The demethylating agent 5-Aza reduces the growth, invasiveness, and clonogenicity of uveal and cutaneous melanoma

• Published in: Investigative ophthalmology & visual science 2014-10, Vol.55 (10), p.6178
• Main Authors: Rajaii, Fatemeh, Asnaghi, Laura, Enke, Raymond, Merbs, Shannath L, Handa, James T, Eberhart, Charles G
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - therapeutic use; Azacitidine - analogs & derivatives; Azacitidine - therapeutic use; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Colony-Forming Units Assay; Decitabine; DNA Modification Methylases - antagonists & inhibitors; DNA, Neoplasm - drug effects; Humans; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Melanoma, Cutaneous Malignant; Mice; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Skin Neoplasms; Uveal Neoplasms - drug therapy; Uveal Neoplasms - metabolism; Uveal Neoplasms - pathology
• ISSN: 1552-5783; 1552-5783
• DOI: 10.1167/iovs.14-13933

Uveal melanoma is the most common primary intraocular malignancy in adults. Although local disease can be controlled with radiation therapy or enucleation, many cases are complicated by metastases, which account for the significant mortality from this disease. To date, no chemotherapeutic regimens effectively treat local or metastatic disease. Epigenetic silencing of tumor suppressor genes has been shown to be an important factor in the growth and metastasis of many cancers. One form of epigenetic alteration is DNA methylation, which often occurs at promoter elements resulting in the silencing of target gene transcription. We used 5-aza-2'-deoxycytidine (5-Aza), a well characterized demethylating agent that is US Food and Drug Administration approved to decrease DNA methylation in multiple uveal and cutaneous melanoma cell lines. Demethylation of melanoma cell lines using 5-Aza causes significant decreases in growth, invasion, and clonogenicity. Treatment of melanoma cells with combined 5-Aza therapy and irradiation showed an even more pronounced effect on cell viability. In addition, treatment with 5-Aza decreased the number of metastases from the eye to the lung in a murine cutaneous melanoma xenograft model. We demonstrate in vitro and in vivo that demethylating agents such as 5-Aza may be promising chemotherapeutic agents for treating melanoma and decreasing progression to metastatic disease. These results provide proof of concept for an exciting potential therapy to reduce mortality from this disease. Future work will focus on identifying pathways that mediate these changes.