IQUIBICEN   23947
INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CIENCIAS EXACTAS Y NATURALES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
EFFECT OF NOVEL INHIBITORS ON THE BIOLOGICAL ACTIVITY OF HSP90 IN PROSTATE CANCER
Autor/es:
CIUCCI S.; CAMISAY M.F.; GALIGNIANA M.D.; GARCIA G.A.; FEDERICCI F.; ERLEJMAN A.G.; DE LEO S.A.; MAZAIRA G.I.
Lugar:
Mar del Plata
Reunión:
Congreso; LXIII Reunión anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018
Institución organizadora:
Sociedad Argentina de Investigación Clínica
Resumen:
Hsp90 is a molecular chaperone that stabilizes in an ATP-dependentmanner, the active conformation of a large number of proteinswith stable tertiary structure. Several substrate proteins of this chaperoneare related to tumor development and progression, hencemaking Hsp90 an attractive target for antitumor therapy. Inhibition ofHsp90 ATPase activity shows strong antitumor effects, and Hsp90inhibitors seem to be the only chemotherapeutic agents capable toaffect all cancer hallmarks. However, drug side effects are still an importantconcern. The aim of the present work was the study of novelcompounds as potential antitumoral therapeutic agents. To its effect,drugs were designed and analyzed by in silico molecular dockingsimulations. Next, we assessed the effects of the drugs on the Hsp90ATPase activity in vitro, viability and migration of prostate cancer cellmodels, and their inhibitory action on glucocorticoid receptor (GR)nuclear translocation. Geldanamycin (GA), a known Hsp90 inhibitor,was used as a positive control in all experiments. A total of 5 compounds(named N15, A15, C3, C6 and P1) were assayed. all of themconfirmed in silico predictions regarding their ability to inhibit Hsp90ATPase activity. As we expected, cell treatment with GA preventedsteroid receptor nuclear import, and showed a negative effect on theviability and migration of PC3 cells. All the synthetic drugs showedan inhibitory action on cell migration, but none had effect on the GRnuclear import. Pyrazoline-derivative compounds (C3 and C6) werethe only compounds that showed inhibition of cell viability. Theseproperties could have pharmacological relevance, given the lack ofside effects such as steroid receptor inhibition, which is a desirablecharacteristic for pharmacological applications. Moreover, the studyprovides novel insights that could contribute to the design of moreactive and less toxic drugs.