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 chemotherapy. We report here that a novel dipeptidyl Proteasome Inhibitor, CEP1612, at low concentrations rapidly induces Apoptosis in human Jurkat T cells overexpressing Bcl-2 and also in all human prostate, breast, tongue and brain tumor cell lines we have tested to date, without exception. In contrast, etoposide, a standard Anticancer drug, fails to kill these cells when employed under the same conditions. The apoptosis-inducing abilities of CEP1612 and its analogous compounds match precisely their order for inhibition of the Proteasome chymotrypsin-like activity. CEP1612-induced Apoptosis is p53-independent, inhibitable by a tetrapeptide Caspase Inhibitor, and associated 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 fibroblasts. Proteasome inhibitors such as those investigated herein might therefore have potential use as novel Anticancer drugs.