Iron chelation by curcumin suppresses both curcumin-induced autophagy and cell death together with iron overload neoplastic transformation

Nathan E Rainey,Franck Sureau,Ana Saric,Gael Nicolas,Aoula Moustapha,Patrice X Petit

doi:10.1038/s41420-019-0234-y

Abstract

Iron overload, notably caused by hereditary hemochromatosis, is an excess storage of iron in various organs that causes tissue damage and may promote tumorigenesis. To manage that disorder, free iron depletion can be induced by iron chelators like deferoxamine that are of increasing interest also in the cancer field since iron stock could be a potent target for managing tumorigenesis. Curcumin, a well-known active substance extracted from the turmeric rhizome, destabilizes endoplasmic reticulum, and secondarily lysosomes, thereby increasing mitophagy/autophagy and subsequent apoptosis. Recent findings show that cells treated with curcumin also exhibit a decrease in ferritin, which is consistent with its chemical structure and iron chelating activity. Here we investigated how curcumin influences the intracellular effects of iron overload via Fe-nitriloacetic acid or ferric ammonium citrate loading in Huh-7 cells and explored the consequences in terms of antioxidant activity, autophagy, and apoptotic signal transduction. In experiments with T51B and RL-34 epithelial cells, we have found evidence that curcumin-iron complexation abolishes both curcumin-induced autophagy and apoptosis, together with the tumorigenic action of iron overload.

Highlights

Iron is a key element of numerous biological processes, but the presence of free or loosely bound iron can be toxic to cells[1]
It is well known that the diketone groups of curcumin likely interact with the Fe-nitrilotriacetic acid (NTA)-resin in a similar fashion to the phosphate oxygens of phosphopeptides, for which this iron affinity chromatography resin was developed[64]
The iron chelation activity of curcumin is related to its chemical structure via the β-diketone group, a known bidentate chelator of Fe2+, similar to the group found in simple analogous complexes of Fe(III) and acetylacetonate

Summary

Introduction

Iron is a key element of numerous biological processes, but the presence of free or loosely bound iron can be toxic to cells[1]. Iron being an active redox metal, the excess free form can generate reactive oxygen species (ROS) through Haber–Weiss reduction followed by Fenton reactions[2,3]. Some iron chelators are able to chelate iron, and to inhibit the redox properties of free labile iron. Such ligands may prevent iron from participating in Fenton reactions, inhibiting the formation of ROS like the hydroxyl radical, which initiates oxidative damage[10] and ferroptosis, recently recognized as a form of regulated necrotic cell death[11]. Ferroptosis is usually designed as one of the multiple variants of cell death that can be characterized by a high intracellular level of free iron associated with ROS12,13. Ferroptosis is linked to the production of reduced glutathione and/or to alterations of Official journal of the Cell Death Differentiation Association

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Results

Conclusion