Elsevier

Cancer Treatment Reviews

Volume 39, Issue 5, August 2013, Pages 473-488
Cancer Treatment Reviews

Anti-Tumour Treatment
Selective sensitization of tumors to chemotherapy by marine-derived lipids: A review

https://doi.org/10.1016/j.ctrv.2012.07.001Get rights and content

Abstract

Despite great improvements, a significant proportion of cancer patients still die, mainly because of the development of metastases. At this stage, current treatments still rely heavily on conventional chemotherapy for most cancers. The efficacy of chemotherapy is dose-dependent, which is limited by toxicity to non-tumor tissues, as a result of its poor tumor selectivity. To improve survival length and preserve quality of life, the challenge is to develop approaches aimed at increasing chemotherapy toxicity to tumor tissue while not affecting non-tumor tissues. Marine-derived lipids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have the potential to differentially sensitize tissues to chemotherapy. These lipids enhance the cytotoxicity of 15 anticancer drugs (antimetabolites, alkylating or intercalating agents, microtubule stabilizers, Abl tyrosine kinase inhibitor and arsenic trioxide) to a variety of cancer cell lines or tumors in animals, used as models for breast, prostate, colonic, lung, cervical, ovarian cancers, neuroblastomas, leukemia or lymphomas. However, DHA and EPA do not sensitize non-tumor tissues to anticancer drugs, which suggests that the effect of these lipids is tumor selective. Two phase II clinical trials already support these results, and randomized, phase III trials are ongoing. In this review, we discuss the double-faceted properties of these lipids, and then focus on their potential for transfer to the patient in the light of current therapeutic strategies. Should their beneficial effects be confirmed, the consequences could be considerable by opening up the prospect of systematic supplementation during cancer treatment, a significant shift in current cancer therapeutic paradigms.

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)

  • C.P. Burns et al.

    Adriamycin transport and sensitivity in fatty acid modified leukemia cells

    Biochim Biophys Acta

    (1986)
  • U.N. Das et al.

    Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites?

    Prostaglandins Leukot Essent Fatty Acids

    (1998)
  • K. Mahéo et al.

    Differential sensitization of cancer cells to doxorubicin by DHA: a role for lipoperoxidation

    Free Radic Biol Med

    (2005)
  • S. Vibet et al.

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

    Free Radic Biol Med

    (2008)
  • Q.Y. Liu et al.

    Effects of cis-unsaturated fatty acids on doxorubicin sensitivity in P388/DOX resistant and P388 parental cell lines

    Life Sci

    (2000)
  • J.E. Kinsella et al.

    Effects of polyunsaturated fatty acids on the efficacy of antineoplastic agents toward L5178Y lymphoma cells

    Biochem Pharmacol

    (1993)
  • S.J. Mackie et al.

    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

    (2006)
  • J.A. Menéndez et al.

    Effects of gamma-linolenic acid and oleic acid on paclitaxel cytotoxicity in human breast cancer cells

    Eur J Cancer

    (2001)
  • S. Sturlan et al.

    Docosahexaenoic acid enhances arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant HL-60 cells

    Blood

    (2003)
  • T.M. de Lima et al.

    Docosahexaenoic acid enhances the toxic effect of imatinib on Bcr-Abl expressing HL-60 cells

    Toxicol In Vitro

    (2007)
  • W.E. Hardman et al.

    Dietary fish oil sensitizes A549 lung xenografts to doxorubicin chemotherapy

    Cancer Lett

    (2000)
  • J.M. Roodhart et al.

    Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids

    Cancer Cell

    (2011)
  • A.C. Beynen et al.

    A mathematical relationship between the fatty acid composition of the diet and that of the adipose tissue in man

    Am J Clin Nutr

    (1980)
  • T. Horie et al.

    Docosahexaenoic acid exhibits a potent protection of small intestine from methotrexate-induced damage in mice

    Life Sci

    (1998)
  • E. Germain et al.

    Anthracycline-induced cardiac toxicity is not increased by dietary omega-3 fatty acids

    Pharmacol Res

    (2003)
  • B.S. van der Meij et al.

