title: Enhanced antitumor activity by the combination of dasatinib and combretastatin A-4 in vitro and in vivo.
abstract: The present study showed that the combination of dasatinib and combretastatin A-4 (CA-4) exhibited synergistic cytotoxicity in multiple types of cancer, including ovarian, hepatocellular, lung and prostate carcinoma. The enhanced apoptosis induced by dasatinib plus CA-4 was accompanied by a greater extent of mitochondrial depolarization, caspase-3 activation and PARP cleavage in HO-8910 cells. Furthermore, elevated expression of Mcl-1 led to a reduced apoptosis induced by dasatinib plus CA-4, highlighting that downregulated Mcl-1 was necessary for the potentiating effect of dasatinib to CA-4-triggered apoptosis. A clear increase in γ-H2AX expression was observed in the dasatinib+CA-4 group compared with the mono-treatment groups, indicating that dasatinib plus CA-4 may induce double-strand breaks (DSBs) in HO-8910 cells. Moreover, the increased anticancer efficacy of dasatinib combined with CA-4 was further validated in a human HO-8910 ovarian cancer xenograft model in nude mice. Our study is the first to show that the combination of dasatinib with CA-4 could be a novel and promising therapeutic approach for the treatment of cancer.
authors.affiliation: School of Medicine, Zhejiang University City College, and Laboratory of Clinical Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310015, PR China. zhangchong@zucc.edu.cn
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.forename: Shuang-Shuang
authors.initials: SS
authors.lastname: Zhou
authors.forename: Xiang-Rong
authors.initials: XR
authors.lastname: Li
authors.forename: Bao-Ming
authors.initials: BM
authors.lastname: Wang
authors.forename: Neng-Ming
authors.initials: NM
authors.lastname: Lin
authors.forename: Lin-Yi
authors.initials: LY
authors.lastname: Feng
authors.forename: Da-Yong
authors.initials: DY
authors.lastname: Zhang
authors.forename: Li-Huang
authors.initials: LH
authors.lastname: Zhang
authors.forename: Jun-Bo
authors.initials: JB
authors.lastname: Wang
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Pan
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D000069439:Dasatinib; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D013267:Stilbenes / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D013267:Stilbenes; D013844:Thiazoles; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; C058728:fosbretabulin; D000069439:Dasatinib