Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, United States of America.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States of America.
PLoS One. 2019 Mar 13;14(3):e0213095. doi: 10.1371/journal.pone.0213095. eCollection 2019.
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.
皮肤鳞状细胞癌是一种常见的高度突变角质形成细胞皮肤癌，尤其在免疫功能低下的患者中引起关注。在这里，我们报告了局部应用 MS-275（一种临床使用的组蛋白去乙酰化酶抑制剂）治疗和管理这种疾病的疗效。在 2mg/kg 时，MS-275 显著降低了 UVB 辐射诱导的皮肤致癌作用的 SKH-1 无毛小鼠模型中的肿瘤负担。MS-275 作为局部制剂具有细胞渗透性，并诱导小鼠肿瘤组织中的组蛋白乙酰化变化。MS-275 还能有效抑制患者来源的皮肤鳞状细胞癌系的增殖，并且对免疫功能低下个体的局部转移中分离的细胞尤其有效。我们的研究结果支持在高危鳞状细胞癌的治疗中使用组蛋白去乙酰化酶抑制剂的替代给药途径，这可能最终导致更精确的递送和降低系统毒性。
