Artova Vocational School, Department of Veterinary Medicine, Laboratory and Veterinary Health Program, Tokat Gaziosmanpaşa University, Tokat, Turkey.
J Chemother. 2021 Dec;33(8):554-563. doi: 10.1080/1120009X.2021.1908650. Epub 2021 Apr 2.
Osteosarcoma is common childhood tumour type of the bone. Chemotherapy is the most important step in treatment of osteosarcoma. Despite advanced diagnosis methods and target specific cancer therapeutics, osteosarcoma has still a high mortality rate and a tendency to metastasize. Therefore, new therapeutic strategies are evaluated in osteosarcoma treatment in pre-clinical and clinical studies. In the last ten years, heat shock protein 90 (HSP90) has been important biological target to design target specific cancer drugs. HSP90 play vital roles in proper folding, stabilization and maintenance of oncogenic client proteins in tumorigenesis. Therefore, inhibition of HSP90 has been significant therapeutic aspects in cancer drug design. STA-9090 (ganetespib) is a second generation small molecule HSP90 inhibitor which blocks tumurogenesis in cancer cells. STA-9090 inhibited ATP hydrolysis and protein folding process of HSP90. In this study, STA-9090 decreased Saos-2 cell proliferation and IC dose of STA-9090 was found out as 18.71 µM and 10.25 µM at 24 h and 48 h, respectively. STA-9090 inhibited HSP90 ATPase function and disrupted oncogenic client protein folding activity. Also, STA-9090 decreased protein level of the HSP90 in osteosarcoma cells. Expression analysis of osteosarcoma and bone metabolism related genes was performed by RT Profiler PCR Array. This study has found the down-regulation of the expression levels of oncogenic genes: , , , , , , , , , , , , and genes, in STA-9090 treated Saso-2 cells. Furthermore, expression levels of osteosarcoma related genes, , , , , and , were found to have increased significantly. Biological activities of STA-9090 on Saos-2 cell line show its potential as a target specific drug to inhibit osteosarcoma and its metastasis.
骨肉瘤是常见的儿童骨肿瘤类型。化疗是骨肉瘤治疗中最重要的步骤。尽管有先进的诊断方法和针对特定癌症的治疗方法，但骨肉瘤的死亡率仍然很高，并且有转移的趋势。因此，新的治疗策略正在临床前和临床研究中评估骨肉瘤的治疗。在过去的十年中，热休克蛋白 90（HSP90）已成为设计针对特定癌症药物的重要生物靶标。HSP90 在肿瘤发生过程中对致癌客户蛋白的适当折叠、稳定和维持起着至关重要的作用。因此，抑制 HSP90 已成为癌症药物设计中的重要治疗方面。STA-9090（ganetespib）是一种第二代小分子 HSP90 抑制剂，可阻断癌细胞中的肿瘤发生。STA-9090 抑制 HSP90 的 ATP 水解和蛋白折叠过程。在这项研究中，STA-9090 降低了 Saos-2 细胞的增殖，STA-9090 的 IC 剂量在 24 h 和 48 h 时分别为 18.71 µM 和 10.25 µM。STA-9090 抑制 HSP90 ATP 酶功能并破坏致癌客户蛋白折叠活性。此外，STA-9090 降低了骨肉瘤细胞中 HSP90 的蛋白水平。通过 RT Profiler PCR 阵列进行骨肉瘤和骨代谢相关基因的表达分析。这项研究发现，在 STA-9090 处理的 Saso-2 细胞中，致癌基因的表达水平下调： 、 、 、 、 、 、 、 、 、 和 基因。此外，骨肉瘤相关基因 、 、 、 、 、 和 的表达水平显著增加。STA-9090 对 Saos-2 细胞系的生物学活性表明，它具有作为抑制骨肉瘤及其转移的针对特定药物的潜力。
