Molecular Mechanism of Anti-cancer Action of PUFAs with Particular Reference to GLA in Glioma

  • Undurti N. Das


The manifold actions of bioactive lipids especially in the regulation of inflammation, immune response, mutagenesis, and carcinogenesis and their unique ability to modulate the actions of various cytokines and cell membrane structure and function and generation of ROS (including nitric oxide, NO) suggest that they may have a crucial role in the pathobiology of cancer. This is especially true of their ability to induce apoptosis/ferroptosis/necrosis and other forms of cell death. Our own studies and those of others clearly demonstrated that bioactive lipids especially GLA, AA, EPA, and DHA can selectively eliminate tumor cells when given in appropriate doses. T derive such an anti-cancer action bioactive lipids need to be delivered to the cancer cells. In vitro, in vivo, and limited clinical studies revealed that GLA can regress human glioma without any side effects. This selective tumoricidal action of GLA and other polyunsaturated fatty acids seems to reside in their ability to augment free radical generation (ROS, NO, PUFA radical, etc.) and consequent formation and accumulation of toxic lipid peroxides only in tumor but not in normal cells. In an extension of these studies, our recent studies showed that co-administration of these bioactive lipids in conjunction with high doses of vitamin C and conventional anti-cancer drugs and immune checkpoint inhibitors can induce remission of other solid tumors in humans. Thus, it is possible that even drug-resistant cancers could be effectively treated using this bioactive lipid-based therapeutic approach.


Glioma Gamma-linolenic acid Apoptosis Ferroptosis Bioactive lipids Lipid peroxides Antioxidants 


  1. 1.
    Brodie AE, Manning VA, Ferguson KR, Jewell DE, Hu CY. Conjugated linoleic acid inhibits differentiation of pre-and post-confluent 3T3-L1 preadipocytes but inhibits cell proliferation only in preconfluent cells. J Nutr. 1999;129:602–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Visonneau S, Cesano A, Tepper SA, Scimeca JA, Santoli D, Kritchevsky D. Conjugated linoleic acid suppresses the growth of human breast adenocarcinoma cells in SCID mice. Anticancer Res. 1997;17:969–73.PubMedGoogle Scholar
  3. 3.
    Leary WP, Robinson KM, Booyens J, Dippenaar N. Some effects of gamma-linolenic acid on cultured human oesophageal carcinoma cells. S Afr Med J. 1982;62:681–3.PubMedGoogle Scholar
  4. 4.
    Begin ME, Das UN, Ells G, Horrobin DF. Selective killing of human cancer cells by polyunsaturated fatty acids. Prostaglandins Leukot Med. 1985;19:177–86.PubMedCrossRefGoogle Scholar
  5. 5.
    Das UN. Essential fatty acids and their metabolites and cancer. Nutrition. 1999;15:239–41.PubMedCrossRefGoogle Scholar
  6. 6.
    Das UN. Tumoricidal action of cis-unsaturated fatty acids and their relationship to free radicals and lipid peroxidation. Cancer Lett. 1991;56:235–43.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Das UN. Gamma-linolenic acid, arachidonic acid, and eicosapentaenoic acid as potential anticancer drugs. Nutrition. 1990;6:429–34.PubMedGoogle Scholar
  8. 8.
    Siegel I, Liu TL, Yaghoubzadeh E, Keskey TS, Gleicher N. Cytotoxic effects of free fatty acids on ascites tumor cells. J Natl Cancer Inst. 1987;78:271–7.PubMedGoogle Scholar
  9. 9.
    Sagar PS, Das UN, Koratkar R, Ramesh G, Padma M, Kumar GS. Cytotoxic action of cis-unsaturated fatty acids on human cervical carcinoma (HeLa) cells: relationship to free radicals and lipid peroxidation and its modulation by calmodulin antagonists. Cancer Lett. 1992;63:189–98.PubMedCrossRefGoogle Scholar
  10. 10.
