Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts

It has been suggested that overexpression of the Bcl-2 oncoprotein in human cancer cells contributes to their resistance to apoptosis induced by chemo therapy, We report here that a novel dipeptidyl proteasome inhibitor, CEP16 12, at low concentrations rapidly induces apoptosis in human Jurkat T cells overexpressing Bcl-2 and also in ail human prostate, breast, tongue and br ain tumor cell lines we have tested to date, without exception. In contrast , etoposide, a standard anticancer drug, fails to kill these cells when emp loyed under the same conditions. The apoptosis-inducing abilities of CEP161 2 and its analogous compounds match precisely their order for inhibition of the proteasome chymotrypsin-like activity. CEP1612-induced apoptosis is p5 3-independent, inhibitable by a tetrapeptide caspase inhibitor, and associa ted with accumulation of the cyclin-dependent kinase inhibitors p21 and p27 . Furthermore, CEP1612 selectively accumulates p27 and induces apoptosis in simian virus 40-transformed, but not the parental normal, human fibroblast s. Proteasome inhibitors such as those investigated herein might therefore have potential use as novel anticancer drugs.