pi103 and Multiple-Myeloma

HSP90 inhibitors effectively reduce expression and activity levels of oncogenic survival proteins. However, their clinical anti-multiple myeloma (MM) activity has been found to be rather weak, spurring the exploration of combination therapies and development of compounds with improved physicochemical properties.. Preclinical effects of the novel orally bioavailable HSP90 inhibitor NVP-HSP990 on the viability, apoptosis and client protein levels of MM cells (established cell lines and clinical specimens) were tested alone and in combination with other drugs.. NVP-HSP990 exerted profound activity against MM cells, with a molecular mode of action conforming well with its role as HSP90 inhibitor. Enhanced activity was most obvious in combination with melphalan. Combination with a phosphatidylinositol-3-kinase (PI3-kinase)/mammalian target of rapamycin (mTOR) inhibitor, rendered the HSP90 blockade-mediated stress response ineffective and considerably increased the anti-MM toxicity.. Given the current interest in both HSP90 and PI3-kinase/mTOR as potential clinical targets, these observations could broaden the therapeutic utility of either class of inhibitor in MM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Dose-Response Relationship, Drug; Furans; HSP72 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Multiple Myeloma; Phosphoinositide-3 Kinase Inhibitors; Pyridines; Pyridones; Pyrimidines; Up-Regulation