    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. 1986;77:1053–62.PubMedGoogle Scholar
  11. 11.
    Das UN. Cis-unsaturated fatty acids as potential anti-mutagenic, tumoricidal, and anti-metastatic agents. Asia pacific J Pharmacol. 1992;7:305–27.Google Scholar
  12. 12.
    Begin ME, Das UN, Ells G. Cytotoxic effects of essential fatty acids (EFA) in mixed cultures of normal and malignant human cells. Prog Lipid Res. 1986;25:573–6.CrossRefGoogle Scholar
  13. 13.
    Naidu MRC, Das UN, Kishan A. Intratumoral gamma-linoleic acid therapy of human gliomas. Prostaglandins Leukot Essent Fatty Acids. 1992;45:181–4.PubMedCrossRefGoogle Scholar
  14. 14.
    Das UN, Prasad VVSK, Reddy DR. Local application of γ-linolenic acid in the treatment of human gliomas. Cancer Lett. 1995;94:147–55.PubMedCrossRefGoogle Scholar
  15. 15.
    Begin ME, Sircar S, Weber JM. Differential sensitivity of tumorigenic and genetically related non-tumorigenic cells to cytotoxic polyunsaturated fatty acids. Anticancer Res. 1989;9:1049–52.PubMedGoogle Scholar
  16. 16.
    Reid T, Ramesha CS, Ringold GM. Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis. J Biol Chem. 1991;266:16580–6.PubMedGoogle Scholar
  17. 17.
    Park WJ, Kothapalli KS, Lawrence P, Brenna JT. FADS2 function loss at the cancer hotspot 11q13 locus diverts lipid signaling precursor synthesis to unusual eicosanoid fatty acids. PLoS One. 2011;6:e28186.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Nassar BA, Das UN, Huang YS, Ells G, Horrobin DF. The effect of chemical hepatocarcinogenesis on liver phospholipid composition in rats fed N-6 and N-3 fatty acid-supplemented diets. Proc Soc Exp Biol Med. 1992;199:365–8.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Das UN. Tuning free radical metabolism to kill tumor cells selectively with emphasis on the interaction(s) between essential fatty acids, free radicals, lymphokines and prostaglandins. Ind J Pathol Microbiol. 1990;33:94–100.Google Scholar
  20. 20.
    Galeotti, et al. In: Das DK, Walter Essman B, editors. Oxygen radicals: systemic events and disease processes. Basel: Karger; 1990. p. 129–48.CrossRefGoogle Scholar
  21. 21.
    Dianzani, et al. In: Pani P, Feo F, Columbano A, Cagliari ESA, editors. Recent trends in chemical carcinogenesis, vol. 1. Italy: Cagliari; 1981. p. 243–57.Google Scholar
  22. 22.
    Cheeseman KH, Emery S, Maddix SP, Slater TF, Burton GW, Ingold KU. Studies on lipid peroxidation in normal and tumour tissues. The Yoshida rat liver tumour. Biochem J. 1988;250:247–52.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Das UN, Begin ME, Ells G, Huang YS, Horrobin DF. Polyunsaturated fatty acids augment free radical generation in tumor cells in vitro. Biochem Biophys Res Commun. 1987;145:15–24.PubMedCrossRefGoogle Scholar
  24. 24.
    Das UN, Huang YS, Begin ME, Ells G, Horrobin DF. Uptake and distribution of cis-unsaturated fatty acids and their effect on free radical generation in normal and tumor cells in vitro. Free Radic Biol Med. 1987;3:9–14.PubMedCrossRefGoogle Scholar
  25. 25.
    Cummings KB, Robertson RP. Prostaglandin: increased production by renal cell carcinoma. J Urol. 1977;118:720–3.PubMedCrossRefGoogle Scholar
  26. 26.
    Su-chen LH, Wheless CM, Levine L. Elevated prostaglandin synthetase activity in methylcholanthrene-transformed mouse BALB/3T3. Prostaglandins. 1977;13:271–9.CrossRefGoogle Scholar
  27. 27.
