The role of the proteasome in apoptosis induced by anthracycline anticancer agents

To elucidate the involvement of proteasome inhibition in apoptosis induced by anthracycline anticancer agents, we investigated the interaction between the proteasome and anthracycline anticancer agents, and the function of the proteasome in apoptosis. Exposure of L1210 mouse lymphocytic leukemia cells to adriamycin (ADM) or 4'-O-tetrahydropyranyladriamycin (THP) resulted in apoptosis in a dose-dependent manner: 5 muM ADM and 0.5 muM THP induced apoptosis efficiently, but the effects of 10 muM ADM and 5 muM THP were markedly decreased or completely absent. Carbobenzoxy-leucyl-leucyl-leucinaI (Z-LLLal), a specific proteasome inhibitor, also induced dose-dependent apoptosis of the cells. The inhibitory effect of THP on chymotrypsin-like protease activity of proteasomes purified from the cytosol of L1210 cells was stronger than that of ADM. Both of these agents showed reversible noncompetitive inhibitory effects. The intracellular content of ubiquitinated protein increased in ADM-, THP- or Z-LLLal-treated L1210 cells during apoptosis. These results suggested that anthracycline anticancer agents induce apoptosis by interacting, at least in part, with proteasomes.