The Proteasome Inhibitor PS-341 Markedly Enhances Sensitivity of Multiple Myeloma Tumor Cells to Chemotherapeutic Agents

摘要: Increased nuclear factor kappaB (NF-kappaB) activity is associated with increased tumor cell survival in multiple myeloma. The function of NF-kappaB inhibited through binding to its inhibitor, IkappaB. Release activated follows proteasome-mediated degradation IkappaB resulting from phosphorylation the inhibitor and, finally, conjugation ubiquitin. We report that myeloma cells have enhanced IkappaBalpha and compared normal hematopoietic cells. proteasome PS-341 blocked translocation NF-kappaB, DNA binding, demonstrated consistent antitumor against chemoresistant chemosensitive sensitivity chemotherapeutic agents was markedly (100,000-1,000,000-fold) when combined a noncytotoxic dose without affecting Similar effects were observed using dominant negative super-repressor for IkappaBalpha. Thus, these results suggest inhibition may overcome chemoresistance allow doses be reduced significant toxicity.