Molecular Neurobiology

, Volume 42, Issue 1, pp 76–88 | Cite as

Lipids, Mitochondria and Cell Death: Implications in Neuro-oncology

  • Alison ColquhounEmail author


Polyunsaturated fatty acids (PUFAs) are known to inhibit cell proliferation of many tumour types both in vitro and in vivo. Their capacity to interfere with cell proliferation has been linked to their induction of reactive oxygen species (ROS) production in tumour tissues leading to cell death through apoptosis. However, the exact mechanisms of action of PUFAs are far from clear, particularly in brain tumours. The loss of bound hexokinase from the mitochondrial voltage-dependent anion channel has been directly related to loss of protection from apoptosis, and PUFAs can induce this loss of bound hexokinase in tumour cells. Tumour cells overexpressing Akt activity, including gliomas, are sensitised to ROS damage by the Akt protein and may be good targets for chemotherapeutic agents, which produce ROS, such as PUFAs. Cardiolipin peroxidation may be an initial event in the release of cytochrome c from the mitochondria, and enriching cardiolipin with PUFA acyl chains may lead to increased peroxidation and therefore an increase in apoptosis. A better understanding of the metabolism of fatty acids and eicosanoids in primary brain tumours such as gliomas and their influence on energy balance will be fundamental to the possible targeting of mitochondria in tumour treatment.


