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

Ismail,Bassel; Ghezali,Lamia; Gueye,Rokhaya; Limami,Youness; Pouget,Christelle; Leger,David  Y.; Martin,Frederique; Beneytout,Jean-Louis; Duroux,Jean-Luc; Diab-Assaf,Mona; Fagnere,Catherine; Liagre,Bertrand

doi:10.3892/ijo.2013.2024

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

Authors:
- Bassel Ismail
- Lamia Ghezali
- Rokhaya Gueye
- Youness Limami
- Christelle Pouget
- David Y. Leger
- Frederique Martin
- Jean-Louis Beneytout
- Jean-Luc Duroux
- Mona Diab-Assaf
- Catherine Fagnere
- Bertrand Liagre
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Affiliations: Biochemistry and Molecular Biology Laboratory, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, GDR CNRS 3049, Limoges, France, Organic Chemistry and Therapeutic Laboratory, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, GDR CNRS 3049, Limoges, France, Biophysical Laboratory, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, GDR CNRS 3049, Limoges, France, Biochemistry Department, TM-PAC Team, Faculty of Science - Section II, Lebanese University, Jdeidet, Lebanon
Published online on: July 19, 2013 https://doi.org/10.3892/ijo.2013.2024
Pages: 1160-1168

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Abstract

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 ∆ψm, 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-κB signalling can significantly contribute to the anticancer effects of RG003 and RG005 in PC-3 prostate cancer cells. NF-κB 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-κB/COX-2 signal transduction pathways in PC-3 prostate cancer cells with a dominant effect for RG003.

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