title: Clitocine targets Mcl-1 to induce drug-resistant human cancer cell apoptosis in vitro and tumor growth inhibition in vivo.
abstract: Drug resistance is a major reason for therapy failure in cancer. Clitocine is a natural amino nucleoside isolated from mushroom and has been shown to inhibit cancer cell proliferation in vitro. In this study, we observed that clitocine can effectively induce drug-resistant human cancer cell apoptosis in vitro and inhibit tumor xenograft growth in vivo. Clitocine treatment inhibited drug-resistant human cancer cell growth in vitro in a dose- and time-dependent manner. Biochemical analysis revealed that clitocine-induced tumor growth inhibition is associated with activation of caspases 3, 8 and 9, PARP cleavage, cytochrome c release and Bax, Bak activation, suggesting that clitocine inhibits drug-resistant cancer cell growth through induction of apoptosis. Analysis of apoptosis regulatory genes indicated that Mcl-1 level was dramatically decreased after clitocine treatment. Over-expression of Mcl-1 reversed the activation of Bax and attenuated clitocine-induced apoptosis, suggesting that clitocine-induced apoptosis was at least partially by inducing Mcl-1 degradation to release Bax and Bak. Consistent with induction of apoptosis in vitro, clitocine significantly suppressed the drug-resistant hepatocellular carcinoma xenograft growth in vivo by inducing apoptosis as well as inhibiting cell proliferation. Taken together, our data demonstrated that clitocine is a potent Mcl-1 inhibitor that can effectively induce apoptosis to suppress drug-resistant human cancer cell growth both in vitro and in vivo, and thus holds great promise for further development as potentially a novel therapeutic agent to overcome drug resistance in cancer therapy.
authors.affiliation: Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Zijinggang Campus, Hangzhou, 310058, People's Republic of China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Sun
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Xueli
authors.initials: X
authors.lastname: Zeng
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Kwok-Pui
authors.initials: KP
authors.lastname: Fung
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D021381:Protein Transport; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011741:Pyrimidine Nucleosides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C055433:clitocine