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P. A. Tsoukas, S. Di Cesare, P. Logan, D. Faingold, S. Bakalian, M. N. Burnier, Jr.; The Effects of Curcumin on the Chemokine Receptor CXCR4 in Human Uveal Melanoma Cell Lines. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3393.
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Studies on a variety of cancers have indicated that the CXC chemokine receptor-4 (CXCR4) plays an important role in cell proliferation and cancer metastasis. It has been demonstrated that curcumin, the primary component of the common spice turmeric, is capable of stimulating apoptosis, reducing cellular proliferation, and inhibiting metastasis. Previous data showed that curcumin reduced the proliferation of uveal melanoma (UM) cell lines and up-regulated the expression of NM23, a metastasis suppressor gene. To further investigate the relationship between curcumin and UM, we evaluated its effect on CXCR4 in UM cell lines.
Five human UM cell lines (92.1, MKT-BR, OCM-1, SP6.5, and UW-1) were tested to determine the maximum non-toxic concentration of curcumin. The appropriate LD50 was found to be 50 µM using a TOX-6 proliferation assay. The CXCR4 expression of curcumin treated UM cells, and untreated UM cells was determined by quantitative real-time PCR. The qPCR was performed using QuantiTect® one step SYBR Green PCR method. Primer sequences were used to determine the expression of CXCR4, and the expression was then normalized with the housekeeper gene β-actin. To verify the CXCR4 expression at the protein level, flow cytometric analysis was performed using a specific monoclonal antibody directed to CXCR4 which was labelled with an appropriate fluorochrome. Negative controls were also included to rule out auto-fluorescence.
Curcumin, at a dose of 50µm killed half of the UM cells in all five cell lines. All surviving cells of the five UM cell lines demonstrated a substantial increase in CXCR4 gene expression when treated with curcumin. The up-regulated mRNA expression of CXCR4 ranged from an increase of 2.4 fold to 20 times the level of normal expression. Flow cytometric analysis confirmed this increase in cell surface CXCR4 protein expression.
Curcumin causes uveal melanoma cell death and inhibits cellular proliferation. However, curcumin also causes an up-regulation of CXCR4 or may select for CXCR4+ UM cells in the surviving fraction, post treatment. Future studies are currently underway in order to determine if the inhibitory effects of curcumin on cellular proliferation are more beneficial than the adverse effects displayed with CXCR4 up-regulation. In addition, future work is also focusing on whether curcumin causes the selection for or the up-regulation of CXCR4+ UM cells.
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