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Novel methylsulfonyl chalcones as potential antiproliferative drugs for human prostate cancer: involvement of the intrinsic pathway of apoptosis

Limited success has been achieved in extending the survival of patients with metastatic and hormone-refractory prostate cancer (HRPC). There is a strong need for novel agents in the treatment and prevention of HRPC. In the present study, the apoptotic mechanism of action of RG003 (2'-hydroxy-4-methylsulfonylchalcone) and RG005 (4'-chloro-2'-hydroxy-4-methylsulfonylchalcone) in association with intracellular signalling pathways was investigated in the hormone-independent prostate carcinoma cells PC-3 and DU145. We showed that these compounds induced apoptosis through the intrinsic pathway but not through the extrinsic one. We showed that synthetic chalcones induced an activation of caspase-9 but not caspase-8 in PC-3 cells. Even if both chalcones induced apoptosis in PC-3 cells, a dominant effect of RG003 treatment was observed resulting in a disruption of ??m, caspase-9 and caspase-3 activation, PARP cleavage and DNA fragmentation. Furthermore, in regard to our results, it is clear that the simultaneous inhibition of Akt and NF-?B signalling can significantly contribute to the anticancer effects of RG003 and RG005 in PC-3 prostate cancer cells. NF-?B inhibition was correlated with the reduction of COX-2 expression and induction of apoptosis. Our results clearly indicate for the first time that RG003 and RG005 exert their potent anti?proliferative and pro-apoptotic effects through the modulation of Akt/NF-?B/COX-2 signal transduction pathways in PC-3 prostate cancer cells with a dominant effect for RG003.

Auteur(s) : Bassel ISMAIL, Lamia GHEZALI, Rokhaya GUEYE, Youness LIMAMI, Christelle POUGET, David Y LEGER, Frédérique MARTIN, Jean-Louis BENEYTOUT, Jean-Luc DUROU
Pages : 1160-1168
Année de publication : 2013
Revue : International Journal of Oncology
N° de volume : 43
Type : Article
Mise en ligne par : GUEYE Rokhaya