    Ylikorkala O, Kauppila A, Viinikka L. Effect of cytostatics on prostaglandin F2 alpha prostacyclin, and thromboxane in patients with gynecologic malignancies. Obstet Gynecol. 1981;58:483–6.PubMedGoogle Scholar
  28. 28.
    Rolland PH, Martin PM, Jacquemier J, Rolland AM, Toga M. Prostaglandin in human breast cancer: evidence suggesting that an elevated prostaglandin production is a marker of high metastatic potential for neoplastic cells. J Natl Cancer Inst. 1980;64:1061–70.PubMedGoogle Scholar
  29. 29.
    Trevisani A, Ferretti E, Capuzzo A, Tomasi V. Elevated levels of prostaglandin E 2 in Yoshida hepatoma and the inhibition of tumour growth by non-steroidal anti-inflammatory drugs. Br J Cancer. 1980;41:341–7.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Young MR, Newby M. Enhancement of Lewis lung carcinoma cell migration by prostaglandin E2 produced by macrophages. Cancer Res. 1986;46:160–4.PubMedGoogle Scholar
  31. 31.
    Cyran J, Lea MA, Lysz TW. Prostaglandin biosynthetic capacity of hepatomas with different growth rates. Int J Biochem. 1989;21:445–51.PubMedCrossRefGoogle Scholar
  32. 32.
    LeFever A, Funahashi A. Elevated prostaglandin E2 levels in bronchoalveolar lavage fluid of patients with bronchogenic carcinoma. Chest. 1990;98:1397–402.PubMedCrossRefGoogle Scholar
  33. 33.
    Baxevanis CN, Reclos GJ, Gritzapis AD, Dedousis GV, Missitzis I, Papamichail M. Elevated prostaglandin E2 production by monocytes is responsible for the depressed levels of natural killer and lymphokine-activated killer cell function in patients with breast cancer. Cancer. 1993;72:491–501.PubMedCrossRefGoogle Scholar
  34. 34.
    Qiao L, Kozoni V, Tsioulias GJ, Koutsos MI, Hanif R, Shiff SJ, Rigas B. Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo. Biochim. Biophys Acta. 1995;1258:215–23.CrossRefGoogle Scholar
  35. 35.
    Hansen-Petrik MB, McEntee MF, Jull B, Shi H, Zemel MB, Whelan J. Prostaglandin E2 protects intestinal tumors from nonsteroidal anti-inflammatory drug-induced regression in ApcMin/+ mice. Cancer Res. 2002;62:403–8.PubMedGoogle Scholar
  36. 36.
    Borrello, et al. In: Rotilio G, editor. Superoxide and superoxide dismutase in chemistry, biology and medicine. Amsterdam: Elsevier; 1988. p. 323–4.Google Scholar
  37. 37.
    Hendrickse CW, Kelly RW, Radley S, Donovan IA, Keighley MRB, Neoptolemos JP. Lipid peroxidation and prostaglandins in colorectal cancer. Br J Surg. 1994;81:1219–23.PubMedCrossRefGoogle Scholar
  38. 38.
    Mund RC, Pizato N, Bonatto S, Nunes EA, Vicenzi T, Tanhoffer R, Fernandes LC. Decreased tumor growth in Walker 256 tumor-bearing rats chronically supplemented with fish oil involves COX-2 and PGE2 reduction associated with apoptosis and increased peroxidation. Prostaglandins Leukot Essent Fatty Acids. 2007;76:113–20.PubMedCrossRefGoogle Scholar
  39. 39.
    Begin ME, Das UN, Ells G, Horrobin DF. Selective killing of tumor cells by polyunsaturated fatty acids. Prostaglandins Leukotrienes Med. 1985;19:177–85.CrossRefGoogle Scholar
  40. 40.
    Begin ME, Ells G, Das UN. Selected fatty acids as possible intermediates for selective cytotoxic activity of anti-cancer agents involving oxygen radicals. Anticancer Res. 1986;6:291–5.PubMedGoogle Scholar
  41. 41.
