title: Activation of mitochondrial pathway is crucial for tumor selective induction of apoptosis by LAQ824.
abstract: HDAC inhibitors are promising antitumor drugs with several HDAC inhibitors already in clinical trials. LAQ824, a potent pan-HDAC inhibitor, has been shown to induce cell cycle arrest and cell death. However, the mechanism of its antitumor effects and specially its tumor selectivity are still poorly understood. The focus of this study is to elucidate LAQ824 mediated anti-proliferative effects in lung carcinoma cells and the mechanism underlying the different sensitivity of LAQ824 to cancer and normal cells. In this study, LAQ824 mediated apoptosis was found to occur mainly via activation of the mitochondrial death pathway by inducing Apaf1 and caspase 9 and promoting mitochondrial release of key proapoptotic factors in lung cancer cells, but not in normal fibroblast cells. Using chromatin immunoprecipitation assay, we found that RNA Pol II binding and histone H3 acetylation levels at Apaf1 promoter were increased following LAQ824 treatment, explaining LAQ824 induced expression of Apaf1 in lung cancer cells. Furthermore, we showed that LAQ824 only triggered the release of mitochondrial proapoptotic factors such as cytochrome C (Cyto C) and apoptosis inducing factor (AIF) in lung cancer cells but not in normal blast cells. In addition, LAQ824 was found to induce Bax translocation in lung cancer cell, which may play important role in the induction of the release of mitochondrial proapoptotic factors. These data provide insight into the mechanism underlying the selective induction of apoptosis by LAQ824 in cancer cells.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA. shaowen.wang@novartis.com
authors.forename: Shaowen
authors.initials: S
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan-Neale
authors.forename: Richard
authors.initials: R
authors.lastname: Cai
authors.forename: Irina
authors.initials: I
authors.lastname: Alimov
authors.forename: Dalia
authors.initials: D
authors.lastname: Cohen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D006657:Histones; D006877:Hydroxamic Acids; C477361:LAQ824; D051028:bcl-2-Associated X Protein; D020169:Caspases