Skip to main content
SpringerLink
Log in

Synergistic Interaction Between Vinorelbine and Gamma-Linolenic Acid in Breast Cancer Cells

  • Conference Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

It has been suggested that exogenous unsaturated fatty acids (UFAs) may increase the cytotoxic activity of cancer chemotherapeutic agents. We examined how γ-linolenic acid (GLA; 18 : 3n-6), the most promising UFA in the treatment of human tumors, affects the effectiveness of the lipophilic drug vinorelbine (VNR) on human breast carcinoma cell lines. Cells were exposed simultaneously to VNR and GLA or sequentially to GLA followed by VNR. Cell viability was determined by MTT assay. The increase in VNR-induced cell growth inhibition was measured by dividing the IC50 and IC70 values (50 and 70% inhibitory concentrations, respectively) that were obtained when the cells were exposed to VNR alone with those with VNR plus GLA. We found that GLA enhanced in a dose-dependent manner the cell growth inhibitory activity of VNR on MCF-7 cells (up to 9-fold). As GLA by itself showed anti-proliferative effects, possible GLA-VNR interactions at the cellular level were assessed employing the isobologram analysis and the combination index (CI) method of Chou–Talalay. Both methods showed an overall synergism between GLA and VNR in MCF-7 cells. At a high level of cell kill, the synergism was greater when a 24 h GLA pre-exposure or co-exposures were tested. Synergy was likewise observed with the GLA-VNR combination in MDA-MB-231, T47D, and SK-Br3 breast cancer cells. In all cell lines, the synergism was independent of the treatment schedule and the exposure time. Under conditions inhibiting lipid peroxidation using Vitamin E (dl-α-tocopherol), the enhancing effect of GLA (an easily oxidizable UFA) on VNR activity was partially abolished. However, when Vitamin E was used in combination, a similar synergistic increase in growth inhibition was obtained. These latter observations strongly implies that the synergistic effects of GLA with VNR are not mediated through a mechanism involving a generation of lipoperoxides. For comparison, the effects of other UFAs were examined on VNR chemosensitivity: GLA was the most potent at enhancing VNR activity, followed by docosahexaenoic acid (22 : 6n-3), eicosapentaenoic acid (20 : 5n-3) and α-linolenic acid (18 : 3n-3), whereas linoleic acid (18 : 2n-6) and arachidonic acid (20 : 4n-6) did not increase VNR chemosensitivity. Very high concentrations of oleic acid (OA; 18 : 1n-9), an UFA inversely correlated with breast cancer risk, also enhanced VNR effectiveness. Thus, various types of UFAs were not equivalent with respect to their actions on VNR effectiveness. In conclusion, our results give experimental support to the hypothesis that some UFAs can be used as modulators of tumor cell chemosensitivity and provide the rationale for in vivo preclinical investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Solanas M, Moral R, Colomer R, Escrich E: Effects of dietary (n-6) polyunsaturated lipids on experimental mammary carcinogenesis. J Women's Cancer 2: 67–72, 2000

    Google Scholar 

  2. Welsch C.W: Relationship between dietary fat and experimental mammary tumorigenesis: a review and critique. Cancer Res. 52: 2040s–2048s, 1992

    CAS  PubMed  Google Scholar 

  3. Rose D.P: Effects of dietary fatty acids on breast and prostate cancers: evidence from in vitro experiments and animal studies. Am J Clin Nutr 66: 1513S–1522S, 1997

    CAS  PubMed  Google Scholar 

  4. Bégin ME, Ells G, Das UN, Horrobin DF: Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst 77: 1053–1062, 1986

    PubMed  Google Scholar 

  5. Bégin ME, Das UN, Ells G: Cytotoxic effects of essential fatty acids in mixed cultures of normal and malignant human cells. Prog Lipid Res 25: 573–576, 1986

    Google Scholar 

  6. Hawkins RA, Sangster K, Arends MJ: Apoptotic death of pancreatic cancer cells induced by polyunsaturated fatty acids varies with double bond number and involves an oxidative mechanism. J Pathol 185: 61–70, 1998

    Article  CAS  PubMed  Google Scholar 

  7. Vartak S, McCaw R, Davis CS, Robbins ME, Spector AA: Gamma-linolenic acid (GLA) is cytotoxic to 36B10 malignant rat astrocytoma cells but not to “normal” rat astrocytes. Br J Cancer 77: 1612–1620, 1998

    CAS  PubMed  Google Scholar 

  8. Jiang WG, Bryce RP, Horrobin DF: Essential fatty acids: molecular and cellular basis of their anti-cancer action and clinical implications. Crit Rev Oncol Hematol 27: 179–209, 1998