    Das UN. Essential fatty acids enhance free radical generation and lipid peroxidation to induce apoptosis of tumor cells. Clin Lipidol. 2011;6:463–89.CrossRefGoogle Scholar
  42. 42.
    Das UN, Madhavi N, Padma M, Sagar PS. Can tumor cell drug-resistance be reversed by essential fatty acids and their metabolites? Prostaglandins Leukotrienes Essential Fatty Acids. 1998;58:39–54.CrossRefGoogle Scholar
  43. 43.
    Madhavi N, Das UN. Effect of n-6 and n-3 fatty acids on the survival of vincristine sensitive and resistant human cervical carcinoma cells in vitro. Cancer Lett. 1994;84:31–41.PubMedCrossRefGoogle Scholar
  44. 44.
    Kumar GS, Das UN. Free radical-dependent suppression of growth of mouse myeloma cells by α-linolenic and eicosapentaenoic acids in vitro. Cancer Lett. 1995;92:27–38.PubMedCrossRefGoogle Scholar
  45. 45.
    Padma M, Das UN. Effect of cis-unsaturated fatty acids on cellular oxidant stress in macrophage tumor (AK-5) cells in vitro. Cancer Lett. 1996;109:63–75.PubMedCrossRefGoogle Scholar
  46. 46.
    Sravan Kumar G, Das UN. Free radical dependent suppression of mouse myeloma cells by alpha-linolenic and eicosapentaenoic acids in vitro. Cancer Lett. 1993;92:27–38.CrossRefGoogle Scholar
  47. 47.
    Tolnai S, Morgan JF. Studies on the in vitro antitumor activity of fatty acids: v unsaturated acids. Can J Biochem Physiol. 1962;40:869–75.CrossRefGoogle Scholar
  48. 48.
    Schlager SI, Madden LD, Meltzer MS, Bara S, Mamula MJ. Role of macrophage lipids in regulating tumoricidal activity. Cell Immunol. 1983;77:52–68.PubMedCrossRefGoogle Scholar
  49. 49.
    Ramesh G, Das UN. Effect of free fatty acids on two-stage skin carcinogenesis in mice. Cancer Lett. 1996;100:199–209.PubMedCrossRefGoogle Scholar
  50. 50.
    Polavarapu S, Mani AM, Gundala NK, Hari AD, Bathina S, Das UN. Effect of polyunsaturated fatty acids and their metabolites on bleomycin-induced cytotoxic action on human neuroblastoma cells in vitro. PLoS One. 2014;9:e114766.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Sangeetha Sagar P, Das UN. Gamma-linolenic acid and eicosapentaenoic acid potentiate the cytotoxicity of anti-cancer drugs on human cervical carcinoma (HeLa) cells in vitro. Med Sci Res. 1993;21:457–9.Google Scholar
  52. 52.
    Ribeiro G, Benadiba M, de Oliveira SD, Colquhoun A. The novel ruthenium—γ linolenic complex [Ru2 (aGLA) 4Cl] inhibits C6 rat glioma cell proliferation and induces changes in mitochondrial membrane potential, increased reactive oxygen species generation and apoptosis in vitro. Cell Biochem Funct. 2010;28:15–23.PubMedCrossRefGoogle Scholar
  53. 53.
    Dai J, Shen J, Pan W, Shen S, Das UN. Effect of polyunsaturated fatty acids on the growth of gastric cancer cells in vitro. Lipids Health Dis. 2013;12:71.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Mills C. M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol. 2012;32:463–88.PubMedCrossRefGoogle Scholar
  55. 55.
    Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A. Tumor associated macrophages and neutrophils in tumor progression. J Cell Phys. 2012;228:1404–12.CrossRefGoogle Scholar
  56. 56.
    Bingle Á, Brown NJ, Lewis CE. The role of tumour associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196:254–65.PubMedCrossRefGoogle Scholar
  57. 57.
