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

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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 Δψm, 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 antiproliferative 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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Document Type: Research Article

Affiliations: 1: Biochemistry and Molecular Biology Laboratory, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, GDR CNRS 3049, Limoges, France 2: Organic Chemistry and Therapeutic Laboratory, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, GDR CNRS 3049, Limoges, France 3: Biophysical Laboratory, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, GDR CNRS 3049, Limoges, France 4: Biochemistry Department, TM-PAC Team, Faculty of Science - Section II, Lebanese University, Jdeidet, Lebanon

Publication date: January 1, 2013

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  • The International Journal of Oncology provides an international forum for the publication of the latest, cutting-edge research in the broad area of oncology and cancer treatment. The journal accepts original high quality works and reviews on all aspects of oncology research including carcinogenesis, metastasis, epidemiology, chemotherapy and viral oncology. Through fair and efficient peer review, the journal is dedicated to publishing top tier research in the field, offering authors rapid publication as well as high standards of copy-editing and production. The International Journal of Oncology is published on a monthly basis in both print and early online.
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