Dairy milk fat augments paclitaxel therapy to suppress tumour metastasis in mice, and protects against the side-effects of chemotherapy

  • Xueying Sun
  • Jie Zhang
  • Rita Gupta
  • Alastair K. H. MacGibbon
  • Barbara Kuhn-Sherlock
  • Geoffrey W. Krissansen
Research Paper


Milk fat is a natural product containing essential nutrients as well as fatty acids and other food factors with reported anti-cancer potential. Here bovine milk fat was tested for its ability to inhibit the growth of breast and colon cancers and their metastasis to the lung and liver; either alone or in combination with the chemotherapeutic agent paclitaxel. A diet containing 5% typical anhydrous milk fat (representing ~70% of the total dietary fat component) fed to Balb/c mice delayed the appearance of subcutaneous 4T1 breast and CT26 colon cancer tumours and inhibited their metastasis to the lung and liver, when compared to the control diet containing soybean oil as the only fat component. It augmented the inhibitory effects of paclitaxel on tumour growth and metastasis, and reduced the microvessel density of tumours. It displayed no apparent organ toxicity, but instead was beneficial for well-being of tumour-bearing mice by maintaining gastrocnemius muscle and epididymal adipose tissue that were otherwise depleted by cachexia. The milk fat diet ameliorated gut damage caused by paclitaxel in non-tumour-bearing mice, as evidenced by retention of jejunal morphology, villi length and intestinal γ-glutamyl transpeptidase activity, and inhibition of crypt apoptosis. It prevented loss of red and white blood cells due to both cancer-mediated immunosuppression and the cytotoxic effects of chemotherapy. The present study warrants the use of milk fat as an adjuvant to inhibit tumour metastasis during cancer chemotherapy, and to spare patients from the debilitating side-effects of cytotoxic drugs.


Angiogenesis Breast cancer Cachexia Chemotherapy Colon cancer Immunosuppression Metastasis Milk fat Mucositis Paclitaxel Soybean oil 



Anhydrous milk fat


Conjugated linoleic acid




Fatty acid methyl ester


γ-Glutamyl transpeptidase


Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling


9-Hydroxystearic acid


Short-chain fatty acids



This work was supported by a grant from the Foundation for Research, Science, and Technology, New Zealand, and supported by Fonterra, New Zealand, and Auckland Uniservices Ltd. We thank Yvonne van der Does for the preparation of the milk fat samples.


