Targeting Akt3 Signaling in Malignant Melanoma Using Isoselenocyanates

Abstract

Purpose: Melanoma is the most invasive and deadly form of skin cancer. Few agents are available for treating advanced disease to enable long-term patient survival, which is driving the search for new compounds inhibiting deregulated pathways causing melanoma. Akt3 is an important target in melanomas because its activity is increased in f70% of tumors, decreasing apoptosis in order to promote tumorigenesis. Experimental Design: Because naturally occurring products can be effective anticancer agents, a library was screened to identifyAkt3 pathway inhibitors. Isothiocyanates were identified as candidates, but low potency requiring high concentrations for therapeutic efficacy made them unsuitable. Therefore, more potent analogs called isoselenocyanates were created using the isothiocyanate backbone but increasing the alkyl chain length and replacing sulfur with selenium. Efficacy was measured on cultured cells and tumors by quantifying proliferation, apoptosis, toxicity, and Akt3 pathway inhibition. Results: Isoselenocyanates significantly decreased Akt3 signaling in cultured melanoma cells and tumors. Compounds having 4 to 6 carbon alkyl side chains with selenium substituted for sulfur, called ISC-4 and ISC-6, respectively, decreased tumor development by f60% compared with the corresponding isothiocyanates, which had no effect. No changes in animal body weight or in blood parameters indicative of liver-, kidney-, or cardiac-related toxicity were observed with isoselenocyanates. Mechanistically, isoselenocyanates ISC-4 and ISC-6 decreased melanoma tumorigenesis by causing an f3-fold increase in apoptosis. Conclusions: Synthetic isoselenocyanates are therapeutically effective for inhibiting melanoma tumor development by targeting Akt3 signaling to increase apoptosis in melanoma cells with negligible associated systemic toxicity.

Antileishmanial activity of imidothiocarbamates and imidoselenocarbamates

“…This observation is in agreement with the previous studies on their antitumor activity (Madhunapantula et al 2008;Sharma et al 2009;Das et al 2009;Emmert et al 2010).…”

“…In addition, and with the aim of confirming whether the isosteric substitution of sulfur for selenium could significantly improve the leishmanicidal activity, as has already been demonstrated for their antitumor activity (Madhunapantula et al 2008;Sharma et al 2009;Das et al 2009;Emmert et al 2010), four sulfur analogs were also screened.…”

MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma

“…The observed changes in pAKT protein level may be a consequence of downregulated total AKT3 protein level. 35,36 …”

The Akt signaling pathway

“…93,100,101 Mechanistically, ISC-4 has been shown to inhibit Akt3 signaling in melanomas and induce apoptotic cell death.…”