Heat-shock protein 90 (Hsp90) acts as a molecular chaperone required for maintain- ing the conformational stability of client proteins regulating cell proliferation, sur- vival, and apoptosis. Here we investigate the biologic significance of Hsp90 inhibition in multiple myeloma (MM) and other hemato- logic tumors using an orally available novel small molecule inhibitor SNX-2112, which exhibits unique activities relative to 17- allyamino-17-demethoxy- geldanamycin (17- AAG). SNX-2112 triggers growth inhibition and is more potent than 17-AAG against MM and other malignancies. It induces apopto- sis via caspase-8, -9, -3, and poly (ADP- ribose) polymerase cleavage. SNX-2112 in- hibits cytokine-induced Akt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages con- ferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. Importantly, SNX-2112 inhibits tube forma- tion by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1. Finally, SNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and pro- longs survival in a xenograft murine model. Our results indicate that blockade of Hsp90 by SNX-2112 not only inhibits MM cell growth but also acts in the bone marrow microenvi- ronment to block angiogenesis and oste- oclastogenesis. Taken together, our data provide the framework for clinical studies of SNX-2112 to improve patient outcome in MM and other hematologic malignancies.
ASJC Scopus subject areas
- Cell Biology