Calpain inhibitor 1 activates p53-dependent apoptosis in tumor cell lines

Reports suggest a role of calpains in degradation of wild-type p53, which m ay regulate p53 induction of apoptosis, A calpain inhibitor, n-acetyl-leu-l eu-norleucinal (calpain inhibitor 1), was assessed for ability to enhance p 53-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 statu s arrested in G(0)/G(1) and were sensitive to calpain inhibitor-induced apo ptosis, Regardless of endogenous p53 status, calpain inhibitor treatment co mbined with rAd-p53, but not empty vector virus, enhanced apoptosis in tumo r cell lines. These results demonstrate p53-dependent apoptosis induced by a calpain inhibitor and further suggest a role for calpains in the regulati on of p53 activity and induction of apoptotic pathways.