  1. 1.
    Harris JR, Lippman ME, Veronesi U, Willett W (1992) Breast cancer. N Engl J Med 327:319–328PubMedCrossRefGoogle Scholar
  2. 2.
    Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N (2010) Colorectal cancer. Lancet 375:1030–1047PubMedCrossRefGoogle Scholar
  3. 3.
    Marupudi NI, Han JE, Li KW, Renard VM, Tyler BM, Brem H (2007) Paclitaxel: a review of adverse toxicities and novel delivery strategies. Expert Opin Drug Saf 6:609–621PubMedCrossRefGoogle Scholar
  4. 4.
    Loos WJ, Szebeni J, ten Tije AJ, Verweij J, van Zomeren DM, Chung KN, Nooter K, Stoter G, Sparreboom A (2002) Preclinical evaluation of alternative pharmaceutical delivery vehicles for paclitaxel. Anticancer Drugs 13:767–775PubMedCrossRefGoogle Scholar
  5. 5.
    Weiss RB, Donehower RC, Wiernik PH, Ohnuma T, Gralla RJ, Trump DL, Baker JR Jr, Van Echo DA, Von Hoff DD, Leyland-Jones B (1990) Hypersensitivity reactions from taxol. J Clin Oncol 8:1263–1268PubMedGoogle Scholar
  6. 6.
    Shimoyama R, Yasui H, Boku N, Onozawa Y, Hironaka S, Fukutomi A, Yamazaki K, Taku K, Kojima T, Machida N, Todaka A, Tomita H, Sakamoto T, Tsushima T (2009) Weekly paclitaxel for heavily treated advanced or recurrent gastric cancer refractory to fluorouracil, irinotecan, and cisplatin. Gastric Cancer 12:206–211PubMedCrossRefGoogle Scholar
  7. 7.
    Yan L, Demars LC (2010) Effects of dietary fat on spontaneous metastasis of Lewis lung carcinoma in mice. Clin Exp Metastasis 27:581–590Google Scholar
  8. 8.
    La Merrill M, Gordon RR, Hunter KW, Threadgill DW, Pomp D (2010) Dietary fat alters pulmonary metastasis of mammary cancers through cancer autonomous and non-autonomous changes in gene expression. Clin Exp Metastasis 27:107–116PubMedCrossRefGoogle Scholar
  9. 9.
    Gordon RR, La Merrill M, Hunter KW, Sørensen P, Threadgill DW, Pomp D (2010) Dietary fat-dependent transcriptional architecture and copy number alterations associated with modifiers of mammary cancer metastasis. Clin Exp Metastasis 27:279–293PubMedCrossRefGoogle Scholar
  10. 10.
    Larsson SC, Bergkvist L, Wolk A (2005) High-fat dairy food and conjugated linoleic acid intakes in relation to colorectal cancer incidence in the Swedish Mammography Cohort. Am J Clin Nutr 82:894–900PubMedGoogle Scholar
  11. 11.
    Bougnoux P, Menanteau J (2005) Dietary fatty acids and experimental carcinogenesis. Bull Cancer 92:685–696PubMedGoogle Scholar
  12. 12.
    Evans LM, Toline EC, Desmond R, Siegal GP, Hashim AI, Hardy RW (2009) Dietary stearate reduces human breast cancer metastasis burden in athymic nude mice. Clin Exp Metastasis 26:415–424PubMedCrossRefGoogle Scholar
  13. 13.
    Yam D, Peled A, Shinitzky M (2001) Suppression of tumor growth and metastasis by dietary fish oil combined with vitamins E and C and cisplatin. Cancer Chemother Pharmacol 47:34–40PubMedCrossRefGoogle Scholar
  14. 14.
    Kushi L, Giovannucci E (2002) Dietary fat and cancer. Am J Med 113(Suppl 9B):63S–70SPubMedCrossRefGoogle Scholar
  15. 15.
    Parodi PW (1999) Conjugated linoleic acid and other anticarcinogenic agents of bovine milk fat. J Dairy Sci 82:1339–1349PubMedCrossRefGoogle Scholar
  16. 16.
    Parodi PW (1997) Cows’ milk fat components as potential anticarcinogenic agents. J Nutr 127:1055–1060PubMedGoogle Scholar
  17. 17.
    Siegel I, Liu TL, Yaghoubzadeh E, Keskey TS, Gleicher N (1987) Cytotoxic effects of free fatty acids on ascites tumor cells. J Natl Cancer Inst 78:271–277PubMedGoogle Scholar
  18. 18.
    Zhu YP, Su ZW, Li CH (1989) Growth-inhibition effects of oleic acid, linoleic acid, and their methyl esters on transplanted tumors in mice. J Natl Cancer Inst 81:1302–1306PubMedCrossRefGoogle Scholar
  19. 19.
