title: The BH3 mimetic ABT-737 induces cancer cell senescence.
abstract: ABT-737, a small molecule cell-permeable Bcl-2 antagonist that acts by mimicking BH3 proteins, induces apoptotic cell death in multiple cancer types. However, when incubated with this agent many solid tumor cell lines do not undergo apoptosis. The current study reveals a novel mechanism whereby ABT-737 when added to apoptosis-resistant cancer cells has profound biologic effects. In PV-10 cells, a renal cell carcinoma that does not die after ABT-737 treatment, this agent induces a two-fold change in the transcription of nearly 430 genes. Many of these induced mRNA changes are in secreted proteins, IL-6, IL-8, and IL-11 and chemokines CXCL2 and CXCL5, or genes associated with an "inflammatory" phenotype. Strikingly, these gene changes are highly similar to those changes previously identified in cellular senescence. Brief exposure of apoptosis-resistant renal, lung and prostate cancer cell lines to ABT-737, although not capable of inducing cell death, causes the induction of senescence-associated β-galactosidase and inhibition of cell growth consistent with the induction of cellular senescence. Evidence indicates that the induction of senescence occurs as a result of reactive oxygen species elevation followed by low-level activation of the caspase cascade, insufficient to induce apoptosis, but sufficient to lead to minor DNA damage and increases in p53, p21, IL-6 and 8 proteins. By overexpression of a dominant-negative p53 protein, we show that ABT-737-induced cellular senescence is p53-dependent. Thus, in multiple cancer types in which ABT-737 is incapable of causing cell death, ABT-737 may have additional cellular activities that make its use as an anticancer agent highly attractive.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Hollings Cancer Center, The Medical University of South Carolina, Charleston, South Carolina 29425, USA. songjin@musc.edu
authors.forename: Jin H
authors.initials: JH
authors.lastname: Song
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Kandasamy
authors.forename: Marina
authors.initials: M
authors.lastname: Zemskova
authors.forename: Ying-Wei
authors.initials: YW
authors.lastname: Lin
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kraft
mesh_terms: D040761:Biomimetic Materials / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D054426:Chemokine CXCL2 / Q000096:biosynthesis / Q000235:genetics; D054365:Chemokine CXCL5 / Q000096:biosynthesis / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004249:DNA Damage; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009596:Nitrophenols / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D013449:Sulfonamides / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; C493956:CDKN1A protein, human; C499706:CXCL2 protein, human; C486263:CXCL5 protein, human; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015850:Interleukin-6; D016209:Interleukin-8; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3