title: Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines.
abstract: Calpain is a class of Ca(2+)-dependent cysteine proteases and has been suggested to be involved in several important signaling cascades. A series of novel aldehyde calpain inhibitors identified in our laboratory were more potent and specific than commercially available calpain inhibitors, and were used to assess the involvement of calpain in cancer. Our inhibitors demonstrated potent anti-proliferative activity in four cancer cell lines (PC-3, HeLa, Jurkat and Daudi) with IC(50)'s ranging from 2 to >30 microM. A non-cancer cell line (CV-1) was 4-7-fold less sensitive than the cancer cell lines. Apoptotic activity was determined and appeared to be inversely correlated to calpain expression levels in the different cell types. Leukemia cell lines (i.e., Daudi and Jurkat) with undetectable m-calpain were more susceptible to the apoptotic effects in response to calpain inhibition, while apoptosis was not detected in PC-3 prostate cancer cells, which highly express m-calpain. The extent of apoptosis in HeLa cells was moderate under identical conditions. Apoptosis induced by calpain inhibition was accompanied by caspase-3 activation. Furthermore, cell cycle analysis showed that aldehyde calpain inhibitors arrested cells at the G2/M boundary in a concentration-dependent manner. These results indicate that aldehyde calpain inhibitors exhibit their cytotoxic effects via induction of G2/M arrest and apoptosis. Importantly, the compounds failed to exert any inhibitory effects toward 20S proteasome. Collectively, our results suggest that calpain is a novel target for the treatment of a variety of cancer diseases and provide leads for further discovery and development of calpain inhibitors.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, 43210, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Guan
authors.forename: Rajani
authors.initials: R
authors.lastname: Korukonda
authors.forename: Eunju
authors.initials: E
authors.lastname: Hurh
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Schmittgen
authors.forename: Isaac O
authors.initials: IO
authors.lastname: Donkor
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002154:Calpain / Q000037:antagonists & inhibitors*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors
chemical_list: D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; C505407:CASP3 protein, human; D002154:Calpain; D053148:Caspase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex