Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cancer Biol Ther. 2013 Apr;14(4):347-56. doi: 10.4161/cbt.23626. Epub 2013 Jan 28.
Outcomes for poor-risk localized prostate cancers treated with radiation are still insufficient. Targeting the "non-oncogene" addiction or stress response machinery is an appealing strategy for cancer therapeutics. Heat-shock-protein-90 (Hsp90), an integral member of this machinery, is a molecular chaperone required for energy-driven stabilization and selective degradation of misfolded "client" proteins, that is commonly overexpressed in tumor cells. Hsp90 client proteins include critical components of pathways implicated in prostate cancer cell survival and radioresistance, such as androgen receptor signaling and the PI3K-Akt-mTOR pathway. We examined the effects of a novel non-geldanamycin Hsp90 inhibitor, AUY922, combined with radiation (RT) on two prostate cancer cell lines, Myc-CaP and PC3, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γ-H2AX foci kinetics and client protein expression in pathways important for prostate cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined treatment (RT-AUY922) on the PI3K-Akt-mTOR and AR pathways in a hind-flank tumor graft model. We observed that AUY922 caused supra-additive radiosensitization in both cell lines at low nanomolar doses with enhancement ratios between 1.4-1.7 (p < 0.01). RT-AUY922 increased apoptotic cell death compared with either therapy alone, induced G 2-M arrest and produced marked changes in client protein expression. These results were confirmed in vivo, where RT-AUY922 combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in Myc-CaP and PC3 tumor grafts (both p < 0.0001). Our data suggest that combined RT-AUY922 therapy exhibits promising activity against prostate cancer cells, which should be investigated in clinical studies.
对于接受放疗的高危局限性前列腺癌患者，其治疗效果仍不理想。靶向“非癌基因”成瘾或应激反应机制是癌症治疗的一种有吸引力的策略。热休克蛋白 90（Hsp90）是该机制的一个组成部分，是一种分子伴侣，需要它来驱动能量稳定和选择性降解错误折叠的“客户”蛋白，这些蛋白在肿瘤细胞中通常过表达。Hsp90 的客户蛋白包括与前列腺癌细胞存活和放疗抵抗相关途径的关键组成部分，如雄激素受体信号和 PI3K-Akt-mTOR 途径。我们使用体外克隆存活、细胞凋亡、细胞周期分布、γ-H2AX 焦点动力学和与前列腺癌存活和放疗抵抗相关途径的客户蛋白表达的检测，研究了新型非格尔德霉素 Hsp90 抑制剂 AUY922 联合放疗（RT）对 Myc-CaP 和 PC3 两种前列腺癌细胞系的影响。然后，我们在后腿肿瘤移植模型中评估了联合治疗（RT-AUY922）对 PI3K-Akt-mTOR 和 AR 途径的肿瘤生长延迟和作用。我们观察到，AUY922 在低纳摩尔剂量下对两种细胞系均引起超相加的放射增敏作用，增强比为 1.4-1.7（p < 0.01）。与单独接受任何一种治疗相比，RT-AUY922 增加了细胞凋亡，诱导了 G2-M 期阻滞，并导致客户蛋白表达发生明显变化。这些结果在体内得到了证实，在 Myc-CaP 和 PC3 肿瘤移植中，与单独接受任何一种治疗相比，RT-AUY922 联合治疗产生了超相加的肿瘤生长延迟（均 p < 0.0001）。我们的数据表明，联合 RT-AUY922 治疗对前列腺癌细胞具有有前途的活性，应该在临床研究中进行调查。
