Brain-Penetrating Histone Deacetylase Inhibitor RG2833: A Potential Malignant Melanoma Growth Suppressor

Histone deacetylases (HDACs) play an important role in the epigenetic control of gene expression in both normal and cancer cells. Previous studies have demonstrated that pharmaceutical inhibition of HDACs can kill and/or suppress the growth of cancer cells. RG2833 is a HDAC inhibitor that targets specific HDACs known to be active in cancer cells. Melanoma cells have previously been shown to respond to HDAC inhibitors that are structurally similar to RG2833. We hypothesized that the inhibition of HDAC activity by RG2833 would result in the reduced growth and/or death of cells from the malignant melanoma cell lines SK-MEL-5 and SK-MEL-28. To test our hypothesis, we exposed SK-MEL-5 and SKMEL-28 cells to increasing concentrations of RG2833. We found that concentrations of RG2833 that effectively inhibited HDAC activity also resulted in reduced melanoma cell growth and viability. These results demonstrate the effectiveness of RG2833 in reducing the growth and viability of malignant melanoma cells in vitro and warrant further investigation of the potential therapeutic use of RG2833 and related compounds in the battle against cancer. INTRODUCTION Approximately 3.5 million people are diagnosed with skin cancer each year, of which, melanoma has the lowest survival rate [7]. Over fifty percent of people with melanoma develop metastatic tumors in the brain [6,7]. Essential functions governed by the brain such as sensory perception and breathing can be tremendously affected or impaired depending on the location of metastatic tumor development in the brain. Anticancer therapeutic studies targeting histone deacetylase inhibitors have shown promising activity in the suppression of cancer cell growth [2,3,10,11]. Histone deacetylase (HDAC) prevents acetylation of lysine receptors on histones, tightening DNA around histones [9]. When lysine receptors are acetylated, DNA is loosened around the histone nucleosome complex and therefore, becomes more accessible. Accessibility to DNA promotes gene expression because RNA polymerase is allowed to facilitate the transcription process. HDAC inhibitors promote acetylation by blocking HDAC activity; this keeps the lysine receptors acetylated, promoting transcription. HDAC inhibitors have a unique ability to make changes in gene expression, which has been shown in previous studies to suppress cancer cell growth. Cancer cells generally display abnormal gene expression that allows them to undergo rapid metastasis and proliferation [11,12]. RG2833 is an HDAC inhibitor that penetrates the blood-barrier of the brain. RG2833 is an effective and efficient acetylation promoter [12]. It is structurally similar to Vorinostat, which is an HDAC inhibitor that is currently used clinically. In this study, we provide a link between two malignant melanoma cell lines (SK-MEL-5 and SKMEL-28) and RG2833 activity. We predict that as the concentrations of RG2833 increase, the growth rates and overall HDAC activity of the malignant melanoma cells will decrease. MATERIALS & METHODS Cell Lines and Cell Culture The two human malignant melanoma cell lines, SK-MEL-5 and SK-MEL-28 (Figure 1), were obtained from the American Type Culture Collection (Manassas, VA). The cells were maintained in high