Heat Shock Protein 90 Inhibitors AUY922, BIIB021 and SNX5422 Induce Bim-mediated Death of Thyroid Carcinoma Cells

Abstract

Background/Aim: Heat shock protein 90 (HSP90) controls maturation of oncogenic client proteins of cancer cells, and thus we studied the effect of HSP 90 inhibitors on cell survival and survival-related mediators in thyroid carcinoma cells. Materials and Methods: Human TPC-1 and SW1736 thyroid carcinoma cells were utilized. Cell viability, cytotoxic activity and apoptosis were estimated using CCK-8 assay, cytotoxicity assay and FACS analysis, respectively. Results: AUY922, BIIB021 and SNX5422 decreased cell viability, and increased cytotoxic activity and the proportion of apoptotic cells. The protein levels of cleaved PARP, cleaved caspase-3, Bax and Bim were elevated, and Bcl2 protein levels were reduced. Knockdown of Bax did not change cell viability, cytotoxic activity, the proportion of apoptotic cells and cleaved caspase-3 protein levels. Meanwhile, knockdown of Bim enhanced cell viability, and diminished cytotoxic activity, the proportion of apoptotic cells and cleaved caspase-3 protein levels. AUY922, BIIB021 and SNX5422 increased the protein levels of phospho-AMPK, and decreased those of phospho-ERK1/2, and total and phospho-AKT. Conclusion: AUY922, BIIB021 and SNX5422 induce cytotoxicity by modulating Bim and ERK1/2, AKT and AMPK signaling in thyroid carcinoma cells.

Combination therapy of tyrosine kinase inhibitor sorafenib with the HSP90 inhibitor onalespib as a novel treatment regimen for thyroid cancer

“…The sensitivity of BHT-101, moderate sensitivity of SW1736 and resistance of 8305C to sorafenib treatment are all in line with previous studies 9 , 26 . Similarly, the strong sensitivity of BHT-101 to HSP90 inhibition was reported by Sang et al using ganetespib, while Kim et al demonstrated how SW1736 was relatively resistant to treatment with the HSP90 inhibitor AUY922 27 , 28 . The significant decrease in viability and inhibition of wound healing capability of the combination treatment presented in this study was more distinct than in previous studies exploring the combination of sorafenib and HSP90 inhibitors in hepatocellular carcinoma cells 29 .…”

Combination therapy of tyrosine kinase inhibitor sorafenib with the HSP90 inhibitor onalespib as a novel treatment regimen for thyroid cancer

“…The sensitivity of BHT-101, moderate sensitivity of SW1736 and resistance of 8305c to sorafenib treatment are all in line with previous studies 9,26 . Similarly, the strong sensitivity of BHT-101 to HSP90 inhibition was reported by Sang et al (2013) using ganetespib, while Kim et al (2020) demonstrated how SW1736 was relatively resistant to treatment with the HSP90 inhibitor AUY922 27,28 . The signi cant decrease in viability and inhibition of wound healing capability of the combination treatment presented in this study was more distinct than in previous studies exploring the combination of sorafenib and HPS90 inhibitors in hepatocellular carcinoma cells 29 .…”