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  • Title: Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma.
    Author: Francis LK, Alsayed Y, Leleu X, Jia X, Singha UK, Anderson J, Timm M, Ngo H, Lu G, Huston A, Ehrlich LA, Dimmock E, Lentzsch S, Hideshima T, Roodman GD, Anderson KC, Ghobrial IM.
    Journal: Clin Cancer Res; 2006 Nov 15; 12(22):6826-35. PubMed ID: 17121904.
    Abstract:
    PURPOSE: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells. EXPERIMENTAL DESIGN: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination. RESULTS: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment. CONCLUSIONS: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients.
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