Abstract
The cytotoxic effects of zeaxanthin on two human uveal melanoma cell lines (SP6.5 and C918) and related signaling pathways were studied and compared to effects on normal ocular cells (uveal melanocytes, retinal pigment epithelial cells, and scleral fibroblasts). MTT assay revealed that zeaxanthin reduced the cell viability of melanoma cells in a dose-dependent manner (10, 30, and 100 μM), with IC50 at 40.8 and 28.7 μM in SP6.5 and C918 cell lines, respectively. Zeaxanthin did not affect the viability of normal ocular cells even at the highest levels tested (300 μM), suggesting that zeaxanthin has a selectively cytotoxic effect on melanoma cells. Zeaxanthin induced apoptosis in melanoma cells as indicated by annexin V and ethidium III flow cytometry. Western blot analysis demonstrated that zeaxanthin decreased the expression of antiapoptotic proteins (Bcl-2 and Bcl-xL) and increased the expression of proapoptotic proteins (Bak and Bax) in zeaxanthin-treated melanoma cells. Zeaxanthin increased mitochondrial permeability as determined by JC-1 fluorescein study. Zeaxanthin also increased the level of cytosol cytochrome c and caspase-9 and -3 activities, but not caspase-8, as measured by ELISA assay or colorimetric assay. All of these findings indicate that the intrinsic (mitochondrial) pathway is involved in zeaxanthin-induced apoptosis in uveal melanoma cells.
Highlights
Uveal melanoma is the most common primary intraocular tumor in the adult population, with an incidence of 6-7 cases per million per year in the US [1]
F-12 culture medium, Dulbecco’s Modified Eagle’s Medium (DMEM), fetal bovine serum (FBS), phosphate buffered saline (PBS), 0.05% trypsin-0.02% EDTA solution, and gentamicin were purchased from GIBCO (Grand Island, NY, USA)
The IC50 dose of zeaxanthin for cultured human uveal melanoma cells (SP6.5 and C918) at 48 h was 40.8 and 28.7 μM, respectively. These results suggested that zeaxanthin at 10–100 μM can selectively reduce the cell viability of melanoma cells without affecting normal uveal melanocytes, fibroblasts, or retinal pigment epithelial (RPE) cells
Summary
Uveal melanoma is the most common primary intraocular tumor in the adult population, with an incidence of 6-7 cases per million per year in the US [1]. Most uveal melanoma patients with liver metastasis die within 6 months [2,3,4]. Zeaxanthin is a carotenoid pigment, which belongs to the xanthophyll subclass, having a chemical formula C40H56O2 It is found at high levels in various foods (e.g., egg yolk, corn, and many vegetables and fruits), herbs, and traditional Chinese medications (Hippophae rhamnoides, Lycium barbarum, Lycium chinense, Lilium hansonii, Cycas revolute, and Crocus sativus) [5, 6]. It has been used in traditional Chinese medicine to treat various diseases and has been tested for its biomedical effects in several experimental disease models, including various cancers [7]
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