Differential sensitization of cancer cells to doxorubicin by DHA: a role for lipoperoxidation.
Polyunsaturated fatty acids have been reported to enhance the cytotoxic activity of several anticancer drugs. In the present study, we observed that doxorubicin chemosensitization of breast cancer cell lines by docosahexaenoic acid (DHA, a long-chain omega-3 polyunsaturated fatty acid) was cell-line selective, affecting MDA-MB-231 and MCF-7 dox (a doxorubicin-resistant cell line) but not the parental MCF-7 cell line. DHA supplementation led to an increase in membrane phospholipid DHA level, but did not induce changes in intracellular [(14)C]doxorubicin accumulation. In MDA-MB-231, doxorubicin efficacy enhancement by DHA was linked to an increase in malondialdehyde level, a final product of lipid peroxidation. DHA elicited by itself a 3.7-fold malondialdehyde level increase, additive to that induced by doxorubicin. Addition of doxorubicin to DHA further increased the glutathione level, indicative of the generation of an oxidative stress. In contrast to MDA-MB-231, doxorubicin did not increase the malondialdehyde level in MCF-7, although DHA induced lipid peroxidation. Therefore in MCF-7, lipid peroxidation induced by DHA itself was not sufficient to trigger an oxidative stress and to subsequently increase sensitivity to doxorubicin. These data indicate that the differential effect of DHA among cells on drug toxicity results from a differential oxidative response to doxorubicin. Chemosensitization through fatty acids appears as a new promising adjuvant therapeutic paradigm, since omega-3 fatty acids are physiological molecules found in food and are nontoxic in vivo.
Mahéo
Karine
K
INSERM E 0211 Nutrition, Croissance et Cancer, IFR 135 Imagerie Fonctionnelle, Université François-Rabelais, Tours, France.
Vibet
Sophie
S
Steghens
Jean Paul
JP
Dartigeas
Caroline
C
Lehman
Magali
M
Bougnoux
Philippe
P
Goré
Jacques
J
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology*; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004357:Drug Synergism; D005227:Fatty Acids / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D008315:Malondialdehyde / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry; D013997:Time Factors; D014810:Vitamin E / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; D010743:Phospholipids; D014810:Vitamin E; D004281:Docosahexaenoic Acids; D008315:Malondialdehyde; D004317:Doxorubicin; D005978:Glutathione; D010100:Oxygen; D019803:Glutathione Disulfide