Department of Internal Medicine II, Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany.
Anticancer Res. 2012 Feb;32(2):453-62.
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.
HSP90 抑制剂能有效降低致癌生存蛋白的表达和活性水平。然而，其临床抗多发性骨髓瘤（MM）活性较弱，这促使人们探索联合治疗和开发具有改善物理化学性质的化合物。
检测新型口服生物利用 HSP90 抑制剂 NVP-HSP990 对 MM 细胞（已建立的细胞系和临床标本）活力、凋亡和客户蛋白水平的单独和联合其他药物的的临床前作用。
NVP-HSP990 对 MM 细胞具有显著的活性，其作用机制符合 HSP90 抑制剂的作用模式。与美法仑联合应用时，活性增强最为明显。与磷脂酰肌醇-3-激酶（PI3-激酶）/哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂联合应用，使 HSP90 阻断介导的应激反应失效，并显著增加了抗 MM 毒性。
鉴于 HSP90 和 PI3-激酶/mTOR 作为潜在的临床靶点的当前研究兴趣，这些观察结果可能会扩大这两类抑制剂在 MM 中的治疗应用。