    Kono Y, Kawakami S, Higuchi Y, Yamashita F, Hashida M. In vitro evaluation of inhibitory effect of nuclear factor-kappaB activity by small interfering RNA on pro-tumor characteristics of M2-like macrophages. Biol Pharm Bull. 2014;37:137–44.PubMedCrossRefGoogle Scholar
  58. 58.
    Seliger B, Marincola FM, Ferrone S, Abken H. The complex role of B7 molecules in tumor immunology. Trends Mol Med. 2008;14:550–9.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56–61.PubMedCrossRefGoogle Scholar
  60. 60.
    Ankri C, Cohen CJ. Out of the bitter came forth sweet: activating CD28-dependent co-stimulation via PD-1 ligands. Onco Targets Ther. 2014;3:e27399.Google Scholar
  61. 61.
    Hilkens CM, Vermeulen H, van Neerven RJ, Snijdewint FG, Wierenga EA, Kapsenber ML. Differential modulation of T helper type 1 (Th1) and T helper type 2 (Th2) cytokine secretion by prostaglandin E2 critically depends on interleukin2. Eur J Immunol. 1995;25:59–63.PubMedCrossRefGoogle Scholar
  62. 62.
    Yao C, Sakata D, Esaki Y, Li Y, Matsuoka T, Kuroiwa K, Narumiya S. Prostaglandin E 2–EP4 signaling promotes immune inflammation through T H 1 cell differentiation and T H 17 cell expansion. Nat Med. 2009;15:633–40.PubMedCrossRefGoogle Scholar
  63. 63.
    Linnemeyer PA, Pollack SB. Prostaglandin E2-induced changes in the phenotype, morphology, and lytic activity of IL-2-activated natural killer cells. J Immunol. 1993;150:3747–54.PubMedGoogle Scholar
  64. 64.
    Sreeramkumar V, Fresno M, Cuesta N. Prostaglandin E2 and T cells: friends or foes? Immunol Cell Biol. 2012;90:579–86.PubMedCrossRefGoogle Scholar
  65. 65.
    Booyens J, Engelbrecht P, Le Roux S, Louwrens CC, Van der Merwe CF, Katzeff IE. Some effects of the essential fatty acids linoleic acid and alpha-linolenic acid and of their metabolites gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and of prostaglandins A1 and E1 on the proliferation of human osteogenic sarcoma cells in culture. Prostaglandins Leukotrienes Med. 1984;15:15–33.CrossRefGoogle Scholar
  66. 66.
    Monjazeb AM, High KP, Connoy A, Hart LS, Koumenis C, Chilton FH. Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006;27:1950–60.PubMedCrossRefGoogle Scholar
  67. 67.
    Monjazeb AM, High KP, Koumenis C, Chilton FH. Inhibitors of arachidonic acid metabolism act synergistically to signal apoptosis in neoplastic cells. Prostaglandins Leukot Essent Fatty Acids. 2005;73:463–74.PubMedCrossRefGoogle Scholar
  68. 68.
    Canuto RA, Muzio G, Bassi AM, Maggiora M, Leonarduzzi G, Lindahl R, Ferro M. Enrichment with arachidonic acid increases the sensitivity of hepatoma cells to the cytotoxic effects of oxidative stress. Free Radic Biol Med. 1995;18:287–93.PubMedCrossRefGoogle Scholar
  69. 69.
    Piazzi G, D’argenio G, Prossomariti A, Lembo V, Mazzone G, Candela M, D’angelo L. Eicosapentaenoic acid free fatty acid prevents and suppresses colonic neoplasia in colitis associated colorectal cancer acting on Notch signaling and gut microbiota. Int J Cancer. 2014;135:2004–13.PubMedCrossRefGoogle Scholar
  70. 70.
