title: Up-regulation of p21(WAF1/CIP1) by histone deacetylase inhibitors reduces their cytotoxicity.
abstract: Histone deacetylase inhibitors show promise as chemotherapeutic agents and have been demonstrated to block proliferation in a wide range of tumor cell lines. Much of this antiproliferative effect has been ascribed to the up-regulated expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). In this article, we report that p21 expression was up-regulated by relatively low doses of the histone deacetylase inhibitor azelaic bishydroxamic acid (ABHA) and correlated with a proliferative arrest. Higher doses of ABHA were cytotoxic. Cells that did not up-regulate p21 expression were hypersensitive to killing by ABHA and died via apoptosis, whereas up-regulation of p21 correlated with reduced sensitivity and a block in the apoptotic mechanism, and these cells seemed to die by necrosis. Using isogenic p21(+/+) and p21(-/-) cell lines and direct inhibition of caspase activity, we demonstrate that the reduced sensitivity to killing by ABHA is a consequence of inhibition of apoptosis by up-regulated p21 expression. These data indicate the enormous potential of therapeutic strategies that bypass the cytoprotective effect of p21 and act on the same molecular targets as the histone deacetylase inhibitors.
authors.affiliation: Joint Experimental Oncology Program, Department of Pathology, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Burgess
authors.forename: S
authors.initials: S
authors.lastname: Pavey
authors.forename: R
authors.initials: R
authors.lastname: Warrener
authors.forename: L J
authors.initials: LJ
authors.lastname: Hunter
authors.forename: T J
authors.initials: TJ
authors.lastname: Piva
authors.forename: E A
authors.initials: EA
authors.lastname: Musgrove
authors.forename: N
authors.initials: N
authors.lastname: Saunders
authors.forename: P G
authors.initials: PG
authors.lastname: Parsons
authors.forename: B G
authors.initials: BG
authors.lastname: Gabrielli
mesh_terms: D017209:Apoptosis; D001896:Boron Compounds; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008689:Methacrylates; D008768:Methylmethacrylates; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001896:Boron Compounds; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008689:Methacrylates; D008768:Methylmethacrylates; C107648:azelaic bishydroxamic acid; C049495:Super-bond