Synthetic Hsp90 inhibitors as promising prostatic cancer therapeutic agentsSynthetic Hsp90 inhibitors as promising prostatic cancer therapeutic agents

FEDERICCI, F; CIUCCI, S; CAMISAY, MF; DE LEO, S; GALIGNIANA, MD; MAZAIRA, G

Mar del Plata

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

Sociedad Argentina de Investigación Clínica

According to current biography, the biological activity of the heat shock protein of 90 KDa (Hsp90) is dependent of its ATPase activity. Hsp90 is not only related to the maintenance of the cellular proteostasis, as the traditional chaperon role implies; it also plays a crucial role in many cellular process and mechanisms. So its not surprisingly associated with the proliferation, migration, invasion and almost all the named ?hallmarks of cancer?. Cancer cell are thought to be ?addicted? to this molecular chaperon with a high sensibility to Hsp90 inhibitors compared to non-tumoral cells. Consequently, Hsp90 inhibitors are interesting for the development of new antitumoral therapies. Geldanamycin (GA) is a known Hsp90 inhibitor, however this drug is not used in clinical treatments for the harmful side effects it produces, such as nephrotoxicity and hepatotoxicity. Nontheless, GA was taken as base structure for the development of potential non toxic therapeutic agents. In previous works we tested synthetic drugs design in an in silico study as potential Hsp90 ATPase inhibitors. In the present work, we focus in the series of compounds, which had shown an interesting inhibition of the ATPase activity, to evaluate their capability to affect a prostatic cancer model. Interestingly our results contradicts the current biographical dogma, drugs that affect the ATPase activity of Hsp90 shown no effect in all the chaperon biological activities. Similar to the effects of GA, these drugs shown a reduction of the viability and migration of prostatic tumoral cells. However, while cell treatment with GA prevented steroid receptor nuclear import, these synthetic drugs were not active in this regard. These properties could have pharmacological relevance since the lack of side effects such as steroid receptor migration is not desirable. Consequently, these compounds could be used as base for the development of new oncological therapies.