Eponemycin exerts its autitumor effect through the inhibition of proteasome function

Cell cycle progression requires the proteasome-mediated degradation of key regulatory proteins such as cyclins, cyclin-dependent kinase inhibitors, an d anaphase-inhibitory proteins. Given the central role of the proteasome in the destruction of these proteins, proteasome inhibition has been proposed as a possible cancer therapy. We report here that dihydroeponemycin, an an alogue of the antitumor and antiangiogenic natural product eponemycin, sele ctively targets the 20S proteasome, Dihydroeponemycin covalently modifies a subset of catalytic proteasomal subunits, binding preferentially to the IF N-gamma-inducible subunits LMP2 and LMP7, Moreover, the three major peptido lytic activities of the proteasome are inhibited by dihydroeponemycin at di fferent rates. In addition, dihydro-eponemycin-mediated proteasome inhibiti on induces a spindle-like cellular morphological change and apoptosis, Thes e results validate the proteasome as a target for antitumor pharmacological intervention and are relevant for the design of novel chemotherapeutic str ategies.