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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / toxicity
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Apoptosis
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism*
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Cyclooxygenase 2 Inhibitors / chemical synthesis
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Cyclooxygenase 2 Inhibitors / pharmacology*
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Cyclooxygenase 2 Inhibitors / toxicity
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Female
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G1 Phase Cell Cycle Checkpoints
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Gene Expression
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Gene Knockdown Techniques
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Glutathione / analogs & derivatives*
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Glutathione / chemical synthesis
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Glutathione / pharmacology
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Glutathione / toxicity
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Humans
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Inhibitory Concentration 50
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MAP Kinase Signaling System
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Melanoma / drug therapy*
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Melanoma / enzymology
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Mice
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Mice, Nude
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Organoselenium Compounds / chemical synthesis
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Organoselenium Compounds / pharmacology*
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Organoselenium Compounds / toxicity
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
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Xenograft Model Antitumor Assays
Substances
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2-amino-4-(1-(carboxymethylcarbamoyl)-2-(5-phenyl-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl)methylselanylthiol-ethylcarbamoyl)butryic acid
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Antineoplastic Agents
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Cyclooxygenase 2 Inhibitors
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Organoselenium Compounds
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RNA, Small Interfering
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Cyclooxygenase 2
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PTGS2 protein, human
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Proto-Oncogene Proteins c-akt
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Glutathione