    Sauer LA, Dauchy RT, Blask DE, Krause JA, Davidson LK, Dauchy EM. Eicosapentaenoic acid suppresses cell proliferation in MCF-7 human breast cancer xenografts in nude rats via a pertussis toxin–sensitive signal transduction pathway. J Nutr. 2005;135:2124–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Gu Z, Wu J, Wang S, Suburu J, Chen H, Thomas MJ, Chen YQ. Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells. Carcinogenesis. 2013;34:1968–75.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Wang S, Wu J, Suburu J, Gu Z, Cai J, Axanova LS, Mucci LA. Effect of dietary polyunsaturated fatty acids on castration-resistant Pten-null prostate cancer. Carcinogenesis. 2011;33:404–12.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Blanckaert V, Ulmann L, Mimouni V, Antol J, Brancquart L, Chénais B. Docosahexaenoic acid intake decreases proliferation, increases apoptosis and decreases the invasive potential of the human breast carcinoma cell line MDA-MB-231. Int J Oncol. 2010;36:737–42.PubMedCrossRefGoogle Scholar
  74. 74.
    Collett ED, Davidson LA, Fan YY, Lupton JR, Chapkin RS. n-6 and n-3 polyunsaturated fatty acids differentially modulate oncogenic Ras activation in colonocytes. Am J Physiol Cell Physiol. 2001;280:C1066–75.PubMedCrossRefGoogle Scholar
  75. 75.
    Arisaka M, Arisaka O, Yamashiro Y. Fatty acid and prostaglandin metabolism in children with diabetes mellitus. II.—the effect of evening primrose oil supplementation on serum fatty acid and plasma prostaglandin levels. Prostaglandins Leukot Essent Fatty Acids. 1991;43:197–201.PubMedCrossRefGoogle Scholar
  76. 76.
    Miyake JA, Benadiba M, Colquhoun A. Gamma-linolenic acid inhibits both tumour cell cycle progression and angiogenesis in the orthotopic C6 glioma model through changes in VEGF, Flt1, ERK1/2, MMP2, cyclin D1, pRb, p53 and p27 protein expression. Lipids Health Dis. 2009;8:8.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Takeda S, Sim PG, Horrobin DF, Sanford T, Chisholm KA, Simmons V. Mechanism of lipid peroxidation in cancer cells in response to gamma-linolenic acid (GLA) analyzed by GC-MS (I): conjugated dienes with peroxyl (or hydroperoxyl) groups and cell-killing effects. Anticancer Res. 1993;13:193–9.PubMedGoogle Scholar
  78. 78.
    Chen QR, Kumar D, Stass SA, Mixson AJ. Liposomes complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice. Cancer Res. 1999;59:3308–12.PubMedGoogle Scholar
  79. 79.
    Meister B, Grünebach F, Bautz F, Brugger W, Fink FM, Kanz L, Möhle R. Expression of vascular endothelial growth factor (VEGF) and its receptors in human neuroblastoma. Eur J Cancer. 1999;35:445–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Xiong M, Elson G, Legarda D, Leibovich SJ. Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. Am J Pathol. 1998;153:587–98.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Salven P, Orpana A, Joensuu H. Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. Clin Cancer Res. 1999;5:487–91.PubMedGoogle Scholar
  82. 82.
    Namiki A, Brogi E, Kearney M, Kim EA, Wu T, Couffinhal T, Isner JM. Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. J Biol Chem. 1995;270:31189–95.PubMedCrossRefGoogle Scholar
  83. 83.
    Svennerholm L. Distribution and fatty acid composition of phosphoglycerides in normal human brain. J Lipid Res. 1968;9:570–9.PubMedGoogle Scholar
  84. 84.
    Martínez M, Mougan I. Fatty acid composition of human brain phospholipids during normal development. J Neurochem. 1998;71:2528–33.PubMedCrossRefGoogle Scholar
  85. 85.