    Zusman I, Gurevich P, Madar Z, Nyska A, Korol D, Timar B, Zuckerman A (1997) Tumor-promoting and tumor-protective effects of high-fat diets on chemically induced mammary cancer in rats. Anticancer Res 17(1A):349–356PubMedGoogle Scholar
  20. 20.
    Galdiero F, Carratelli CR, Nuzzo I, Bentivoglio C, De Martino L, Gorga F, Folgore A, Galdiero M (1994) Beneficial effects of myristic, stearic or oleic acid as part of liposomes on experimental infection and antitumor effect in a murine model. Life Sci 55:499–509PubMedCrossRefGoogle Scholar
  21. 21.
    Gulaia NM, Smirnov IM, IuP Shmal’ko, Mel’nik AA, Mel’nik SN (1993) Effect of N-palmitoyl- and N-stearoylethanolamines on lipid peroxidation in mouse tissues in metastatic Lewis carcinoma. Ukr Biokhim Zh 65:96–101PubMedGoogle Scholar
  22. 22.
    Bougnoux P, Chajes V, Lanson M, Hacene K, Body G, Couet C, Le Floch O (1992) Prognostic significance of tumor phosphatidylcholine stearic acid level in breast carcinoma. Breast Cancer Res Treat 20:185–194PubMedCrossRefGoogle Scholar
  23. 23.
    Andrade LN, de Lima TM, Curi R, Castrucci AM (2005) Toxicity of fatty acids on murine and human melanoma cell lines. Toxicol In Vitro 19:553–560PubMedCrossRefGoogle Scholar
  24. 24.
    Harada H, Yamashita U, Kurihara H, Fukushi E, Kawabata J, Kamei Y (2002) Antitumor activity of palmitic acid found as a selective cytotoxic substance in a marine red alga. Anticancer Res 22:2587–2590PubMedGoogle Scholar
  25. 25.
    Menendez JA, Vellon L, Colomer R, Lupu R (2005) Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu (erbB-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (Herceptin) in breast cancer cells with Her-2/neu oncogene amplification. Ann Oncol 16:359–371PubMedCrossRefGoogle Scholar
  26. 26.
    Colomer R, Menendez JA (2006) Mediterranean diet, olive oil and cancer. Clin Transl Oncol 8:15–21PubMedCrossRefGoogle Scholar
  27. 27.
    Yamaki T, Yano T, Satoh H, Endo T, Matsuyama C, Kumagai H, Miyahara M, Sakurai H, Pokorny J, Shin SJ, Hagiwara K (2002) High oleic acid oil suppresses lung tumorigenesis in mice through the modulation of extracellular signal-regulated kinase cascade. Lipids 37:783–788PubMedCrossRefGoogle Scholar
  28. 28.
    Kimura Y (2002) Carp oil or oleic acid, but not linoleic acid or linolenic acid, inhibits tumor growth and metastasis in Lewis lung carcinoma-bearing mice. J Nutr 132:2069–2075PubMedGoogle Scholar
  29. 29.
    Suzuki I, Iigo M, Ishikawa C, Kuhara T, Asamoto M, Kunimoto T, Moore MA, Yazawa K, Araki E, Tsuda H (1997) Inhibitory effects of oleic and docosahexaenoic acids on lung metastasis by colon-carcinoma-26 cells are associated with reduced matrix metalloproteinase-2 and -9 activities. Int J Cancer 73:607–612PubMedCrossRefGoogle Scholar
  30. 30.
    Van Duuren BL, Goldschmidt BM (1976) Co-carcinogenic and tumor-promoting agents in tobacco carcinogenesis. J Natl Cancer Inst 56:1237–1242PubMedGoogle Scholar
  31. 31.
    Fermor BF, Masters JR, Wood CB, Miller J, Apostolov K, Habib NA (1992) Fatty acid composition of normal and malignant cells and cytotoxicity of stearic, oleic and sterculic acids in vitro. Eur J Cancer 28A:1143–1147PubMedCrossRefGoogle Scholar
  32. 32.
    Belobrajdic DP, McIntosh GH (2000) Dietary butyrate inhibits NMU-induced mammary cancer in rats. Nutr Cancer 36:217–223PubMedCrossRefGoogle Scholar
  33. 33.
    Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951PubMedGoogle Scholar
  34. 34.
    Dvorin A, Zoref Z, Mokady S, Nitsan Z (1998) Nutritional aspects of hydrogenated and regular soybean oil added to diets of broiler chickens. Poult Sci 77:820–825PubMedGoogle Scholar
  35. 35.
    Kayar SR, Archer PG, Lechner AJ, Banchero N (1982) Evaluation of the concentric-circles method for estimating capillary-tissue diffusion distances. Microvasc Res 24:342–353PubMedCrossRefGoogle Scholar
