Cytotoxic Effects of Curcumin in Human Retinal Pigment Epithelial Cells
et al. (2013) Cytotoxic Effects of Curcumin in Human Retinal Pigment Epithelial
Cells. PLoS ONE 8(3): e59603. doi:10.1371/journal.pone.0059603
Cytotoxic Effects of Curcumin in Human Retinal Pigment Epithelial Cells
Leon Kohen 0
Margrit Hollborn 0
Rui Chen 0
Peter Wiedemann 0
Andreas Reichenbach 0
Andreas Bringmann 0
Arto Urtti, University of Helsinki, Finland
0 1 Department of Ophthalmology and Eye Hospital, University of Leipzig , Leipzig, Germany , 2 Paul Flechsig Institute of Brain Research, University of Leipzig , Leipzig, Germany, 3 Helios Klinikum Aue, Aue , Germany
Backround: Curcumin from turmeric is an ingredient in curry powders. Due to its antiinflammatory, antioxidant and anticarcinogenic effects, curcumin is a promising drug for the treatment of cancer and retinal diseases. We investigated whether curcumin alters the viability and physiological properties of human retinal pigment epithelial (RPE) cells in vitro. Methodology/Principal Findings: Cellular proliferation was investigated with a bromodeoxy-uridine immunoassay, and chemotaxis was investigated with a Boyden chamber assay. Cell viability was determined by trypan blue exclusion. Apoptosis and necrosis rates were determined with a DNA fragmentation ELISA. Gene expression was determined by realtime PCR, and secretion of VEGF and bFGF was examined with ELISA. The phosphorylation level of proteins was revealed by Western blotting. The proliferation of RPE cells was slightly increased by curcumin at 10 mM and strongly reduced by curcumin above 50 mM. Curcumin at 50 mM increased slightly the chemotaxis of the cells. Curcumin reduced the expression and secretion of VEGF under control conditions and abolished the VEGF secretion induced by PDGF and chemical hypoxia. Whereas low concentrations of curcumin stimulated the expression of bFGF and HGF, high concentrations caused downregulation of both factors. Curcumin decreased dose-dependently the viability of RPE cells via induction of early necrosis (above 10 mM) and delayed apoptosis (above 1 mM). The cytotoxic effect of curcumin involved activation of caspase-3 and calpain, intracellular calcium signaling, mitochondrial permeability, oxidative stress, increased phosphorylation of p38 MAPK and decreased phosphorylation of Akt protein. Conclusion: It is concluded that curcumin at concentrations described to be effective in the treatment of tumor cells and in inhibiting death of retinal neurons (,10 mM) has adverse effects on RPE cells. It is suggested that, during the intake of curcumin as concomitant therapy of cancer or in the treatment of eye diseases, retinal function should be monitored carefully.
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The natural phenolic compound curcumin (diferuloylmethane),
the yellow pigment of turmeric and an ingredient in curry
powders, has a long history of use in traditional Asian medicine for
a wide variety of disorders. Curcumin has been shown to have
antiinflammatory, antioxidant, and antiproliferative effects in
various cell systems [1,2]. In addition, curcumin has antiviral
effects, inhibits the proliferation of bacteria and fungi [36], and
induces immunosupression in subjects with renal transplants [7].
Curcumin is recognized as a promising anticancer drug and is
believed to be helpful as concomitant therapy of a variety of
diseases associated with chronic inflammation and as adjuvant
immunosuppressant [1,8,9]. Curcumin influences multiple
intracellular signaling pathways and has both antioxidant and
prooxidant effects in dependence on the concentration of the
compound [1013]. It induces apoptosis of cancer cells by
activation of procaspases and the release of cytochrome c from
mitochondria [1416]. Both antioxidant and prooxidant activities
were shown to be involved in the anticancer activity of curcumin
[1013]. However, it is conceivable that cytotoxic effects of
curcumin may also concern non-transformed cells. Indeed, it has
been found that curcumin may cause toxicity to non-transformed
cells under some circumstances [9,17,18].
Elevated oxidative stress contributes to the pathogenesis of
various blinding retinal diseases including diabetic retinopathy,
retinitis pigmentosa, and age-related macular degeneration [19
24]. Antioxidant nutrients may decrease the risk of the
development of age-related macular degeneration [2527]. Based
upon data obtained in animal models of retinopathies and cultured
retinal cells, it has been suggested that curcumin could have
potential benefits in inhibiting the development of diabetic
retinopathy, age-related macular degeneration, and retinitis
pigmentosa [2830]. Dietary curcumin reduced oxidative changes
and inhibited the elevations of interleukin-1, tumor necrosis
factor (TNF)-a, and vascular endothelial growth factor (VEGF) in
the retina of hyperglycemic rats [28,31,32]. Dietary curcumin also
inhibited the upregulation of inflammatory genes in a rat model of
light-induced retinal degeneration, and protected retinal cells from
oxidative cell death [29]. It p (...truncated)