Selenium-containing histone deacetylase inhibitors for melanoma management

Raghavendra Gowda, Subba Rao V. Madhunapantula, Dhimant Desai, Shantu Amin, Gavin P. Robertson

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 PA RP 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.

Original languageEnglish (US)
Pages (from-to)756-765
Number of pages10
JournalCancer Biology and Therapy
Volume13
Issue number9
DOIs
StatePublished - Jul 1 2012

Fingerprint

Histone Deacetylase Inhibitors
Selenium
Melanoma
Histone Deacetylases
Skin
Mortality
Cyclin D1
Incidence
Drug Combinations
Phosphatidylinositol 3-Kinases
Caspase 3
Toxicology
bis(5-phenylcarbamoylpentyl) diselenide
Cell Proliferation
Apoptosis
Population
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

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title = "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 PA RP 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.",
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Selenium-containing histone deacetylase inhibitors for melanoma management. / Gowda, Raghavendra; Madhunapantula, Subba Rao V.; Desai, Dhimant; Amin, Shantu; Robertson, Gavin P.

In: Cancer Biology and Therapy, Vol. 13, No. 9, 01.07.2012, p. 756-765.

Research output: Contribution to journalArticle

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AU - Gowda, Raghavendra

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