Anti-Tumour TreatmentSelective sensitization of tumors to chemotherapy by marine-derived lipids: A review
Introduction
In 2008, more than 12.5 million new cases of cancer were diagnosed around the world (1,603,870 in Northern America and 3,208,882 in Europe) (http://globocan.iarc.fr/). Despite great improvements in screening strategies and adjuvant therapies, a large number of these patients still die (7,564,802 deaths around the world in 2008, 638,328 in Northern America and 1,715,240 in Europe) (http://globocan.iarc.fr/), mainly because of the development of metastases. When metastases develop, survival length and quality of life depend upon tumor sensitivity to anticancer treatments. For most cancers, current treatments still rely heavily on conventional chemotherapy.
Since the 1950s, when chemotherapy was first introduced, the loss of tumor sensitivity to anticancer drugs and drug toxicity to non-tumor tissues are the daily concerns of oncologists. After exposure to a drug, a tumor loss of sensitivity to the drug, also termed acquired resistance, is a major cause of chemotherapy failure. Increasing the dosage of the drug would increase tumor exposure to the drug and thus circumvent, totally or partially, the loss of sensitivity. However, this scenario is dampened by the side effects of the drugs to non-tumor tissues, which result from their non-selective distribution. These side effects have required adjustment in the dosage and the schedule of administration of cytotoxic drugs to allow non-tumor tissues to repair chemotherapy-induced injuries. The difference in anticancer drug toxicity between tumor and non-tumor tissues, namely the therapeutic index, is the key element guiding the development of chemotherapy strategies. Efforts to preserve non-tumor tissues have shifted from regional chemotherapy in the 1960s (regional administration of drugs around the tumor to minimize their systemic distribution), to targeted therapies in the 1990s. The current approach of targeted therapy is aimed at preserving non-tumor tissues by developing drugs that selectively target cancer cells. Although their antitumor activity is not in dispute, their selectivity is not complete. Among the most frequently used, trastuzumab can cause cardiac side effects,1 bevacizumab can cause hypertension or intestinal perforation,2 rituximab presents risks of infections or immunological reactions,3 and cetuximab induces skin toxicities,4 which, although non-life-threatening, can impair the quality of life.
The development of approaches aimed at increasing chemotherapy toxicity to tumors while not affecting other tissues is a challenging issue because it could improve the outcome of patients with advanced cancers and preserve their quality of life. The ideal approach would consist of increasing the drug sensitivity of tumors while decreasing or at least not altering the drug sensitivity of non-tumor tissues. The marine-derived lipids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), can differentially sensitize tissues to chemotherapy. These lipids sensitize cancer cells or tumors to anticancer drugs while preserving or even protecting non-tumor tissues. While the potential of DHA and EPA to improve chemotherapy has been reviewed,5, 6, 7, 8, 9, 10 neither their differential effect on tumor and non-tumor tissues nor the possibility to use them in clinical practice has been discussed. We report herein (i) the preclinical and clinical studies supporting the double-faceted properties of these lipids, (ii) the mechanisms involved in their effects, and (iii) discuss the potential for DHA and EPA transfer to the patient.
Section snippets
Methodology
In vitro studies, animal experiments, and clinical studies addressing DHA, EPA, or DHA plus EPA effects on anticancer drugs toxicity to cancer cells, non-transformed cells, tumors or non-tumor tissues were searched within the Pubmed database by using various combinations of the following keywords: “docosahexaenoic acid, eicosapentaenoic acid, n−3 PUFA, fish oil, cancer, tumors, chemotherapy, anticancer drugs, cytotoxic drugs, toxicity”. Papers not published in English were excluded. Preclinical
Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)
DHA and EPA are long chain polyunsaturated fatty acids (PUFA) of the n−3 family, found in large amounts in products of marine origin (e.g., algae and fish). DHA, with 22 carbon atoms and 6 double bonds, is the longest and the most unsaturated fatty acid of this family that is common in mammalian tissues. EPA has 20 carbons and 5 double bonds (Fig. 1). Mammalian cells cannot synthesize long chain PUFA de novo because they cannot introduce double bonds beyond the Δ9 position. EPA and DHA
DHA and EPA increase the toxicity of chemotherapy to cancer cells or tumors
In addition to their direct cytotoxic effect on cancer cells,33, 34 numerous in vitro and in vivo studies have also reported that DHA or EPA, even when used at doses that have no substantial impact on cell viability or tumor growth, can increase the cytotoxicity of anticancer drugs to cancer cells or tumors. This indicates that these lipids have the potential to increase the sensitivity of cancer cells or tumors to anticancer drugs.
