Response of Rosiglitazone, UAB 30, and SR 13668 in the human melanoma prevention assay

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Due to the increasing frequency of malignant melanoma, which is projected to reach 59,000 cases in 2005 (http://seer.cancer.gov), and the poor prognosis for patients with late stage disease, we have developed a screening assay for identifying melanoma prevention agents. The assay measures chemopreventive agent induced changes in melanoma-related biomarkers in radial growth phase human melanoma cells (WM3211). We report data on Rosiglitazone - a PPARγ agonist, UAB 30 - a retinoid that is selective for RXRα, and SR 13668 - a derivative of indole-3-carbinol. The assay incorporates an exposure to UVB (25 mJ/cm²) with both pre- and post-treatment with potential preventive agents. Biomarkers used to measure agent efficacy include: induction of annexin V, an early marker for apoptosis; induction of E-cadherin, a biomarker that is expressed in melanocytes and WM3211 cells but is lost in metastatic melanoma cells; inhibition of n-cadherin, a biomarker that is expressed in melanoma cells but not in melanocytes. E-cadherin plays a key roll in the communication between melanocytes and keratinocytes, which is important in the control of melanocyte growth in vivo. N-cadherin expression allows the fibroblasts to control the growth of melanocytes. The following are some of the important findings from our study. Rosiglitazone was positive for E-cadherin induction and strongly positive for N-cadherin inhibition. UAB 30 and SR 13668 induced E-cadherin at multiple concentrations. All three agents demonstrated a positive effect on the N-cadherin/E-cadherin expression ratios relative to the ratios with cells treated with UV-B alone. Rosiglitazone was active at clinically achievable concentrations. The activities of these agents in the assay were: rosiglitazone > UAB 30> SR 13668. The assay data suggests that rosiglitazone, UAB 30, and SR 13668 have potential to prevent melanoma. Supported by NCI contract No. HHSN261200433000C.