title: Arsenic trioxide and paclitaxel induce apoptosis by different mechanisms.
abstract: Arsenic trioxide (ATO) and paclitaxel (TAXOL) are effective in the treatment of various types of cancers. Both drugs induce G2/M arrest. We have previously shown that ATO is a potent inducer of apoptosis in myeloma cells expressing mutant p53 engaging both the intrinsic and extrinsic apoptotic pathways. Here we compared the effect of ATO and TAXOL on myeloma cells expressing mutant p53 and varying levels of Bcl-2. ATO rapidly induced Apo2/TRAIL, activation of caspase 8, cleavage of BID, depolarization of mitochondrial membrane (MM) and release of AIF from mitochondria in a Bcl-2 independent fashion. Apoptosis was associated with early formation of ring-like perinuclear condensed chromatin colocalized with AIF. In contrast, paclitaxel-induced apoptosis MM depolarization, cytochrome C release and activation of caspase 9 were all blocked by Bcl-2. Apoptosis was associated with a random chromatin condensation and nuclear fragmentation with no early involvement of AIF.
authors.affiliation: University of Texas Health Science Center, San Antonio, Texas 78284, USA.
authors.forename: Cagla
authors.initials: C
authors.lastname: Akay
authors.forename: Charles
authors.initials: C
authors.lastname: Thomas
authors.forename: Yair
authors.initials: Y
authors.lastname: Gazitt
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D005420:Flavoproteins / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D010768:Phosphoserine / Q000378:metabolism; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D002843:Chromatin; D005420:Flavoproteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D010768:Phosphoserine; D045304:Cytochromes c; D020169:Caspases; D017239:Paclitaxel; D000077237:Arsenic Trioxide