DHA and EPA do not increase the toxicity of chemotherapy to normal cells or non-tumor tissues
DHA and EPA sensitize cancer cells and tumors to anticancer drugs. Whether DHA or EPA also sensitize non-tumor tissues to anticancer drugs is a critical point since these fatty acids are ubiquitously distributed to tissues, as is chemotherapy. In fact, brain, heart, skeletal muscle, and liver content of DHA is already higher than the DHA content of tumor tissue in unsupplemented animals. When the diet was supplemented with DHA, the amount of DHA increased in tumors but also in normal tissues,
Mechanisms involved in the selective sensitization of tumors to chemotherapy by DHA and EPA
It is assumed that the toxicity of chemotherapy to normal tissues is due to its non-selective distribution to tissues, and is driven by mechanisms similar to those responsible for its toxicity to tumors. DHA or EPA enhance the antitumor activity of 15 anticancer drugs which represent six families of drugs: antimetabolites (5-FU and cytarabine),92, 93 alkylating (cyclophosphamide, mitomycin-C and cisplatin)94, 95, 96 or intercalating agents (doxorubicin, epirubicin, irinotecan and mitoxantrone),
Preclinical data fit with current chemotherapy strategies
Most of the preclinical studies performed during the last two decades are relevant to current chemotherapy strategies. A summary of the studies that fit with current chemotherapy strategies is presented according to the type of cancer and the stage of investigation (studies in cancer cell lines, animal models or patients) in Fig. 6.
Doxorubicin, epirubicin, docetaxel, paclitaxel, cyclophosphamide, vinorelbine, and mitoxantrone are all indicated in the current chemotherapy strategies for advanced
Conclusions
Thirty years of research have produced consistent preclinical and clinical studies indicating that DHA and EPA selectively increases the sensitivity of tumors but not non-tumor tissues to chemotherapy. Although further studies are required to elucidate the various mechanisms that mediate this selectivity, these results are strong enough to justify clinical investigation. Several clinical trials are ongoing to investigate the effects of DHA and EPA on chemotherapy efficacy or on patient
Conflict of interest
Authors declare no conflict of interest.
Acknowledgments
We thank Norman Salem Jr. and Pierre Besson for their critical comments. N.H. was supported by a grant “Poste d’Accueil” from Inserm.
References (179)
- et al.
Risk of cardiac dysfunction with trastuzumab in breast cancer patients: a meta-analysis
Cancer Treat Rev
(2011) - et al.
Bevacizumab toxicities and their management in ovarian cancer
Gynecol Oncol
(2010) - et al.
Fatty acids and breast cancer: sensitization to treatments and prevention of metastatic re-growth
Prog Lipid Res
(2010) - et al.
The potential for treatment with dietary long-chain polyunsaturated n−3 fatty acids during chemotherapy
J Nutr Biochem
(2008) Nutritional intervention with omega-3 fatty acids enhances tumor response to anti-neoplastic agents
Chem Biol Interact
(2006)The roles of anabolic and catabolic reactions in the synthesis and recycling of polyunsaturated fatty acids
Prostaglandins Leukot Essent Fatty Acids
(2002)- et al.
Alpha-linolenic acid supplementation and conversion to n−3 long-chain polyunsaturated fatty acids in humans
Prostaglandins Leukot Essent Fatty Acids
(2009) Fatty acid biosynthesis in microorganisms being used for Single Cell Oil production
Biochimie
(2004)- et al.
A review of the safety of DHA45-oil
Food Chem Toxicol
(2003) - et al.
Docosahexaenoic acid: membrane properties of a unique fatty acid
Chem Phys Lipids
(2003)
Adriamycin transport and sensitivity in fatty acid modified leukemia cells
Biochim Biophys Acta
Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites?
