Cancer is one of the leading causes of death in humans and animals, with no successful cure presently. However, heat shock protein 90 (HSP90) inhibition has promising anti-cancer effects, especially with its involvement in many cellular processes through its clients, including cell proliferation. Its function is supported by interactions with co-chaperones and regulation by ATPase activity. Though HSP90 is often overexpressed in cancer in response to the stressful microenvironment of cancer cells and protects its mutated oncogenic clients to support tumour cell proliferation. HSP90 inhibitors have succeeded in degrading client proteins and inhibiting the formation of the HSP90 multi-chaperone complex, but their progression has been challenged by dose-limiting toxicity. To overcome this and improve clinical efficacy further, HSP90 inhibitors can be combined with the mTOR inhibitor, rapamycin. Using yeast strains expressing human or rat HSP90 as their sole HSP90, this study aimed to determine the role of rats as mammalian models and the effect of individual and combined drug use on yeast growth. Drug assays were performed at increasing concentrations of HSP90 inhibitors, radicicol and 17-AAG, and mTOR inhibitor, rapamycin, and the yeast growth was recorded. Rapamycin reduced yeast growth most effectively for individual drug use. However, 17-AAG and rapamycin combined were the most successful at HSP90 inhibition, as lower drug concentrations were required for the same inhibitory effect. Yeast growth was below 50% at 31nM rapamycin and 500nM 17-AAG in rat and human HSP90, a significant reduction of 8.9% rapamycin and 73% 17-AAG in rats, and 439% rapamycin and 926% 17-AAG in humans from the monotherapy concentrations. Together they synergistically inhibit cell proliferation via HSF1 inactivation by rapamycin, reducing HSP90 expression and limiting the required 17-AAG concentration for HSP90 inhibition. Despite some variation between the isoforms, generally, rats were a suitable mammalian model for human HSP90 inhibition.
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