title: Mechanism of synergy of BH3 mimetics and paclitaxel in chronic myeloid leukemia cells: Mcl-1 inhibition.
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 S1 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 S1. Furthermore, paclitaxel/ABT737 synergized to drastically upregulate Bim to displace Bak from Mcl-1, whereas S1 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.
authors.affiliation: School of Chemistry, State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, Dalian, China.
authors.forename: Gaobo
authors.initials: G
authors.lastname: Chai
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, Dalian, China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, Dalian, China.
authors.forename: Mingzhou
authors.initials: M
authors.lastname: Xie
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, Dalian, China.
authors.forename: Qingbin
authors.initials: Q
authors.lastname: Chen
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, Dalian, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yu
authors.affiliation: School of Chemistry, State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, China.
authors.forename: Hongkun
authors.initials: H
authors.lastname: Sheng
authors.affiliation: School of Chemistry, State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, China. Electronic address: zczhang@dlut.edu.cn.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D040761:Biomimetic Materials / Q000008:administration & dosage* / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage* / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C474007:Bax protein (53-86); C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D017239:Paclitaxel
keywords: ABT-737 (PubChem CID: 11228183); BH3 mimetics; CML; Cisplatin (PubChem CID: 5702198); Paclitaxel; Paclitaxel (PubChem CID: 36314); Synergism