Lutein Protects against Methotrexate-Induced and Reactive Oxygen Species-Mediated Apoptotic Cell Injury of IEC-6 Cells

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Abstract

Purpose

High-dose chemotherapy using methotrexate (MTX) frequently induces side effects such as mucositis that leads to intestinal damage and diarrhea. Several natural compounds have been demonstrated of their effectiveness in protecting intestinal epithelial cells from these adverse effects. In this paper, we investigated the protection mechanism of lutein against MTX-induced damage in IEC-6 cells originating from the rat jejunum crypt.

Methods

The cell viability, induced-apoptosis, reactive oxygen species (ROS) generation, and mitochondrial membrane potential in IEC-6 cells under MTX treatment were examined in the presence or absence of lutein. Expression level of Bcl2, Bad and ROS scavenging enzymes (including SOD, catalase and Prdx1) were detected by quantitative RT-PCR.

Results

The cell viability of IEC-6 cells exposed to MTX was decreased in a dose- and time-dependent manner. MTX induces mitochondrial membrane potential loss, ROS generation and caspase 3 activation in IEC-6 cells. The cytotoxicity of MTX was reduced in IEC-6 cells by the 24 h pre-treatment of lutein. We found that pre-treatment of lutein significantly reduces MTX-induced ROS and apoptosis. The expression of SOD was up-regulated by the pre-treatment of lutein in the MTX-treated IEC-6 cells. These results indicated that lutein can protect IEC-6 cells from the chemo-drugs induced damage through increasing ROS scavenging ability.

Conclusion

The MTX-induced apoptosis of IEC-6 cells was shown to be repressed by the pre-treatment of lutein, which may represent a promising adjunct to conventional chemotherapy for preventing intestinal damages.

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Most cited references 38

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Mitochondria and apoptosis.

D Green, J Reed (1998)

A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, and participation of pro- and antiapoptotic Bcl-2 family proteins. The different signals that converge on mitochondria to trigger or inhibit these events and their downstream effects delineate several major pathways in physiological cell death.

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Neuroprotective Effects of Lutein in the Retina

Yoko Ozawa, Mariko Sasaki, Noriko Takahashi … (2012)

Although a large variety of pharmaceutical therapies for treating disease have been developed in recent years, there has been little progress in disease prevention. In particular, the protection of neural tissue is essential, because it is hardly regenerated. The use of nutraceuticals for maintaining the health has been supported by several clinical studies, including cross-sectional and interventional studies for age-related macular disease. However, mechanistic evidence for their effects at the molecular level has been very limited. In this review, we focus on lutein, which is a xanthophyll type of carotenoid. Lutein is not synthesized in mammals, and must be obtained from the diet. It is delivered to the retina, and in humans, it is concentrated in the macula. Here, we describe the neuroprotective effects of lutein and their underlying molecular mechanisms in animal models of vision-threatening diseases, such as innate retinal inflammation, diabetic retinopathy, and light-induced retinal degeneration. In lutein-treated mouse ocular disease models, oxidative stress in the retina is reduced, and its downstream pathological signals are inhibited. Furthermore, degradation of the functional proteins, rhodopsin (a visual substance) and synaptophysin (a synaptic vesicle protein also influenced in other neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease), the depletion of brain-derived neurotrophic factor (BDNF), and DNA damage are prevented by lutein, which preserves visual function. We discuss the possibility of using lutein, an antioxidant, as a neuroprotective treatment for humans.

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Mitochondria and apoptosis.

J L Vayssière, B. Mignotte (1998)

Programmed cell death serves as a major mechanism for the precise regulation of cell numbers and as a defense mechanism to remove unwanted and potentially dangerous cells. Despite the striking heterogeneity of cell death induction pathways, the execution of the death program is often associated with characteristic morphological and biochemical changes, and this form of programmed cell death has been termed apoptosis. Genetic studies in Caenorhabditis elegans had led to the identification of cell death genes (ced). The genes ced-3 and ced-4 are essential for cell death; ced-9 antagonizes the activities of ced-3 and ced-4, and thereby protects cells that should survive from any accidental activation of the death program. Caspases (cysteine aspartases) are the mammalian homologues of CED-3. CED-9 protein is homologous to a family of many members termed the Bcl-2 family (Bcl-2s) in reference to the first discovered mammalian cell death regulator. In both worm and mammalian cells, the antiapoptotic members of the Bcl-2 family act upstream of the execution caspases somehow preventing their proteolytic processing into active killers. Two main mechanisms of action have been proposed to connect Bcl-2s to caspases. In the first one, antiapoptotic Bcl-2s would maintain cell survival by dragging caspases to intracellular membranes (probably the mitochondrial membrane) and by preventing their activation. The recently described mammalian protein Apaf-1 (apoptosis protease-activating factor 1) could be the mammalian equivalent of CED-4 and could be the physical link between Bcl-2s and caspases. In the second one, Bcl-2 would act by regulating the release from mitochondria of some caspases activators: cytochrome c and/or AIF (apoptosis-inducing factor). This crucial position of mitochondria in programmed cell death control is reinforced by the observation that mitochondria contribute to apoptosis signaling via the production of reactive oxygen species. Although for a long time the absence of mitochondrial changes was considered as a hallmark of apoptosis, mitochondria appear today as the central executioner of programmed cell death. In this review, we examine the data concerning the mitochondrial features of apoptosis. Furthermore, we discuss the possibility that the mechanism originally involved in the maintenance of the symbiosis between the bacterial ancestor of the mitochondria and the host cell precursor of eukaryotes, provided the basis for the actual mechanism controlling cell survival.

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Author and article information

Contributors

Xianglin Shi: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 6 September 2013

Volume: 8

Issue: 9

Electronic Location Identifier: e72553

Affiliations

[1 ]Division of Pediatric Surgery, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

[2 ]School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan

[3 ]Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

[4 ]Children's Hospital Informatics Program, Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, United States of America

[5 ]Department of Chemistry, Fu-Jen Catholic University, New Taipei, Taiwan

University of Kentucky, United States of America

Author notes

* E-mail: skin@ 123456mail.fju.edu.tw

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: CJC JFL CFH. Performed the experiments: CJC JFL. Analyzed the data: JFL HHC GAL. Contributed reagents/materials/analysis tools: JFL CFH. Wrote the paper: CJC JFL CFH.

Article

Publisher ID: PONE-D-13-17110

DOI: 10.1371/journal.pone.0072553

PMC ID: 3765170

PubMed ID: 24039779

SO-VID: 3b0e6473-2c27-49e5-95ad-2972caca7d19

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 25 April 2013

Date accepted : 11 July 2013

Page count

Pages: 8

Funding

This study was supported by National Science Council, Taiwan (NSC 101-2320-B-030-005-MY3 to C.F.H). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Lutein Protects against Methotrexate-Induced and Reactive Oxygen Species-Mediated Apoptotic Cell Injury of IEC-6 Cells

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Abstract

Purpose

Methods

Results

Conclusion

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PLOS Climate

Most cited references 38

Mitochondria and apoptosis.

Neuroprotective Effects of Lutein in the Retina

Mitochondria and apoptosis.

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