Selenium-containing histone deacetylase inhibitors for melanoma management

Abstract

Melanoma incidence and mortality rates continue to increase each year. Lack of clinically viable agents, drug combinations, effective targeted delivery approaches and success inhibiting targets in tumor tissue have made this disease one of the most difficult to treat, which makes prevention an important option for decreasing disease incidence and mortality rates. Inhibiting histone deacetylases (HDAC) is an approach currently being explored to more effectively treat melanoma but use for prevention has not been explored. In this study, novel selenium containing derivatives of the FDA approved HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) called 5-phenylcarbamoylpentyl selenocyanide (PCP-SeCN) and Bis{5-phenylcarbamoylpentyl} diselenide (B(PCP)-2Se) were created and efficacy tested for preventing early melanocytic lesion development in skin. Topical application of PCP-SeCN and B(PCP)-2Se inhibited melanocytic lesion development in laboratory-generated skin by up to 87% with negligible toxicological effect. Mechanistically, PCP-SeCN and B(PCP)-2Se inhibited HDAC activity and had new inhibitory properties by moderating Akt activity to induce cellular apoptosis as demonstrated by an increase in the sub-G₀-G₁ cell population, and cleaved caspase-3 as well as PARP levels. Furthermore, PCP-SeCN and B(PCP)-2Se inhibited cell proliferation by inhibiting cyclin D1 expression and increasing p21 levels. Thus, PCP-SeCN and B(PCP)-2Se are potential melanoma chemopreventive agents with enhanced efficacy compared with SAHA due to new PI3 kinase pathway inhibitory properties.

Keywords: :

• B(PCP)- 2Se
• HDAC inhibitor(s)
• PCP-SeCN
• PI3K/Akt pathway
• SAHA
• chemoprevention
• melanoma
• selenium

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Arati Sharma, Omer Kuzu, Keen Chung and Kenneth Huang for technical assistance.

NIH CA-127892–01A, NIH NCI contract (NO2-CB-56603), The Foreman Foundation for Melanoma Research and Melanoma Research Foundation.

Note

PCP-SeCN (5-phenylcarbamoylpentyl selenocyanide) and B(PCP)-2Se (Bis {5-phenylcarbamoylpentyl} diselenide) are also referred to as SelSA-2 (containing one selenium atom) and SelSA-1 (containing 2 selenium atoms) respectively in the published reports by Desai et al.³⁶ Since names were misleading regarding the number of selenium atoms, this manuscript uses names derived from the established IUPAC nomenclature.