Sensitization by docosahexaenoic acid (DHA) of breast cancer cells to anthracyclines through loss of glutathione peroxidase (GPx1) response

Docosahexaenoic acid (DHA, a lipid of marine origin) has been found to enhance the activity of several anticancer drugs through an oxidative mechanism. To examine the relation between chemosensitization by DHA and tumor cells antioxidant status, we used two breast cancer cell lines: MDA-MB-231, in w...

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Bibliographic Details
Published in:Free radical biology & medicine 2008-04, Vol.44 (7), p.1483-1491
Main Authors: Vibet, Sophie, Goupille, Caroline, Bougnoux, Philippe, Steghens, Jean-Paul, Goré, Jacques, Mahéo, Karine
Format: Article
Language:English
Subjects:
Animals
Anthracyclines - metabolism
Antineoplastic Agents - pharmacology
Biochemistry, Molecular Biology
Breast cancer
Breast Neoplasms - metabolism
Cancer
Cell Line, Tumor
Cellular Biology
Chemotherapy sensitization
DHA
Docosahexaenoic Acids - metabolism
Female
Food and Nutrition
Gene Expression Regulation, Neoplastic
Glutathione - metabolism
Glutathione peroxidase
Glutathione Peroxidase - metabolism
Humans
Life Sciences
Mammary Neoplasms, Animal - drug therapy
Oxidative Stress
Rats
Reactive Oxygen Species
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Summary:Docosahexaenoic acid (DHA, a lipid of marine origin) has been found to enhance the activity of several anticancer drugs through an oxidative mechanism. To examine the relation between chemosensitization by DHA and tumor cells antioxidant status, we used two breast cancer cell lines: MDA-MB-231, in which DHA increases sensitivity to doxorubicin, and MCF-7, which does not respond to DHA. Under these conditions, reactive oxygen species (ROS) level increased on anthracycline treatment only in MDA-MB-231. This was concomitant with a decreased cytosolic glutathione peroxidase (GPx1) activity, a crucial enzyme for protection against hydrogen and lipid peroxides, while major antioxidant enzyme activities increased in both cell lines in response to ROS. GPx-decreased activity was accompanied by an accumulation of glutathione, the GPx cosubstrate, and resulted from a decreased amount of GPx protein. In rat mammary tumors, when a DHA dietary supplementation led to an increased tumor sensitivity to anthracyclines, GPx1 activity was similarly decreased. Furthermore, vitamin E abolished both DHA effects on chemotherapy efficacy enhancement and on GPx1 inhibition. Thus, loss of GPx response to an oxidative stress in transformed cells may account for the ability of peroxidizable targets such as DHA to enhance tumor sensitivity to ROS-generating anticancer drugs.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2008.01.009