Sauvageot Claire Marie-Elisabeth, Weatherbee Jessica Leigh, Kesari Santosh, Winters Susan Elizabeth, Barnes Jessica, Dellagatta Jamie, Ramakrishna Naren Raj, Stiles Charles Dean, Kung Andrew Li-Jen, Kieran Mark W, Wen Patrick Yung Chih
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115.
Neuro Oncol. 2009 Apr;11(2):109-21. doi: 10.1215/15228517-2008-060. Epub 2008 Aug 5.
Glioblastoma multiforme (GBM) arises from genetic and signaling abnormalities in components of signal transduction pathways involved in proliferation, survival, and the cell cycle axis. Studies to date with single-agent targeted molecular therapy have revealed only modest effects in attenuating the growth of these tumors, suggesting that targeting multiple aberrant pathways may be more beneficial. Heat-shock protein 90 (HSP90) is a molecular chaperone that is involved in the conformational maturation of a defined group of client proteins, many of which are deregulated in GBM. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a well-characterized HSP90 inhibitor that should be able to target many of the aberrant signal transduction pathways in GBM. We assessed the ability of 17-AAG to inhibit the growth of glioma cell lines and glioma stem cells both in vitro and in vivo and assessed its ability to synergize with radiation and/or temozolomide, the standard therapies for GBM. Our results reveal that 17-AAG is able to inhibit the growth of both human glioma cell lines and glioma stem cells in vitro and is able to target the appropriate proteins within these cells. In addition, 17-AAG can inhibit the growth of intracranial tumors and can synergize with radiation both in tissue culture and in intracranial tumors. This compound was not found to synergize with temozolomide in any of our models of gliomas. Our results suggest that HSP90 inhibitors like 17-AAG may have therapeutic potential in GBM, either as a single agent or in combination with radiation.
多形性胶质母细胞瘤（GBM）源于参与增殖、存活和细胞周期轴的信号转导通路成分中的基因和信号异常。迄今为止，单药靶向分子疗法的研究仅显示在减缓这些肿瘤生长方面有适度效果，这表明靶向多个异常通路可能更有益。热休克蛋白90（HSP90）是一种分子伴侣，参与一组特定客户蛋白的构象成熟，其中许多在GBM中失调。17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）是一种特征明确的HSP90抑制剂，应该能够靶向GBM中的许多异常信号转导通路。我们评估了17-AAG在体外和体内抑制胶质瘤细胞系和胶质瘤干细胞生长的能力，并评估了其与放疗和/或替莫唑胺（GBM的标准疗法）协同作用的能力。我们的结果显示，17-AAG能够在体外抑制人胶质瘤细胞系和胶质瘤干细胞的生长，并能够靶向这些细胞内的相应蛋白。此外，17-AAG可以抑制颅内肿瘤的生长，并且在组织培养和颅内肿瘤中都能与放疗协同作用。在我们所有的胶质瘤模型中均未发现该化合物与替莫唑胺有协同作用。我们的结果表明，像17-AAG这样的HSP90抑制剂在GBM中可能具有治疗潜力，无论是作为单药还是与放疗联合使用。