    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

    (2010)
  • L.N. Shulman

    The biology of alkylating-agent cellular injury

    Hematol Oncol Clin North Am

    (1993)
  • F.E. Durr et al.

    Molecular and biochemical pharmacology of mitoxantrone

    Cancer Treat Rev

    (1983)
  • M.C. Winter et al.

    Ten years of rituximab in NHL

    Expert Opin Drug Saf

    (2009)
  • T. Li et al.

    Skin toxicities associated with epidermal growth factor receptor inhibitors

    Target Oncol

    (2009)
  • G. Calviello et al.

    Antineoplastic effects of n−3 polyunsaturated fatty acids in combination with drugs and radiotherapy: preventive and therapeutic strategies

    Nutr Cancer

    (2009)
  • I.A. Shaikh et al.

    Enhancing cytotoxic therapies for breast and prostate cancers with polyunsaturated fatty acids

    Nutr Cancer

    (2010)
  • Y.M. Dupertuis et al.

    Colon cancer therapy: new perspectives of nutritional manipulations using polyunsaturated fatty acids

    Curr Opin Clin Nutr Metab Care

    (2007)
  • M. Plourde et al.

    Extremely limited synthesis of long chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements

    Appl Physiol Nutr Metab

    (2007)
  • US FDA

    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

    (1989)
  • US FDA. Letter regarding dietary supplement health claim for omega-3 fatty acids and coronary heart disease (Docket No....
  • N. Salem et al.

    Docosahexaenoic acid: membrane function and metabolism

  • T.G. Atkinson et al.

    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

    (1997)
  • T.G. Atkinson et al.

    DHA feeding provides host protection and prevents fibrosarcomas-induced hyperlipidemia while maintaining the tumor response to araC in Fischer 344 rats

    Nutr Cancer

    (1997)
  • C.P. Burns et al.

    Membrane lipid alteration: effect on cellular uptake of mitoxantrone

    Lipids

    (1988)
  • T.G. Atkinson et al.

    Regulation of nucleoside drug toxicity by transport inhibitors and omega-3 polyunsaturated fatty acids in normal and transformed rat-2 fibroblasts

    Cell Pharmacol

    (1995)
  • H.M. de Salis et al.

    EPA and DHA alter nucleoside drug and doxorubicin toxicity in L1210 cells but not in normal murine S1 macrophages

    Cell Pharmacol

    (1995)
  • L. Maehle et al.

    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

    (1995)
  • D.P. Rose et al.

    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

    (1996)
  • Q.-Y. Liu et al.

    Dietary fish oil and vitamin E enhance doxorubicin effects in P388 tumor-bearing mice

    Lipids

    (2002)
  • S. Colas et al.

    Sensitization by dietary docosahexaenoic acid of rat mammary carcinoma to anthracycline: a role for tumor vascularization

    Clin Cancer Res

    (2006)
  • N. Hajjaji et al.

    Determinants of DHA incorporation into tumor tissue during dietary DHA supplementation

    Lipids

    (2011)
  • M.E. Begin et al.

    Differential killing of human carcinoma cells supplemented with n−3 and n−6 polyunsaturated fatty acids

    J Natl Cancer Inst

    (1986)
  • M.E. Begin et al.

    Polyunsaturated fatty acid-induced cytotoxicity against tumor cells and its relationship to lipid peroxidation

    J Natl Cancer Inst

    (1988)
  • E. Germain et al.

    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

    (1998)
  • Cited by (61)

    • Emerging insights on drug delivery by fatty acid mediated synthesis of lipophilic prodrugs as novel nanomedicines

      2020, Journal of Controlled Release
      Citation Excerpt :

      These FAs demonstrate significant physiological effects on human health by: Playing a key role in the normal function of stem cells and biomembranes [41]; Improving cardiovascular health due to their effect on reducing the viscosity of blood via decreasing the blood concentration of triglycerides and cholesterol [42];

    View all citing articles on Scopus
    View full text