Curcumin Inhibits Growth of Saccharomyces cerevisiae through Iron Chelation

Abstract

Curcumin, a polyphenol derived from turmeric, is an ancient therapeutic used in India for centuries to treat a wide array of ailments. Interest in curcumin has increased recently, with ongoing clinical trials exploring curcumin as an anticancer therapy and as a protectant against neurodegenerative diseases. In vitro, curcumin chelates metal ions. However, although diverse physiological effects have been documented for this compound, curcumin's mechanism of action on mammalian cells remains unclear. This study uses yeast as a model eukaryotic system to dissect the biological activity of curcumin. We found that yeast mutants lacking genes required for iron and copper homeostasis are hypersensitive to curcumin and that iron supplementation rescues this sensitivity. Curcumin penetrates yeast cells, concentrates in the endoplasmic reticulum (ER) membranes, and reduces the intracellular iron pool. Curcumin-treated, iron-starved cultures are enriched in unbudded cells, suggesting that the G 1 phase of the cell cycle is lengthened. A delay in cell cycle progression could, in part, explain the antitumorigenic properties associated with curcumin. We also demonstrate that curcumin causes a growth lag in cultured human cells that is remediated by the addition of exogenous iron. These findings suggest that curcumin-induced iron starvation is conserved from yeast to humans and underlies curcumin's medicinal properties.Curcumin is the major chemical component of turmeric, a dietary spice made from the root of the Curcuma longa Linn plant and used extensively in traditional Indian medicine (38). Curcumin is a potent bioactive compound that is used to treat cancer (5, 35), atherosclerosis (33), and neurodegenerative diseases, such as Alzheimer's (26, 45) and Parkinson's (44) disease, as well as to promote wound healing (15,36). Curcumin is particularly appealing as a therapeutic agent because of its extremely low toxicity. Many biological activities have been ascribed to curcumin. For example, curcumin suppresses inflammatory responses in cultured cells and in animals and also exhibits antioxidant properties. Furthermore, curcumin's ability to inhibit tumorigenesis and proliferation of a wide variety of cancerous cells has been well documented. Curcumin is a polyphenol and complexes readily with a number of different metal ions. In aqueous solutions of neutral pH, curcumin is an effective chelator of Fe(III) (2). Curcumin is also lipophilic and readily crosses membranes (19), so therefore it may also chelate metal ions intracellularly. How these chemical properties contribute to curcumin's biological activities, however, is not understood.Identifying relevant in vivo targets of small molecules is technically challenging. Recently, several genetic and genomic approaches have been developed that use the simple eukaryote Saccharomyces cerevisiae, or budding yeast, to study the mechanism of drug action (17,27,31). One such method, termed homozygous profiling, uses a comprehensive collection of 4,700 homozygous diploid deletion yeast...

Driving the Cell Cycle Through Metabolism

“…For example, CDC1, mutants of which arrest at G 1 , encodes a Mn 2+ -dependent protein (Supek et al 1997). Iron chelation by curcumin treatment inhibits cell cycle progression at G 1 (Minear et al 2011). Ca 2+ regulates the onset of mitosis through the calcium-dependent phosphatase calcineurin and Mpk1p, a component of the MAPK pathway (Mizunuma et al 1998).…”

Degradation of Curcumin: From Mechanism to Biological Implications

“…8). 41-47 The metal chelating activity of the β-diketo moiety is independent of oxidative transformation. It may be disturbed by the formation of the cyclopentadione ring which is more nucleophilic (acidic) than the β-diketo moiety of curcumin.…”

Neuroprotective Effects of Curcumin and Highly Bioavailable Curcumin on Oxidative Stress Induced by Sodium Nitroprusside in Rat Striatal Cell Culture

“…36) Minear et al reported that curcumin significantly decreased intracellular iron levels. 38) Thus, our results suggested that curcumin entered the cells and protected against SNP-induced cytotoxicity by its free radical-scavenging and iron-chelating abilities.…”