  36. 36.
    Sun X, Kanwar JR, Leung E, Lehnert K, Wang D, Krissansen GW (2001) Gene transfer of antisense hypoxia inducible factor-1α enhances the therapeutic efficacy of cancer immunotherapy. Gene Ther 8:638–645PubMedCrossRefGoogle Scholar
  37. 37.
    Ziotnik Y, Patya M, Vanichkin A, Novogrodsky A (2005) Tyrphostins reduce chemotherapy-induced intestinal injury in mice: assessment by a biochemical assay. Br J Cancer 92:294–297Google Scholar
  38. 38.
    Aslakson CJ, Miller FR (1992) Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52:1399–1405PubMedGoogle Scholar
  39. 39.
    Lerner WA, Pearlstein E, Ambrogio C, Karpatkin S (1983) A new mechanism for tumor induced platelet aggregation. Comparison with mechanisms shared by other tumor with possible pharmacologic strategy toward prevention of metastases. Int J Cancer 31:463–469PubMedCrossRefGoogle Scholar
  40. 40.
    Mensink RP (1993) Effects of the individual saturated fatty acids on serum lipids and lipoprotein concentrations. Am J Clin Nutr 57(5 Suppl):711S–714SPubMedGoogle Scholar
  41. 41.
    Melichar B, Dvorak J, Hyspler R, Zadak Z (2005) Intestinal permeability in the assessment of intestinal toxicity of cytotoxic agents. Chemotherapy 51:336–338PubMedCrossRefGoogle Scholar
  42. 42.
    Ferraris RP, Villenas SA, Diamond J (1992) Regulation of brush-border enzyme activities and enterocyte migration rates in mouse small intestine. Am J Physiol 262:G1047–G1059PubMedGoogle Scholar
  43. 43.
    Keefe DMK, Brealey J, Goland GJ, Cummins AG (2000) Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 47:632–637PubMedCrossRefGoogle Scholar
  44. 44.
    Ge R, Rajeev V, Ray P, Lattime E, Rittling S, Medicherla S, Protter A, Murphy A, Chakravarty J, Dugar S, Schreiner G, Barnard N, Reiss M (2006) Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo. Clin Cancer Res 12:4315–4330PubMedCrossRefGoogle Scholar
  45. 45.
    Johnson IT (1995) Butyrate and markers of neoplastic change in the colon. Eur J Cancer Prev 4:365–371PubMedCrossRefGoogle Scholar
  46. 46.
    Ramos MG, Rabelo FL, Brumatti G, Bueno-da-Silva AE, Amarante-Mendes GP, Alvarez-Leite JI (2004) Butyrate increases apoptosis induced by different antineoplastic drugs in monocytic leukemia cells. Chemotherapy 50:221–228PubMedCrossRefGoogle Scholar
  47. 47.
    Miller A, Stanton C, Murphy J, Devery R (2003) Conjugated linoleic acid (CLA)-enriched milk fat inhibits growth and modulates CLA-responsive biomarkers in MCF-7 and SW480 human cancer cell lines. Br J Nutr 90:877–885PubMedCrossRefGoogle Scholar
  48. 48.
    O’Shea M, Devery R, Lawless F, Murphy J, Stanton C (2000) Milk fat conjugated linoleic acid (CLA) inhibits growth of human mammary MCF-7 cancer cells. Anticancer Res 20:3591–3601PubMedGoogle Scholar
  49. 49.
    Kim KH, Park HS (2003) Dietary supplementation of conjugated linoleic acid reduces colon tumour incidence in DMH-treated rats by increasing apoptosis with modulation of biomarkers. Nutrition 19:772–777PubMedCrossRefGoogle Scholar
  50. 50.
    Ha YL, Grimm NK, Pariza MW (1987) Anticarcinogens from fried ground beef: heat-altered derivatives of linoleic acid. Carcinogenesis 8:1881–1887PubMedCrossRefGoogle Scholar
  51. 51.
    Chen BQ, Xue YB, Liu JR, Yang YM, Zheng YM, Wang XL, Liu RH (2003) Inhibition of conjugated linoleic acid on mouse forestomach neoplasia induced by benzo (a) pyrene and chemopreventive mechanisms. World J Gastroenterol 9:44–49PubMedGoogle Scholar
  52. 52.
    Corl BA, Barbano DM, Bauman DE, Ip C (2003) cis-9, trans-11 CLA derived endogenously from trans-11 18:1 reduces cancer risk in rats. J Nutr 133:2893–2900PubMedGoogle Scholar
  53. 53.
