title: Simultaneous targeting of COX-2 and AKT using selenocoxib-1-GSH to inhibit melanoma.
abstract: Melanoma is a highly metastatic and deadly disease. An agent simultaneously targeting the COX-2, PI3K/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways that are deregulated in up to 70% of sporadic melanomas might be an effective treatment, but no agent of this type exists. To develop a single drug inhibiting COX-2 and PI3K/Akt signaling (and increasing MAPK pathway activity to inhibitory levels as a result of Akt inhibition), a selenium-containing glutathione (GSH) analogue of celecoxib, called selenocoxib-1-GSH was synthesized. It killed melanoma cells with an average IC(50) of 7.66 μmol/L compared with control celecoxib at 55.6 μmol/L. The IC(50) range for normal cells was 36.3 to 41.2 μmol/L compared with 7.66 μmol/L for cancer cells. Selenocoxib-1-GSH reduced development of xenografted tumor by approximately 70% with negligible toxicity by targeting COX-2, like celecoxib, and having novel inhibitory properties by acting as a PI3K/Akt inhibitor (and MAPK pathway activator to inhibitory levels due to Akt inhibition). The consequence of this inhibitory activity was an approximately 80% decrease in cultured cell proliferation and an approximately 200% increase in apoptosis following 24-hour treatment with 15.5 μmol/L of drug. Thus, this study details the development of selenocoxib-1-GSH, which is a nontoxic agent that targets the COX-2 and PI3K/Akt signaling pathways in melanomas to inhibit tumor development.
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Gowda
authors.forename: Subbarao V
authors.initials: SV
authors.lastname: Madhunapantula
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C581918:2-amino-4-(1-(carboxymethylcarbamoyl)-2-(5-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl)methylselanylthiol-ethylcarbamoyl)butryic acid; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016566:Organoselenium Compounds; D034741:RNA, Small Interfering; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D005978:Glutathione