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Updated: May 21, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Selenium-containing histone deacetylase inhibitors for melanoma management
Raghavendra Gowda1, Subbarao V Madhunapantula, Dhimant Desai
1Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
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.
Insights
Novel selenium compounds, PCP-SeCN and B(PCP)-2Se, show promise as melanoma chemopreventive agents. Topical application significantly inhibited melanocytic lesion development with minimal toxicity.
Area of Science:
- Oncology
- Dermatology
- Medicinal Chemistry
Background:
- Melanoma incidence and mortality are rising, highlighting the need for effective prevention strategies.
- Histone deacetylase (HDAC) inhibition is a therapeutic approach for melanoma, but its preventive potential is unexplored.
- Current treatment limitations necessitate novel chemopreventive agents for melanoma.
Purpose of the Study:
- To synthesize and evaluate novel selenium-containing HDAC inhibitors, PCP-SeCN and B(PCP)-2Se, for melanoma chemoprevention.
- To investigate the mechanism of action of these compounds in preventing early melanocytic lesion development.
- To compare the efficacy of these novel agents with the FDA-approved HDAC inhibitor SAHA.
Main Methods:
- Synthesis of novel selenium derivatives: 5-phenylcarbamoylpentyl selenocyanide (PCP-SeCN) and Bis{5-phenylcarbamoylpentyl} diselenide (B(PCP)-2Se).
- Topical application of compounds on laboratory-generated skin to assess inhibition of melanocytic lesion development.
- Mechanistic studies including HDAC activity assays, Akt moderation assessment, apoptosis marker analysis (sub-G₀-G₁ population, cleaved caspase-3, PARP), and cell proliferation marker analysis (cyclin D1, p21).
Main Results:
- Topical PCP-SeCN and B(PCP)-2Se inhibited melanocytic lesion development by up to 87% with negligible toxicity.
- Compounds demonstrated HDAC inhibition and moderated Akt activity, leading to increased cellular apoptosis.
- Inhibition of cell proliferation was observed through decreased cyclin D1 expression and increased p21 levels.
Conclusions:
- PCP-SeCN and B(PCP)-2Se are effective melanoma chemopreventive agents.
- These novel selenium compounds exhibit enhanced efficacy compared to SAHA, potentially due to additional PI3K pathway inhibitory properties.
- The findings support the development of PCP-SeCN and B(PCP)-2Se as promising candidates for melanoma prevention.
