Investigation into the use of histone deacetylase inhibitor MS-275 as a topical agent for the prevention and treatment of cutaneous squamous cell carcinoma in an SKH-1 hairless mouse model

PLoS One. 2019 Mar 13;14(3):e0213095. doi: 10.1371/journal.pone.0213095. eCollection 2019.

Abstract

Cutaneous squamous cell carcinomas are a common form of highly mutated keratinocyte skin cancers that are of particular concern in immunocompromised patients. Here we report on the efficacy of topically applied MS-275, a clinically used histone deacetylase inhibitor, for the treatment and management of this disease. At 2 mg/kg, MS-275 significantly decreased tumor burden in an SKH-1 hairless mouse model of UVB radiation-induced skin carcinogenesis. MS-275 was cell permeable as a topical formulation and induced histone acetylation changes in mouse tumor tissue. MS-275 was also effective at inhibiting the proliferation of patient derived cutaneous squamous cell carcinoma lines and was particularly potent toward cells isolated from a regional metastasis on an immunocompromised individual. Our findings support the use of alternative routes of administration for histone deacetylase inhibitors in the treatment of high-risk squamous cell carcinoma which may ultimately lead to more precise delivery and reduced systemic toxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Animals
  • Benzamides / administration & dosage*
  • Benzamides / pharmacology
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / etiology
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / prevention & control
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Deacetylase Inhibitors / administration & dosage*
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Mice
  • Mice, Hairless
  • Neoplasms, Radiation-Induced / drug therapy*
  • Neoplasms, Radiation-Induced / metabolism
  • Neoplasms, Radiation-Induced / prevention & control
  • Pyridines / administration & dosage*
  • Pyridines / pharmacology
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / etiology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / prevention & control
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Benzamides
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histone Deacetylase Inhibitors
  • Pyridines
  • entinostat