title: The novel NF-κB inhibitor DHMEQ synergizes with celecoxib to exert antitumor effects on human liver cancer cells by a ROS-dependent mechanism.
abstract: In a previous work of ours dehydroxymethyl-epoxyquinomicin (DHMEQ), an inhibitor of NF-κB, was shown to induce apoptosis through Reactive Oxygen Species (ROS) production in hepatoma cells. The present study demonstrated that DHMEQ cooperates with Celecoxib (CLX) to decrease NF-κB DNA binding and to inhibit cell growth and proliferation more effectively than treatment with these single agents alone in the hepatoma cell lines HA22T/VGH and Huh-6. ROS production induced by the DHMEQ-CLX combination in turn generated the expression of genes involved in endoplasmic reticulum (ER) stress and silencing TRB3 mRNA significantly decreased DHMEQ-CLX-induced cell growth inhibition. Moreover, the DHMEQ-CLX combination was associated with induction of PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2, Mcl-1 and survivin, as well as activated Akt. CD95 and CD95 ligand expression increased synergistically in the combination treatment, which was reversed in the presence of NAC. Knockdown of CD95 mRNA expression significantly decreased DHMEQ-CLX-induced cell growth inhibition in both cell lines. These data suggest that the DHMEQ-CLX combination kills hepatoma cells via ROS production, ER stress response and the activation of intrinsic and extrinsic apoptotic pathways.
authors.affiliation: Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council, Palermo, Italy. lampiasi@ibim.cnr.it
authors.forename: Nadia
authors.initials: N
authors.lastname: Lampiasi
authors.forename: Antonina
authors.initials: A
authors.lastname: Azzolina
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Montalto
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: Melchiorre
authors.initials: M
authors.lastname: Cervello
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D000068579:Celecoxib; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D003512:Cyclohexanones; D052246:Cyclooxygenase 2 Inhibitors; C491901:FAS protein, human; D016328:NF-kappa B; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D013449:Sulfonamides; C474831:TRIB3 protein, human; C464444:dehydroxymethylepoxyquinomicin; D019014:fas Receptor; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D000068579:Celecoxib; D000111:Acetylcysteine