IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Novel Hsp90 pharmacological inhibitors in prostate cancer
Autor/es:
FEDERICCI F, GALIGNIANA MD, MAZAIRA GI
Reunión:
Congreso; LXII Reunión Anual de SAIC; 2017
Resumen:
The heat shock protein of 90 KDa (Hsp90) is known to be associated with many of the so named hallmarks of cancer. Hsp90 is the major soluble protein of the cell and interacts with nearly 10% of the eukaryotic genome, acting as a heterocomplex. This molecular chaperone is related to the activity and stability of many oncoproteins, thus tumor cells evade death programs. Tumor cells are thought to be ?addicted? to Hsp90 and the inhibition of the chaperone ATPase activity shows strong antitumor effects. Consequently Hsp90 inhibitors seems to be interesting chemotherapeutic agents. However, side effects are still an important concern. Geldanamicyn, a known Hsp90 ATPase inhibitor, has shown concerning side effects such as nephrotoxicity and hepatotoxicity. Previous studies showed that some Schiff bases like imines and azometines exhibit cytotoxic properties on tumor cells, and some show only a moderated effect on the Hsp90 ATPase activity. In this work, we studied novel drugs designed and analyzed by in silico molecular docking simulations. Then, the effects on the ATPase activity of in vitro Hsp90 was studied and with these results viability of prostate cancer cells, and inhibitory action on GR and AR nuclear translocation were assessed. Geldanamycin (GA) was always used as a control of all test. A total of 20 drugs were tested (named as 4a to 5j) and although the effects on the ATPase activity of the drugs were similar to those observed for GA, as the in silico analysis predicted; the effects on cell viability showed no relation with the drug ATPase inhibitory capability. This finding support our previous works that hypothesized that the Hsp90 ATPase activity is not completely correlated with its biological activity. The study here presented provides novel insights to design more active and less toxic drugs with promising future perspectives.