Prostaglandins Leukot Essent Fatty Acids
Differential sensitization of cancer cells to doxorubicin by DHA: a role for lipoperoxidation
Free Radic Biol Med
Sensitization by docosahexaenoic acid (DHA) of breast cancer cells to anthracyclines through loss of glutathione peroxidase (GPx1) response
Free Radic Biol Med
Effects of cis-unsaturated fatty acids on doxorubicin sensitivity in P388/DOX resistant and P388 parental cell lines
Life Sci
Effects of polyunsaturated fatty acids on the efficacy of antineoplastic agents toward L5178Y lymphoma cells
Biochem Pharmacol
Meglumine Eicosapentaenoic acid (MeEPA) a new soluble omega-3 fatty acid formulation: in vitro bladder cancer cytotoxicity tests in combination with epirubicin and mitomycin
Prostaglandins Leukot Essent Fatty Acids
Effects of gamma-linolenic acid and oleic acid on paclitaxel cytotoxicity in human breast cancer cells
Eur J Cancer
Docosahexaenoic acid enhances arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant HL-60 cells
Blood
Docosahexaenoic acid enhances the toxic effect of imatinib on Bcr-Abl expressing HL-60 cells
Toxicol In Vitro
Dietary fish oil sensitizes A549 lung xenografts to doxorubicin chemotherapy
Cancer Lett
Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids
Cancer Cell
A mathematical relationship between the fatty acid composition of the diet and that of the adipose tissue in man
Am J Clin Nutr
Docosahexaenoic acid exhibits a potent protection of small intestine from methotrexate-induced damage in mice
Life Sci
Anthracycline-induced cardiac toxicity is not increased by dietary omega-3 fatty acids
Pharmacol Res
Oral nutritional supplements containing (n−3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment
J Nutr
The biology of alkylating-agent cellular injury
Hematol Oncol Clin North Am
Molecular and biochemical pharmacology of mitoxantrone
Cancer Treat Rev
Ten years of rituximab in NHL
Expert Opin Drug Saf
Skin toxicities associated with epidermal growth factor receptor inhibitors
Target Oncol
Antineoplastic effects of n−3 polyunsaturated fatty acids in combination with drugs and radiotherapy: preventive and therapeutic strategies
Nutr Cancer
Enhancing cytotoxic therapies for breast and prostate cancers with polyunsaturated fatty acids
Nutr Cancer
Colon cancer therapy: new perspectives of nutritional manipulations using polyunsaturated fatty acids
Curr Opin Clin Nutr Metab Care
Extremely limited synthesis of long chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements
Appl Physiol Nutr Metab
Substances affirmed as generally recognized as safe: hydrogenated and partially hydrogenated menhaden oils; final rule (21 CFR, Part 184, Docket No. 86G-0289)
US Fed Regist
Docosahexaenoic acid: membrane function and metabolism
Incorporation of long-chain n−3 fatty acids in tissues and enhanced bone marrow cellularity with docosahexaenoic acid feeding in post-weanling Fischer 344 rats
Lipids
DHA feeding provides host protection and prevents fibrosarcomas-induced hyperlipidemia while maintaining the tumor response to araC in Fischer 344 rats
Nutr Cancer
Membrane lipid alteration: effect on cellular uptake of mitoxantrone
Lipids
Regulation of nucleoside drug toxicity by transport inhibitors and omega-3 polyunsaturated fatty acids in normal and transformed rat-2 fibroblasts
Cell Pharmacol
EPA and DHA alter nucleoside drug and doxorubicin toxicity in L1210 cells but not in normal murine S1 macrophages
Cell Pharmacol
Effects of n−3 fatty acids during neoplastic progression and comparison of in vitro and in vivo sensitivity of two human tumour cell lines
Br J Cancer
Effect of omega-3 fatty acids on the progression of metastases after the surgical excision of human breast cancer cell solid tumors growing in nude mice
Clin Cancer Res
Dietary fish oil and vitamin E enhance doxorubicin effects in P388 tumor-bearing mice
Lipids
Sensitization by dietary docosahexaenoic acid of rat mammary carcinoma to anthracycline: a role for tumor vascularization
Clin Cancer Res
Determinants of DHA incorporation into tumor tissue during dietary DHA supplementation
Lipids
Differential killing of human carcinoma cells supplemented with n−3 and n−6 polyunsaturated fatty acids
J Natl Cancer Inst
Polyunsaturated fatty acid-induced cytotoxicity against tumor cells and its relationship to lipid peroxidation
J Natl Cancer Inst
Enhancement of doxorubicin cytotoxicity by polyunsaturated fatty acids in the human breast tumor cell line MDA-MB-231: relationship to lipid peroxidation
Int J Cancer
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