EFFECTS OF PHARMACOLOGICAL INHIBITION OF THE ATP DOMAIN OF HSP90 IN PROSTATE AND BREAST CANCER CELLS

NICOLÁS BRUNO, IARA SANTA CRUZ, AGOSTINA ARAMBURU, VALENTINA HANSEN, CAMILA RUBINO, ALEJANDRA ERLEJMAN, MARIO GALIGNIANA, GISELA MAZAIRA.

Congreso; LXVIII Reunión Anual de SAIC; 2023

In recent decades, heat-shock protein 90 has become an attractive target for antitumor therapies since Hsp90 stabilizes many oncoproteins in their active conformation, it is overexpressed in tumor cells, and its inhibition simultaneously affects all hallmarks of cancer. It is accepted that the intrinsic ATPase activity of Hsp90 is directly responsible for its biological activity and therefore is the main target of pharmacological inhibition. The first generation of chaperone inhibitors was derived from geldanamycin (GA) and radicicol, two natural compounds that bind to the ATP-binding pocket of Hsp90. Although preclinical studies were promising, the clinical trials evidenced severe toxic effects, mainly nephro- and hepato-toxicity. The aim of this work was to analyze the biological actions of synthetic compounds predesigned by computational modelling according to their putative inhibitory effect on the ATPase activity of Hsp90. Such effect was inferred from their elemental molecular structures, which were chosen based on their proven low toxic effects. GA was used as a control in all assays. Results show that both the pyrazoline-derived compounds (C3 and C6) and the imine-derived compound (4f) reduce cell viability and cell migration for the two cell lines used as experimental models, i.e., PC3 prostate cancer cells and MDA-MB-231 breast cancer cells. It is shown that cell migration is affected by the reorganization of the actin cytoskeleton, whereas the effect on cell viability was due to an induced generation of reactive oxygen species. As predicted by in silico assays, all compounds significantly inhibited Hsp90 ATPase activity in vitro. Nonetheless, none of the compounds affected the migration to the nucleus of the glucocorticoid receptor, a known Hsp90-dependent process. Therefore, these results lead to propose that the intrinsic ATPase activity of Hsp90 is not directly responsible for all its biological functions.