JNK/Bim pathway was identified as the apical mechanism for ABT-737/paclitaxel synergism. Together, our results demonstrated potent synergy between BH3 mimetics and paclitaxel in the killing of CML cells and revealed an important role for Mcl-1 in mediating synergism by these agents. (C) 2015 Elsevier B.V. All rights reserved.