title: Clitocine induces apoptosis and enhances the lethality of ABT-737 in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak.
abstract: ABT-737 is a novel anti-apoptotic Bcl-2 family protein inhibitor with high affinity to Bcl-2, Bcl-xl and Bcl-w but relatively low affinity to Mcl-1/A1. Therefore, high level Mcl-1 usually confers human tumor cell resistance to ABT-737. At the present study, we observed that clitocine can induce apoptosis in six tested human colon cancer cell lines accompanied by suppression of Mcl-1. More interestingly, clitocine significantly enhances the ABT-737-mediated lethality by inducing apoptosis. At the molecular level we determined Mcl-1 is the potential target through which clitocine can sensitize human colon cancer cells to ABT-737 induced apoptosis. Knocking-down of Mcl-1 is sufficient to increase cancer cell susceptibility to ABT-737 while its over-expression can significantly reverse this susceptibility. We also determined that clitocine may activate Bak by disrupting the interaction between Mcl-1 and Bak to induce mitochondrial membrane permeabilization. Furthermore, silence of Bak with the specific siRNA effectively attenuates the apoptosis induction by co-treatment of clitocine and ABT-737. Finally, clitocine in combination with ABT-737 significantly suppress the xenograft growth in animal model. Collectively, our studies suggest clitocine can induce apoptosis and potentiate ABT-737 lethality in human colon cancer cells by disrupting the interaction of Mcl-1 and Bak to trigger apoptosis.
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Zijinggang Campus, Hangzhou, China; Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Zijinggang Campus, Hangzhou, China.
authors.forename: Jian-guo
authors.initials: JG
authors.lastname: Sun
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Zijinggang Campus, Hangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Zijinggang Campus, Hangzhou, China.
authors.forename: Xue-li
authors.initials: XL
authors.lastname: Zeng
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Zijinggang Campus, Hangzhou, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Zijinggang Campus, Hangzhou, China; Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Zijinggang Campus, Hangzhou, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Zijinggang Campus, Hangzhou, China; School of Biomedical Sciences (SBS)v, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Kwok Pui
authors.initials: KP
authors.lastname: Fung
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Zijinggang Campus, Hangzhou, China; Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Zijinggang Campus, Hangzhou, China. Electronic address: liuf64@zju.edu.cn.
authors.forename: Fei-yan
authors.initials: FY
authors.lastname: Liu
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011741:Pyrimidine Nucleosides / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
chemical_list: C501332:ABT-737; C494772:BAK1 protein, human; D001713:Biphenyl Compounds; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011741:Pyrimidine Nucleosides; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; C055433:clitocine
keywords: ABT-737; Apoptosis; Bak; Clitocine; Mcl-1