title: Induction of apoptosis by HAC-Y6, a novel microtubule inhibitor, through activation of the death receptor 4 signaling pathway in human hepatocellular carcinoma cells.
abstract: The present data showed that a novel synthesized compound, 6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido [2,3-b]indole (HAC-Y6), exhibited potent antitumor activity against human hepatocellular carcinoma (HCC) cells in vitro. Western blot and immunofluorescence experiments showed that HAC-Y6 depolymerized microtubules similarly to the effects of colchicine. HAC-Y6-treatment in Hep3B cells resulted in the accumulation of the G2/M phase and induced apoptosis. In addition, HAC-Y6-treatment influenced the expression of cell cycle and apoptosis related proteins in Hep3B cells. HAC-Y6 exposure increased caspases-3, -8, -9 and Bax protein levels, while reducing levels of Bcl-2 family proteins. Moreover, Bid, a substrate of caspase-8, was also activated by HAC-Y6. Treatment of cells caused the up-regulation of the death receptor 4 (DR4) and phosphorylation of p38. Taken together, we show that HAC-Y6 exhibited its antitumor activity by disrupting microtubule assembly, causing cell cycle arrest and apoptosis through both extrinsic and intrinsic pathways in Hep3B cells. Therefore, the novel compound HAC-Y6 is a promising microtubule inhibitor that has great potential for treatment of HCC.
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Jui-Ying
authors.initials: JY
authors.lastname: Tsai
authors.forename: Chao-Ming
authors.initials: CM
authors.lastname: Hung
authors.forename: Shih-Ting
authors.initials: ST
authors.lastname: Bai
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Huang
authors.forename: Wei-Chih
authors.initials: WC
authors.lastname: Chen
authors.forename: Jinh-Gung
authors.initials: JG
authors.lastname: Chung
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Tzong-Der
authors.initials: TD
authors.lastname: Way
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002243:Carbolines / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002243:Carbolines; D007093:Imidazoles; D011725:Pyridines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; C093642:SB 203580