    Wu T, Levine SJ, Lawrence MG, Logun C, Angus CW, Shelhamer JH. Interferon-gamma induces the synthesis and activation of cytosolic phospholipase A2. J Clin Invest. 1994;93:571–7.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Miyakawa Y, Kagaya K, Watanabe K, Fukazawa Y. Characteristics of macrophage activation by gamma interferon for tumor cytotoxicity in peritoneal macrophages and macrophage cell line J774.1. Microbiol. Immunol. 1989;33:1027–38.PubMedCrossRefGoogle Scholar
  87. 87.
    Diamond RD, Lyman CA, Wysong DR. Disparate effects of interferon-gamma and tumor necrosis factor-alpha on early neutrophil respiratory burst and fungicidal responses to Candida albicans hyphae in vitro. J Clin Invest. 1991;87:711–20.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Jiang H, Stewart CA, Leu RW. Tumor-derived factor synergizes with IFN-γ and LPS, IL-2 or TNF-α to promote macrophage synthesis of TNF-α and TNF receptors for autocrine induction of nitric oxide synthase and enhanced nitric oxide-mediated tumor cytotoxicity. Immunobiology. 1995;192:321–42.PubMedCrossRefGoogle Scholar
  89. 89.
    Martin JH, Edwards SW. Interferon-gamma enhances monocyte cytotoxicity via enhanced reactive oxygen intermediate production. Absence of an effect on macrophage cytotoxicity is due to failure to enhance reactive nitrogen intermediate production. Immunology. 1994;81:592.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Sample AK, Czuprynski CJ. Priming and stimulation of bovine neutrophils by recombinant human interleukin1 alpha and tumor necrosis factor alpha. J Leukoc Biol. 1991;49:107–15.PubMedCrossRefGoogle Scholar
  91. 91.
    Kharazmi A, Nielsen H, Bendtzen K. Modulation of human neutrophil and monocyte chemotaxis and superoxide responses by recombinant TNF-alpha and GM-CSF. Immunobiology. 1988;177:363–70.PubMedCrossRefGoogle Scholar
  92. 92.
    Yoshikawa T, Takano H, Naito Y, Oyamada H, Ueda S, Kondo M. Augmentative effects of tumor necrosis factor-alpha (human, natural type) on polymorphonuclear leukocyte-derived superoxide generation induced by various stimulants. Int J Immunopharmacol. 1992;14:1391–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Nunokawa Y, Tanaka S. Interferon-γ inhibits proliferation of rat vascular smooth muscle cells by nitric oxide generation. Biochem Biophys Res Commun. 1992;188:409–15.PubMedCrossRefGoogle Scholar
  94. 94.
    Gao X, Zhang H, Belmadani S, Wu J, Xu X, Elford H, Zhang C. Role of TNF-α-induced reactive oxygen species in endothelial dysfunction during reperfusion injury. Am J Physiol Heart Circ Physiol. 2008;295:H2242–9.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Gauss KA, Nelson-Overton LK, Siemsen DW, Gao Y, DeLeo FR, Quinn MT. Role of NFκB in transcriptional regulation of the phagocyte NADPH oxidase by tumor necrosis factor α. J Leukoc Biol. 2007;82:729–41.PubMedCrossRefGoogle Scholar
  96. 96.
    Neale ML, Fiera RA, Matthews N. Involvement of phospholipase A2 activation in tumour cell killing by tumour necrosis factor. Immunology. 1988;64:81.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Spriggs DR, Sherman ML, Imamura K, Mohri M, Rodriguez C, Robbins G, Kufe DW. Phospholipase A2 activation and autoinduction of tumor necrosis factor gene expression by tumor necrosis factor. Cancer Res. 1990;50:7101–7.PubMedGoogle Scholar
  98. 98.
    Seeds MC, Jones DF, Chilton FH, Bass DA. Secretory and cytosolic phospholipases A2 are activated during TNF priming of human neutrophils. Biochim Biophys Acta. 1998;1389:273–84.PubMedCrossRefGoogle Scholar
  99. 99.
