title: Novel methylsulfonyl chalcones as potential antiproliferative drugs for human prostate cancer: involvement of the intrinsic pathway of apoptosis.
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.
authors.affiliation: Biochemistry and Molecular Biology Laboratory, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, GDR CNRS 3049, Limoges, France.
authors.forename: Bassel
authors.initials: B
authors.lastname: Ismail
authors.forename: Lamia
authors.initials: L
authors.lastname: Ghezali
authors.forename: Rokhaya
authors.initials: R
authors.lastname: Gueye
authors.forename: Youness
authors.initials: Y
authors.lastname: Limami
authors.forename: Christelle
authors.initials: C
authors.lastname: Pouget
authors.forename: David Y
authors.initials: DY
authors.lastname: Leger
authors.forename: Frederique
authors.initials: F
authors.lastname: Martin
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Beneytout
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Duroux
authors.forename: Mona
authors.initials: M
authors.lastname: Diab-Assaf
authors.forename: Catherine
authors.initials: C
authors.lastname: Fagnere
authors.forename: Bertrand
authors.initials: B
authors.lastname: Liagre
mesh_terms: D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000235:genetics*; D053453:Caspase 9 / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047188:Chalcones / Q000008:administration & dosage* / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000378:metabolism; D053938:DNA Fragmentation; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011471:Prostatic Neoplasms; D015398:Signal Transduction; D013450:Sulfones / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: C000601196:2'-hydroxy-4-methylsulfonylchalcone; C000601197:4'-chloro-2'-hydroxy-4-methylsulfonylchalcone; D000970:Antineoplastic Agents; D047188:Chalcones; D016328:NF-kappa B; D013450:Sulfones; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011065:Poly(ADP-ribose) Polymerases; D051058:Oncogene Protein v-akt; D053181:Caspase 8; D053453:Caspase 9