Investigation of anticancer activities of STA-9090 (ganetespib) as a second generation HSP90 inhibitor in Saos-2 osteosarcoma cells

Abstract

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 IC₅₀ 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 RT² Profiler PCR Array. This study has found the down-regulation of the expression levels of oncogenic genes: DKK1, TWIST1, WNT10B, WNT3A, RANK, RANKL, PTH, FGFR1, FGFR2, LTBP2, IL6, TGFβ1, MMP2 and SPARC genes, in STA-9090 treated Saso-2 cells. Furthermore, expression levels of osteosarcoma related genes, OPG, ERα, ERβ, IL15, BMP2 and BMP7, 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.

Keywords:

• Osteosarcoma
• Saos-2
• HSP90
• STA-9090
• ganetespib
• chemotherapy

Note on contributor

Aykut Özgür is an assistant professor at Tokat GaziosmanpaÅŸa University, Artova Vocational School, Department of Veterinary Medicine, Laboratory and Veterinary Health Program, Turkey. His primary research field is molecular drug design and protein engineering.

Additional information

Funding

This work was supported by Tokat Gaziosmanpaşa University, Foundation of Scientific Researches Projects. (Project number: 2019/76).