    Latchoumycandane C, Marathe GK, Zhang R, McIntyre TM. Oxidatively truncated phospholipids are required agents of tumor necrosis factor α (TNFα)-induced apoptosis. J Biol Chem. 2012;287:17693–705.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Zhao L, Gandhi CR, Gao ZH. Involvement of cytosolic phospholipase A2 alpha signalling pathway in spontaneous and transforming growth factor beta induced activation of rat hepatic stellate cells. Liver Int. 2011;31:1565–73.PubMedCrossRefGoogle Scholar
  101. 101.
    Dong M, Guda K, Nambiar PR, Rezaie A, Belinsky GS, Lambeau G, Rosenberg DW. Inverse association between phospholipase A 2 and COX-2 expression during mouse colon tumorigenesis. Carcinogenesis. 2003;24:307–15.PubMedCrossRefGoogle Scholar
  102. 102.
    Leaver HA, Williams JR, Ironside JW, Miller EP, Gregor A, Su BH, Prescott RJ, Whittle IR. Dynamics of reactive oxygen intermediate production in human glioma: n-6 essential fatty acid effects. Eur J Clin Investig. 1999;29:220–31.CrossRefGoogle Scholar
  103. 103.
    Bell HS, Wharton SB, Leaver HA, Whittle IR. Effects of N-6 essential fatty acids on glioma invasion and growth: experimental studies with glioma spheroids in collagen gels. J Neurosurg. 1999;91:989–96.PubMedCrossRefGoogle Scholar
  104. 104.
    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. 1998;77:1612–20.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Vartak S, Robbins ME, Spector AA. The selective cytotoxicity of gamma-linolenic acid (GLA) is associated with increased oxidative stress. Adv Exp Med Biol. 1999;469:493–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Leaver HA, Wharton SB, Bell HS, Leaver-Yap IM, Whittle IR. Highly unsaturated fatty acid induced tumour regression in glioma pharmacodynamics and bioavailability of gamma linolenic acid in an implantation glioma model: effects on tumour biomass, apoptosis and neuronal tissue histology. Prostaglandins Leukot Essent Fatty Acids. 2002;67:283–92.PubMedCrossRefGoogle Scholar
  107. 107.
    Antal O, Hackler L Jr, Shen J, Mán I, Hideghéty K, Kitajka K, Puskás LG. Combination of unsaturated fatty acids and ionizing radiation on human glioma cells: cellular, biochemical and gene expression analysis. Lipids Health Dis. 2014;13:142.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Leaver HA, Bell HS, Rizzo MT, Ironside JW, Gregor A, Wharton SB, Whittle IR. Antitumour and pro-apoptotic actions of highly unsaturated fatty acids in glioma. Prostaglandins Leukot Essent Fatty Acids. 2002;66:19–29.PubMedCrossRefGoogle Scholar
  109. 109.
    Cai J, Jiang WG, Mansel RE. Inhibition of angiogenic factor- and tumour-induced angiogenesis by gamma linolenic acid. Prostaglandins Leukot Essent Fatty Acids. 1999;60:21–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Das UN. From bench to the clinic: gamma-linolenic acid therapy of human gliomas. Prostaglandins Leukot Essent Fatty Acids. 2004;70:539–52.PubMedCrossRefGoogle Scholar
  111. 111.
    Antal O, Péter M, Hackler L Jr, Mán I, Szebeni G, Ayaydin F, Hideghéty K, Vigh L, Kitajka K, Balogh G, Puskás LG. Lipidomic analysis reveals a radiosensitizing role of gamma-linolenic acid in glioma cells. Biochim Biophys Acta. 1851;2015:1271–82.Google Scholar
  112. 112.
    Das UN. Gamma-linolenic acid therapy of human glioma-a review of in vitro, in vivo, and clinical studies. Med Sci Monit. 2007;13:RA119–RA31.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, Part of Springer Nature 2020

Authors and Affiliations

  • Undurti N. Das
    • 1
    • 2
  1. 1.BioScience Research Centre and Department of MedicineGVP Medical College and HospitalVisakhapatnamIndia
  2. 2.UND Life SciencesBattle GroundUSA

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