title: Calpain inhibitor 1 activates p53-dependent apoptosis in tumor cell lines.
abstract: Reports suggest a role of calpains in degradation of wild-type p53, which may regulate p53 induction of apoptosis. A calpain inhibitor, n-acetyl-leu-leu-norleucinal (calpain inhibitor 1), was assessed for ability to enhance p53-dependent apoptosis in human tumor cell lines with endogenous wild-type p53 and in altered p53 cell lines with the replacement of wild-type p53 by a recombinant adenovirus (rAd-p53). Calpain inhibitor 1 treatment resulted in increased levels of activated p53, increased p21 protein, and activation of caspases. Cell lines with wild-type, but not mutated or null, p53 status arrested in G0/G1 and were sensitive to calpain inhibitor-induced apoptosis. Regardless of endogenous p53 status, calpain inhibitor treatment combined with rAd-p53, but not empty vector virus, enhanced apoptosis in tumor cell lines. These results demonstrate p53-dependent apoptosis induced by a calpain inhibitor and further suggest a role for calpains in the regulation of p53 activity and induction of apoptotic pathways.
authors.affiliation: Canji, Inc., San Diego, California 92121, USA. isabella.atencio@canji.com
authors.forename: I A
authors.initials: IA
authors.lastname: Atencio
authors.forename: M
authors.initials: M
authors.lastname: Ramachandra
authors.forename: P
authors.initials: P
authors.lastname: Shabram
authors.forename: G W
authors.initials: GW
authors.lastname: Demers
mesh_terms: D000257:Adenoviridae Infections / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular; D020169:Caspases / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000502:physiology; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006023:Glycoproteins; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; C039304:calpain inhibitors; D020169:Caspases