title: Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy.
abstract: The BRAFV600E mutation is common in human melanoma. This mutation enhances IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) and extracellular signal-regulated kinase/activator protein signaling cascades. In this study, we evaluated the efficacy of targeting either B-Raf or IKKbeta in combination with the DNA alkylating agent temozolomide for treatment of advanced metastatic melanoma. Xenografts of Hs294T human metastatic melanoma cells exhibiting the BRAFV600E mutation were treated with inhibitors of IKKbeta (BMS-345541), B-Raf (BAY 54-9085), and/or temozolomide. Drug response was mechanistically analyzed in vitro and in vivo. In this study, we determined that the antitumor activity of all three drugs depends on inhibition of NF-kappaB. BMS-345541 inhibits IKKbeta-mediated phosphorylation of IkappaBalpha and thus blocks the nuclear localization of NF-kappaB, whereas BAY 54-9085 inhibits activation of NF-kappaB through a mechanism that does not involve stabilization of IkappaBalpha. Moreover, BMS-345541, but not BAY 54-9085, activates the death pathways of p53 and c-Jun-NH2-kinase, contributing to the killing of melanoma cells. Temozolomide inhibits both NF-kappaB and extracellular signal-regulated kinase activity, conferring effective in vivo antitumor activity. Thus, temozolomide, but not BAY 54-9085, has a synergistic in vivo antitumor effect with BMS-345541. We conclude that the efficacy of antimelanoma therapy depends on inhibition of expression of antiapoptotic genes transcriptionally regulated by NF-kappaB. In contrast, drug targeting of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway alone in melanoma cells is ineffective for melanoma therapy in cases where NF-kappaB is not also targeted.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, 771 PRB, 2220 Pierce Avenue, Nashville, TN 37232, USA.
authors.forename: Jinming
authors.initials: J
authors.lastname: Yang
authors.forename: Snjezana
authors.initials: S
authors.lastname: Zaja-Milatovic
authors.forename: Yee-Mon
authors.initials: YM
authors.lastname: Thu
authors.forename: Francis
authors.initials: F
authors.lastname: Lee
authors.forename: Richard
authors.initials: R
authors.lastname: Smykla
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use; D011810:Quinoxalines / Q000008:administration & dosage / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077157:Sorafenib; D013379:Substrate Specificity; D000077204:Temozolomide; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; D007093:Imidazoles; D010671:Phenylurea Compounds; D011725:Pyridines; D011810:Quinoxalines; D009536:Niacinamide; D003606:Dacarbazine; D000077157:Sorafenib; D000077204:Temozolomide