title: 2'-Hydroxy-4-methylsulfonylchalcone enhances TRAIL-induced apoptosis in prostate cancer cells.
abstract: Prostate cancer is the most common malignant cancer in men and the second leading cause of cancer deaths. Previously, we have shown that 2'-hydroxy-4-methylsulfonylchalcone (RG003) induced apoptosis in prostate cancer cell lines PC-3 and DU145. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, some cancer cells are resistant to TRAIL treatment. PC-3 and LNCaP prostatic cancer cell lines have been reported to be resistant to TRAIL-induced apoptosis. Here, we show for the first time that RG003 overcomes TRAIL resistance in prostate cancer cells. RG003 can enhance TRAIL-induced apoptosis through DR5 upregulation and downregulation of Bcl-2, PI3K/Akt, NF-κB, and cyclooxygenase-2 (COX-2) survival pathways. When used in combined treatment, RG003 and TRAIL amplified TRAIL-induced activation of apoptosis effectors and particularly activation of caspase-8 and the executioner caspase-3, leading to increased poly-ADP-ribose polymerase cleavage and DNA fragmentation in prostate cancer cells. Furthermore, we showed that RG003 reduced COX-2 expression in cells. Previously, we showed that COX-2 was involved in resistance to an apoptosis mechanism; then, its inhibition by RG003 could render cells more sensitive to TRAIL treatment. We showed that nuclear factor-κB activation was inhibited after RG003 treatment. This inhibition was correlated with reduction in COX-2 expression and induction of apoptosis. Overall, we conclude, for the first time, that RG003 can enhance TRAIL-induced apoptosis in human prostate cancer cells. The significance of our in-vitro study with RG003 and TRAIL combined is very encouraging, suggesting the relevance of testing this combined treatment in xenograft animal models.
authors.affiliation: aBiochemistry and Molecular Biology Laboratory bOrganic Chemistry and Therapeutic Laboratory cBiophysical Laboratory, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, GDR CNRS 3049 dPlate-forme CIM, University of Limoges, Limoges, France eBiochemistry Department, Faculty of Science - Section II, Lebanese University, TM-PAC Team, Jdeidet, Lebanon.
authors.forename: Bassel
authors.initials: B
authors.lastname: Ismail
authors.forename: Catherine
authors.initials: C
authors.lastname: Fagnere
authors.forename: Youness
authors.initials: Y
authors.lastname: Limami
authors.forename: Lamia
authors.initials: L
authors.lastname: Ghezali
authors.forename: Christelle
authors.initials: C
authors.lastname: Pouget
authors.forename: Chloë
authors.initials: C
authors.lastname: Fidanzi
authors.forename: Catherine
authors.initials: C
authors.lastname: Ouk
authors.forename: Rokhaya
authors.initials: R
authors.lastname: Gueye
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: David Y
authors.initials: DY
authors.lastname: Leger
authors.forename: Bertrand
authors.initials: B
authors.lastname: Liagre
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C000601196:2'-hydroxy-4-methylsulfonylchalcone; C000601197:4'-chloro-2'-hydroxy-4-methylsulfonylchalcone; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D047188:Chalcones; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D013450:Sulfones; D053221:TNF-Related Apoptosis-Inducing Ligand; D018808:Transcription Factor AP-1