    CAS  PubMed  Google Scholar 

  9. Germain E, Chajès V, Cognault S, Lhuillery C, Bougnoux P: Enhancement of doxorubicin cytotoxicity by polyunsaturated fatty acids in the human breast tumor cell line MDAMB-231, relationship to lipid peroxidation. Int J Cancer 75: 578–583, 1998

    Article  CAS  PubMed  Google Scholar 

  10. Burns CP, Spector AA: Biochemical effects of lipids in cancer therapy. J Nutr Biochem 5: 114–123, 1994

    CAS  Google Scholar 

  11. Borgeson CE, Pardini L, Pardini RS, and Reitz R: Effects of dietary fish oil on human mammary carcinoma and on lipid-metabolizing enzymes. Lipids 24: 290–295, 1989

    CAS  PubMed  Google Scholar 

  12. Shao Y, Pardini L, Pardini RS: Dietary menhanden oil enhances mitomycin C antitumor activity toward human mammary carcinoma MX-1. Lipids 30: 1035–1045, 1995

    CAS  PubMed  Google Scholar 

  13. Shao Y, Pardini L, Pardini RS: Intervention of transplantable human mammary carcinoma MX-1 chemotherapy with dietary menhaden oil in athymic mice: increased therapeutic effects and decreased cytotoxicity of cyclophosphamide. Nutr Cancer 28: 63–73, 1997

    CAS  PubMed  Google Scholar 

  14. Bougnoux P, Germai E, Chàjes V, Hubert B, Lhuillery C, Le Floche O, Body G, Calais G: Cytotoxic drugs efficacy correlates with adipose tissue docohexaenoic acid level in locally advanced breast carcinoma. Br J Cancer 79: 1765–1769, 1999

    Article  CAS  PubMed  Google Scholar 

  15. Bruno S, Puerto VL, Mickiewicz E, Hegg R, Texeira LC, Gaitan L, Martinez L, Fernandez O, Otero J, Kesselring G, Noguera C, Delgado G, Gaubert P, Delgado FM, Solidoro A: Phase II trial of weekly IV vinorelbine as a single agent in first-line advanced breast cancer chemotherapy. Am J Clin Oncol 18: 392–396, 1995

    CAS  PubMed  Google Scholar 

  16. Livingston RB, Ellis GK, Gralow JR, Williams MA, White R, McGuirt C, Adamkiewicz BB, Long CA: Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 15: 1395–1400, 1997

    CAS  PubMed  Google Scholar 

  17. Adams DJ, Knick VC: P-glycoprotein mediated resistance to 5-nor-andhydro-vinblastine (Navelbine_) Invest New Drugs 13: 13–21, 1995

    CAS  PubMed  Google Scholar 

  18. Dumontet C: Mechanisms of action and resistance to tubulin-binding agents. Expert Opin Investig Drugs 9: 779–788, 2000

    Article  CAS  PubMed  Google Scholar 

  19. Horrobin DF: Unsaturated lipids and cancer. In: Horrobin DF (ed) New Approaches to Cancer Treatment. Edinburgh: Churchill Communications, 1994, pp 3–29

    Google Scholar 

  20. De Bravo MG, Schinella G, Tournier H, Quintans C: Effects of dietary gamma and alpha linolenic acid on a human lung carcinoma growth in nude mice. Med Sci Res 22: 667–668, 1994

    CAS  Google Scholar 

  21. Pritchard GA, Jones DL, Mansel RE: Lipids in breast carcinogenesis. Br J Surg 76: 1069–1073, 1989

    CAS  PubMed  Google Scholar 

  22. Van Der Merwe CF, Booyens J, Kateef IE: Oral gammalinolenic acid in 21 patients with untreatable malignancy. An ongoing pilot open clinical trial. Br J Clin Prac 41: 907–915, 1987

    CAS  Google Scholar 

  23. Fearon KCH, Falconer JS, Ross JA, Carter DC, Hunter JO, Reynolds PD, Tuffnell, Q: An open-label phase I/II dose escalation study of the treatment of pancreatic cancer using lithium gammalinolenate. Anticancer Res 16: 867–874, 1996

    CAS  PubMed  Google Scholar 

  24. Kenny FS, Pinder SE, Ellis IO, Gee JMW, Nicholson RI, Bryce RP, Robertson JFR: Gamma linolenic acid with tamoxifen as primary therapy in breast cancer. Int J Cancer 85: 643–648, 2000

