TP-110, a new proteasome inhibitor, down-regulates IAPs in human multiple myeloma cells

TP-110, a new Proteasome Inhibitor, has previously shown potent growth inhibition in various tumor cell lines. In this study, the mechanism of TP-110-induced Apoptosis is investigated in a human multiple myeloma cell line. Treatment with TP-110 for 24 h in vitro induced Apoptosis in multiple myeloma cell line RPMI8226. Although the expression of Bcl-2, Bcl-xL and Bax was not affected by the treatment of TP-110, cleavage of Bid and release of cytochrome c were enhanced. Interestingly, TP-110 reduced the intrinsic inhibitor of Apoptosis proteins (IAPs), cIAP-1 and XIAP, that suppress executioner caspases. The reduction of IAPs was observed not only by TP-110, but also by another Proteasome Inhibitor, MG-132. These results indicate that Proteasome inhibitors reduce the level of IAPs and that the Apoptosis induced by TP-110 is correlated with the level of IAPs in leukemia cell lines. Additionally, a reduction of cIAP-1 and XIAP by TP-110 contributes to the sensitization of Fas-mediated Apoptosis. Taken together, the alteration of the Apoptosis regulatory proteins by a Proteasome Inhibitor induces Apoptosis in tumor cells.