Stühmer, Thorsten, Iskandarov, Karmol, Gao, Zhenhai, Bumm, Thomas, Grella, Evelyn, Jensen, Michael Rugaard, Einsele, Hermann, Chatterjee, Manik and Bargou, Ralf C. (2011) Preclinical Activity of the Novel Orally Bioavailable HSP90 Inhibitor NVP-HSP990 against Multiple Myeloma Cells. Anticancer Res, 32 (2). pp. 453-462. ISSN 0250-7005

Abstract

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Item Type:	Article
Related URLs:	Organisation
Related URLs:	Organisation
Date Deposited:	13 Oct 2015 13:15
Last Modified:	13 Oct 2015 13:15
URI:	https://oak.novartis.com/id/eprint/5778