The novel HSP90 inhibitor STA-1474 exhibits biologic activity against osteosarcoma cell lines
The novel HSP90 inhibitor STA-1474 exhibits biologic activity against osteosarcoma cell lines
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DOI：
10.1002/ijc.24660
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发表时间：
2009-12-15
影响因子：
6.4
通讯作者：
London, Cheryl A.
中科院分区：
文献类型：
--
作者：
McCleese, Jennifer K.;Bear, Misty D.;London, Cheryl A.
骨肉瘤(OSA)是狗和儿童最常见的恶性骨肿瘤，在两个物种中表现出相似的临床表现和分子生物学。不幸的是，尽管进行了积极的治疗，但仍有30-40%的儿童和90%的狗死于疾病。本研究旨在检测新型热休克蛋白90(HSP90)抑制剂STA-1474对阻塞性睡眠呼吸暂停低通气综合征(OSA)的生物活性。用STA-1474处理犬、人OSA细胞系和正常犬成骨细胞，评价其对细胞增殖(CyQuant)、凋亡(Annexin V、PARP裂解、caspase3/7激活)和已知HSP90客户蛋白的影响。用免疫共沉淀法从正常和恶性成骨细胞中分离HSP90，并用Western blotting检测辅助伴侣蛋白。用STA-1474治疗犬OSA异种移植瘤小鼠，并对肿瘤标本进行caspase-3激活和p-Akt/Akt丢失的评估。STA-1474可促进OSA细胞株的细胞活力丧失、细胞增殖抑制和诱导细胞凋亡。与17-AAG相比，STA-1474及其活性代谢物STA-9090的药效也有所增强。与正常犬成骨细胞相比，STA-1474对OSA细胞具有选择性，HSP90在犬OSA细胞中与共伴侣p23和Hop共沉淀，而在正常犬成骨细胞中不表达。此外，STA-1474还下调p-Met/Met、p-Akt/Akt和p-STAT3的表达。最终，STA-1474诱导OSA移植瘤肿瘤消退，caspase-3激活，p-Met/Met和p-Akt/Akt表达下调。综上所述，这些数据表明HSP90是阻塞性睡眠呼吸暂停综合征治疗干预的相关靶点。(C)2009年UICC
Osteosarcoma (OSA), the most common malignant bone tumor in dogs and children, exhibits a similar clinical presentation and molecular biology in both species. Unfortunately, 30-40% of children and 90% of dogs still die of disease despite aggressive therapy. The purpose of this study was to test the biologic activity of a novel heat shock protein 90 (HSP90) inhibitor, STA-1474, against OSA. Canine and human OSA cell lines and normal canine osteoblasts were treated with STA-1474 and evaluated for effects on proliferation (CyQuant), apoptosis (Annexin V, PARP cleavage, caspase 3/7 activation) and known HSP90 client proteins. HSP90 was immunoprecipitated from normal and malignant osteoblasts and Western blotting for co-chaperones was performed. Mice bearing canine OSA xenografts were treated with STA-1474, and tumors samples were evaluated for caspase-3 activation and loss of p-Akt/Akt. Treatment with STA-1474 promoted loss of cell viability, inhibition of cell proliferation and induction of apoptosis in OSA cell lines. STA-1474 and its active metabolite STA-9090 also demonstrated increased potency compared to 17-AAG. STA-1474 exhibited selectivity for OSA cells versus normal canine osteoblasts, and HSP90 co-precipitated with co-chaperones p23 and Hop in canine OSA cells but not in normal canine osteoblasts. Furthermore, STA-1474 downregulated the expression of p-Met/Met, p-Akt/Akt and p-STAT3. Finally, STA-1474 induced tumor regression, caspase-3 activation and downregulation of p-Met/Met and p-Akt/Akt in OSA xenografts. Together, these data suggest that HSP90 represents a relevant target for therapeutic intervention in OSA. (C) 2009 UICC