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.