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• W2896829483 abstract "90 kDa heat shock proteins (Hsp90) act as protein chaperones and play a role in modulating endoplasmic reticulum (ER) stress. Hsp90 inhibitors are under clinical investigation as cancer treatment. Mitotane therapy of adrenocortical carcinoma (ACC) has been shown to act through lipid-induced ER-stress. To explore the potential of Hsp90 inhibitors in ACC as a single agent and in combination with mitotane, we analyzed two independent gene expression data sets of adrenal tumors in silico and treated the ACC cell line model NCI-H295 with Hsp90 inhibitors BIIB021 (B) and CCT18159 (C) alone and in combination with mitotane. ER-stress markers were monitored by immunoblotting. Drug synergism was quantified using the median effect model with cell viability as read-out. Cytosolic Hsp90 isoforms AA1 and AB1 were significantly overexpressed in ACC. Viability of H295 cells was impaired by B and C as single agents with an EC50 of 5.7 × 10−6M and 12.1 × 10−6M. B but not C dose-dependently increased XBP1 splicing and CHOP expression indicative of ER-stress activation. ER-stress marker expression was enhanced by co-incubation of B with 10 μM but not 5 μM mitotane. Maximal CHOP expression was induced by 25 μM mitotane alone with no additional effect of B. Combination indices (CI) of B and C with mitotane ranged from 0.64 to 1.38 and 0.68 to 1.30, respectively where CI values < 0.5 support clinically-relevant drug synergism. In conclusion, Hsp90 paralogs are differentially expressed in ACC and B but not C activates ER-stress in ACC cells. No meaningful drug synergism of Hsp90 inhibitors with mitotane was observed." @default.
• W2896829483 created "2018-10-26" @default.
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• W2896829483 date "2019-01-01" @default.
• W2896829483 modified "2023-10-10" @default.
• W2896829483 title "Hsp90 inhibition in adrenocortical carcinoma: Limited drug synergism with mitotane" @default.
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• W2896829483 doi "https://doi.org/10.1016/j.mce.2018.10.009" @default.
• W2896829483 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30315857" @default.
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