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Tumor and non-tumor tissues differential oxidative stress response to supplemental DHA and chemotherapy in rats

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Abstract

Purpose

Developing approaches that will increase the selectivity of anticancer drugs remains a challenge. Docosahexaenoic acid (DHA) has the potential to increase tumor sensitivity to chemotherapy with no sensitization of normal tissues. This study was aimed at exploring the mechanism involved in this differential sensitization with a focus on oxidative stress, one of the main determinants involved in DHA enhancement of anthracycline-based chemotherapy.

Methods

In a previously validated model of chemically induced mammary tumors in rats where supplemental DHA sensitized tumors to epirubicin, DHA level, lipid hydroperoxides (LPO), total antioxidant activity, glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities were measured in tumors, intestine, liver, and heart in rats treated with DHA+epirubicin and in control rats (palm oil, no chemotherapy).

Results

At baseline, the level of LPO was similar in tumors, liver, heart, and small intestine. The proportion of DHA was higher in non-tumor tissues compared to tumors (liver or heart, p < 0.0001; intestine, p = 0.01). DHA and epirubicin induced a significant increase in LPO in tumors (p = 0.03), but no increase was detected in liver, heart, or intestine. The difference in LPO production between these tissues was associated with differences in their antioxidant defenses. In tumors, the adjustment of GPx activity was possible but limited, and no adjustment of their total antioxidant and SOD activities was observed compared to other tissues.

Conclusion

Supplementing DHA during an anthracycline-based chemotherapy induced a selective increase of LPO in tumors. This selectivity might result from a differential handling of oxidative stress between tumor and non-tumor tissues.

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Abbreviations

DHA:

Docosahexaenoic acid

DTT:

Dithiothreitol

EPA:

Eicosapentaenoic acid

FAME:

Fatty acid methyl ester

GPx:

Glutathione peroxidase

LPO:

Lipid hydroperoxides

NMU:

N-Nitroso N-Methyl Urea

PUFA:

Polyunsaturated fatty acid

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TBARS:

Thiobarbituric acid-reactive materials

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Acknowledgments

DHASCO was graciously provided by Martek Biosciences (Columbia, MD, USA) and palm oil by the Société Industrielle des Oléagineux (St Laurent Blangy, France). We also thank Valérie Schubnel for her contribution to this work. NH was supported by a grant “Poste d’Accueil” from Inserm.

Conflict of interest

The authors report no conflict of interest.

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Authors and Affiliations

  1. Cancer Research Laboratory, University Hospital of Tours, Tours, France

    Nawale Hajjaji & Philippe Bougnoux

  2. INSERM U921, Tours, France

    Nawale Hajjaji, Pierre Besson & Philippe Bougnoux

  3. Henry S. Kaplan Cancer Center, University Hospital of Tours, CHRU de Tours, 2 Boulevard Tonnellé, 37 044, Tours, France

    Nawale Hajjaji & Philippe Bougnoux

  4. University François-Rabelais, Tours, France

    Pierre Besson

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  1. Nawale Hajjaji
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Correspondence to Nawale Hajjaji.

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Hajjaji, N., Besson, P. & Bougnoux, P. Tumor and non-tumor tissues differential oxidative stress response to supplemental DHA and chemotherapy in rats. Cancer Chemother Pharmacol 70, 17–23 (2012). https://doi.org/10.1007/s00280-012-1884-0

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  • DOI: https://doi.org/10.1007/s00280-012-1884-0

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