Synthetic Hsp90 inhibitors as promising prostatic cancer therapeutic agents

FEDERICCI, FERNANDO; CIUCCI, SOL; CAMISAY, MARIA F; DE LEO, SONIA A; ERLEJMAN ALEJANDRA; GALIGNIANA, MARIO D.; MAZAIRA, GISELA I.

Mar del Plata

Congreso; LXIII Reunión anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Sociedad Argentina de Investigación Clínica

According to current bibliography, the biological activity of the heat shock protein of90 KDa (Hsp90) is dependent of its ATPase activity. Hsp90 is not only associated to themaintenance of cellular proteostasis, as the traditional chaperone role implies; it alsoplays a crucial role in many cellular process and mechanisms. Therefore, it is notsurprising to find it associated to cell proliferation, migration, invasion and almost allthe named ?hallmarks of cancer?. Cancer cells are thought to be ?addicted? to thismolecular chaperone showing high sensitivity to Hsp90 inhibitors compared to non-tumoral cells. Consequently, Hsp90 inhibitors are interesting for the development ofnew antitumoral therapies. Geldanamycin (GA) is a known Hsp90 inhibitor, however itis not used in clinical treatments for its harmful side effects. Nonetheless, GA wastaken as base structure for the development of potential non-toxic therapeutic agents.In previous works we tested synthetic drugs design in silico as potential Hsp90 ATPaseinhibitors. In this study, we focused on a group of compounds (named as series 4),which had shown an interesting inhibition of the ATPase activity, to evaluate theircapability to affect a prostatic cancer model. In particular, compounds 4C, 4D, 4F showa reduction of the viability and migration of prostatic tumoral cells, with comparableeffects to GA. However, while cell treatment with GA prevented steroid receptornuclear import, all the synthetic drugs were not active in this regard. These propertiescould have pharmacological relevance since the lack of side effects such as steroidreceptor inactivation could not be desirable. Interestingly, our results contradicts thecurrent dogma, i.e. drugs that affect the ATPase activity of Hsp90 show no effect in allthe chaperone biological activities. Consequently, these compounds could be used asbase for the development of potential new oncological therapies.