    Article  CAS  PubMed  Google Scholar 

  25. Menéndez JA, Barbacid MM, Montero S, Sevilla E, Escrich E, Solanas M, Cortés-Funes H, Colomer R: Effects of gamma-linolenic acid and oleic acid on paclitaxel cytotoxicity in human breast cancer cells. Eur J Cancer 37: 402–413, 2001

    Article  PubMed  Google Scholar 

  26. Berenbaum MC: What is synergy? Pharmacol Rev 41: 93–141, 1989

    CAS  PubMed  Google Scholar 

  27. Chou T-C, Talalay, P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22: 27–55, 1984

    CAS  PubMed  Google Scholar 

  28. Bégin ME, Ells G, Horrobin DF 1988 Polyunsaturated fatty acid-induced cytotoxicity against tumor cells and its relationship to lipid peroxidation. J Natl Cancer Inst 80: 188–194, 1988

    PubMed  Google Scholar 

  29. Ford JM, Hait WN: Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev 42: 155–199, 1990

    CAS  PubMed  Google Scholar 

  30. Burns CP, Haugstad BN, Mossman CJ, North JA, Ingraham LM: Membrane lipid alteration: effect on cellular uptake of mitoxantrone. Lipids 23: 393–397, 1988

    CAS  PubMed  Google Scholar 

  31. Zhou XJ, Rahmani R: Preclinical and clinical pharmacology of vinca alkaloids. Drugs 44 S4: 1–16, 2000

    Google Scholar 

  32. Davies CL, Loizidou M, Cooper AJ, Taylor I: Effect of γ-linolenic acid on cellular uptake of structurally related anthracyclines in human drug sensitive and multidrug resistant bladder and breast cancer cell lines. Eur J Cancer 35: 1534–1540, 1999

    CAS  PubMed  Google Scholar 

  33. Chajes V, Mahon M, Kostner GM: Influence of LDL oxidation on the proliferation of human breast cancer cells. Free Radic Biol Med 20: 113–120, 1996

    Article  CAS  PubMed  Google Scholar 

  34. Hawkins RA, Sangster K, Arends MJ: The apoptosisinducing effects of polyunsaturated fatty acids (PUFAs) on benign and malignant breast cells in vitro. The Breast 8: 16–20, 1999

    Article  Google Scholar 

  35. Wang LG, Liu XM, Kreis W, Budman DR: The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemother Pharmacol 44: 355–361, 1999

    Article  CAS  PubMed  Google Scholar 

  36. Sugiyama K, Shimizu M, Akiyama T, Ishida H, Okabe M, Tamaoki T, Akinaga S: Combined effect of navelbine with medroxyprogesterone acetate against human breast carcinoma MCF-7 cells in vitro. Br J Cancer 77: 1737–1743, 1998

    CAS  PubMed  Google Scholar 

  37. Das UN: Essential fatty acids, lipid peroxidation and apoptosis. Prostaglandins Leukot Essent Fatty Acids 61: 157–163, 1999

    Article  CAS  PubMed  Google Scholar 

  38. Cunnane SC, Chen ZY, Yang J, Liede AC, Hamadeh M, Crawford MA: Alpha-linolenic acid in humans: direct functional role or dietary precursor? Nutrition 7: 437–439, 1991

    CAS  PubMed  Google Scholar 

  39. Sandstrom PA, Pardi D, Tebbey PW, Dudek R, Terrian D, Folks T, Buttke T: Lipid hydroperoxide-induced apoptosis: lack of inhibition by Bcl-2 overexpression. FEBS Lett 365: 66–70, 1995

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain

    Javier Abel Menéendez, Santiago Ropero, Maria del Mar Barbacid, Sagrario Montero, Hernán Cortés-Funes & Ramon Colomer

  2. Department of Cellular Biology, Physiology, Immunology, Medical Physiology Unit, Medical School, Universidad Autónoma de Barcelona, Spain

    Montserrat Solanas & Eduard Escrich

Authors
  1. Javier Abel Menéendez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Santiago Ropero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria del Mar Barbacid
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sagrario Montero
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Montserrat Solanas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eduard Escrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hernán Cortés-Funes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ramon Colomer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Menéendez, J.A., Ropero, S., Barbacid, M.d.M. et al. Synergistic Interaction Between Vinorelbine and Gamma-Linolenic Acid in Breast Cancer Cells. Breast Cancer Res Treat 72, 203–219 (2002). https://doi.org/10.1023/A:1014968415759

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1014968415759

Search

Navigation