    Banni S, Angioni E, Murru E, Carta G, Melis MP, Bauman D, Dong Y, Ip C (2001) Vaccenic acid feeding increases tissue levels of conjugated linoleic acid and suppresses development of premalignant lesions in rat mammary gland. Nutr Cancer 41:91–97PubMedGoogle Scholar
  54. 54.
    Whipple GH, Robscheit FS (1926) Blood regeneration in severe anemia. Am J Physiol 79:280–288Google Scholar
  55. 55.
    Gibson GR, Wang X (1994) Regulatory effects of bifidobacteria on the growth of other colonic bacteria. J Appl Bacteriol 77:412–420PubMedCrossRefGoogle Scholar
  56. 56.
    Sakata T (1987) Stimulatory effect of short-chain fatty acids on epithelial cell proliferation in the rat intestine: a possible explanation for trophic effects of fermentable fibre, gut microbes and luminal trophic factors. Br J Nutr 58:95–103PubMedCrossRefGoogle Scholar
  57. 57.
    Sakata T (1997) Influence of short-chain fatty acids on intestinal growth and functions. In: Kritchevsky D, Bonfeld C (eds) Dietary fiber in health and disease. Plenum, New York, pp 191–199CrossRefGoogle Scholar
  58. 58.
    Scheppach W, Sommer H, Kirchner T, Paganelli GM, Bartram P, Christl S, Richter F, Dusel G, Kasper H (1992) Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 103:51–56PubMedGoogle Scholar
  59. 59.
    Butzner JD, Parmar R, Bell CJ, Dalal V (1996) Butyrate enema therapy stimulates mucosal repair in experimental colitis in the rat. Gut 38:568–573PubMedCrossRefGoogle Scholar
  60. 60.
    Rani R (2008) Molecular mechanism of protective effect of milk fat in breast cancer. PhD thesis, NDRI, KarnalGoogle Scholar
  61. 61.
    Rani R, Kansal VK, Kaushal D, De S (2011) Dietary intervention of cow ghee and soybean oil on expression of cell cycle and apoptosis related genes in normal and carcinogen treated rat mammary gland. Mol Biol Rep 38:3299–3307Google Scholar
  62. 62.
    Rose DP, Connolly JM, Liu XH (1994) Effects of linoleic acid on the growth and metastasis of two human breast cancer cell lines in nude mice and the invasive capacity of these cell lines in vitro. Cancer Res 54:6557–6562PubMedGoogle Scholar
  63. 63.
    Actis AB, Cremonezzi DC, King IB, Joekes S, Eynard AR, Valentich MA (2005) Effects of soy oil on murine salivary tumorigenesis. Prostaglandins Leukot Essent Fatty Acids 72:187–194PubMedCrossRefGoogle Scholar
  64. 64.
    Salerno JW, Smith DE (1991) The use of sesame oil and other vegetable oils in the inhibition of human colon cancer growth in vitro. Anticancer Res 11:209–215PubMedGoogle Scholar
  65. 65.
    Meydani SN, Lichtenstein AH, White PJ, Goodnight SH, Elson CE, Woods M, Gorbach SL, Schaefer EJ (1991) Food use and health effects of soybean and sunflower oils. J Am Coll Nutr 10:406–428PubMedGoogle Scholar
  66. 66.
    Dai Q, Shu XO, Jin F, Gao YT, Ruan ZX, Zheng W (2002) Consumption of animal foods, cooking methods, and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 11:801–808PubMedGoogle Scholar
  67. 67.
    Menéndez JA, del Mar Barbacid M, Montero S, Sevilla E, Escrich E, Solanas M, Cortés-Funes H, Colomer R (2001) Effects of gamma-linolenic acid and oleic acid on paclitaxel cytotoxicity in human breast cancer cells. Eur J Cancer 37:402–413PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Xueying Sun
    • 1
    • 2
  • Jie Zhang
    • 1
    • 2
  • Rita Gupta
    • 1
    • 2
  • Alastair K. H. MacGibbon
    • 1
    • 3
  • Barbara Kuhn-Sherlock
    • 1
    • 3
  • Geoffrey W. Krissansen
    • 1
    • 2
  1. 1.Lactopharma Consortium, University of AucklandAucklandNew Zealand
  2. 2.Department of Molecular Medicine & Pathology, Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand
  3. 3.Fonterra Research CentrePalmerston NorthNew Zealand

Personalised recommendations