Lipids Mitochondria Cell death Neuro-oncology 


  1. 1.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007) WHO classification of tumours of the central nervous system, 4th edn. IARC, FranceGoogle Scholar
  2. 2.
    Booyens J, Engelbrecht P, le Roux S, Louwrens CC, Van der Merwe CF, Katzeff IE (1984) 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 Leukot Med 15(1):15–33PubMedGoogle Scholar
  3. 3.
    Bégin ME, Ells G, Das UN, Horrobin DF (1986) Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst 77(5):1053–1062PubMedGoogle Scholar
  4. 4.
    Fujiwara F, Todo S, Imashuku S (1986) Antitumor effect of gamma-linolenic acido n cultured human neuroblastoma cells. Prostaglandins Leukot Med 23(2–3):311–320PubMedGoogle Scholar
  5. 5.
    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(3):188–194PubMedGoogle Scholar
  6. 6.
    Das UN, Huang YS, Begin ME, Ells G, Horrobin DF (1987) 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 3:9–14PubMedGoogle Scholar
  7. 7.
    Colquhoun A, Curi R (1998) Effects of saturated and polyunsaturated fatty acids on human tumor cell proliferation. Gen Pharmac 30:191–194Google Scholar
  8. 8.
    Hawkins RA, Sangster K, Arends MJ (1998) Apoptotic death of pancreatic cancer cells induced by polyunsaturated fatty acids varies with double bond number and involves an oxidative mechanism. J Pathol 185(1):61–70PubMedGoogle Scholar
  9. 9.
    Vartak S, McCaw R, Davis CS, Robbins ME, Spector AA (1998) Gamma-linolenic acid (GLA) is cytotoxic to 36B10 malignant rat astrocytoma cells but not to ‘normal’ rat astrocytes. Br J Cancer 77(10):1612–1620PubMedGoogle Scholar
  10. 10.
    Das UN, Begin ME, Ells G, Huang YS, Horrobin DF (1987) Polyunsaturated fatty acids augment free radical generation in tumor cells in vitro. B B Res Com 145:15–24Google Scholar
  11. 11.
    Das UN (1991) Tumoricidal action of cis-unsaturated fatty acids and their relationship to free radicals and lipid peroxidation. Cancer Letts 56:235–243Google Scholar
  12. 12.
    Vartak S, Robbins ME, Spector AA (1999) The selective cytotoxicity of gamma-linolenic acid (GLA) is associated with increased oxidative stress. Adv Exp Med Biol 469:493–498PubMedGoogle Scholar
  13. 13.
    Das UN (2002) A radical approach to cancer. Med Sci Monit 8(4):RA79–RA92PubMedGoogle Scholar
  14. 14.
    Rose DP, Connolly JM (1999) Omega-3 fatty acids as cancer chemopreventive agents. Pharmacol Ther 83(3):217–244PubMedGoogle Scholar
  15. 15.
    Nkondjock A, Shatenstein B, Maisonneuve P, Ghadirian P (2003) Specific fatty acids and human colorectal cancer: an overview. Cancer Detect Prev 27(1):55–66PubMedGoogle Scholar
  16. 16.
    Simopoulos AP (2001) The Mediterranean diets: what is so special about the diet of Greece? The scientific evidence. J Nutr 131(11 Suppl):3065S–3073SPubMedGoogle Scholar
  17. 17.
    Ziegler RG, Hoover RN, Pike MC, Hildesheim A, Nomura AM, West DW, Wu-Williams AH, Kolonel LN, Horn-Ross PL, Rosenthal JF, Hyer MB (1993) Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst 85(22):1819–1827PubMedGoogle Scholar
  18. 18.
    Hillyard LA, Abraham S (1979) Effect of dietary polyunsaturated fatty acids on growth of mammary adenocarcinomas in mice and rats. Cancer Res 39(11):4430–4437PubMedGoogle Scholar
  19. 19.
    Abraham S, Hillyard LA (1983) Effect of dietary 18-carbon fatty acids on growth of transplantable mammary adenocarcinomas in mice. J Natl Cancer Inst 71(3):601–605PubMedGoogle Scholar
  20. 20.
    Welsch CW (1992) Relationship between dietary fat and experimental mammary tumorigenesis: a review and critique. Cancer Res 52(7 Suppl):2040s–2048s, 1PubMedGoogle Scholar
  21. 21.
    Sauer LA, Blask DE, Dauchy RT (2007) Dietary factors and growth and metabolism in experimental tumors. J Nutr Biochem 18(10):637–649PubMedGoogle Scholar
  22. 22.
    Rose DP, Connolly JM (1993) Effects of dietary omega-3 fatty acids on human breast cancer growth and metastases in nude mice. J Natl Cancer Inst 85(21):1743–1747PubMedGoogle Scholar
  23. 23.
    Cohen LA, Chen-Backlund JY, Sepkovic DW, Sugie S (1993) Effect of varying proportions of dietary menhaden and corn oil on experimental rat mammary tumor promotion. Lipids 28(5):449–456PubMedGoogle Scholar
  24. 24.
    Gonzalez MJ, Schemmel RA, Dugan L Jr, Gray JI, Welsch CW (1993) Dietary fish oil inhibits human breast carcinoma growth: a function of increased lipid peroxidation. Lipids 28(9):827–832PubMedGoogle Scholar
  25. 25.
    Chapkin RS, McMurray DN, Lupton JR (2007) Colon cancer, fatty acids and anti-inflammatory compounds. Curr Opin Gastroenterol 23(1):48–54PubMedGoogle Scholar
  26. 26.
    Rose DP, Connolly JM, Liu XH (1997) Fatty acid regulation of breast cancer cell growth and invasion. Adv Exp Med Biol 422:47–55PubMedGoogle Scholar
  27. 27.
    Colquhoun A, Miyake JA, Benadiba M (2009) Fatty acids, eicosanoids and cancer. Nutritional Therapy and Metabolism 27(3):105–112Google Scholar
  28. 28.
    Kobayashi N, Barnard RJ, Henning SM, Elashoff D, Reddy ST, Cohen P, Leung P, Hong-Gonzalez J, Freedland SJ, Said J, Gui D, Seeram NP, Popoviciu LM, Bagga D, Heber D, Glaspy JA, Aronson WJ (2006) Effect of altering dietary omega-6/omega-3 fatty acid ratios on prostate cancer membrane composition, cyclooxygenase-2, and prostaglandin E2. Clin Cancer Res 12(15):4662–4670PubMedGoogle Scholar
  29. 29.
    Nathoo N, Barnett GH, Golubic M (2004) The eicosanoid cascade: possible role in gliomas and meningiomas. J Clin Pathol 57(1):6–13PubMedGoogle Scholar
  30. 30.
    Gillies RJ, Gatenby RA (2007) Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? J Bioenerg Biomembr 39:251–257PubMedGoogle Scholar
  31. 31.
    Herrmann PC, Herrmann EC (2007) Oxygen metabolism and a potential role for cytochrome c oxidase in the Warburg effect. J Bioenerg Biomembr 39:247–250PubMedGoogle Scholar
  32. 32.
    Prip-Buus C, Bouthillier-Voisin AC, Kohl C, Demaugre F, Girard J, Pegorier JP (1992) Evidence for an impaired long-chain fatty acid oxidation and ketogenesis in Fao hepatoma cells. Eur J Biochem 209(1):291–298PubMedGoogle Scholar
  33. 33.
    Colquhoun A, Curi R (1995) Human and rat tumour cells possess mitochondrial carnitine palmitoyltransferase I and II: effects of insulin. Biochem Mol Biol Int 37:599–605PubMedGoogle Scholar
  34. 34.
    Colquhoun A, Curi R (1996) Immunodetection of rat Walker 256 tumour mitochondrial carnitine palmitoyltransferase I and II: evidence for the control of CPT II expression by insulin. Biochem Mol Biol Int 38:171–174PubMedGoogle Scholar
  35. 35.
    Colquhoun A, Curi R (1997) Metabolic fate and effects of saturated and unsaturated fatty acids in Hep2 human larynx tumor cells. Biochem Mol Biol Int 41:597–607PubMedGoogle Scholar
  36. 36.
    Colquhoun A (2002) Gamma-linolenic acid alters the composition of mitochondrial membrane subfractions, decreases outer mitochondrial membrane binding of hexokinase and alters carnitine palmitoyltransferase I properties in the Walker 256 rat tumour. Biochim Biophys Acta 1583(1):74–84PubMedGoogle Scholar
  37. 37.
    Colquhoun A, de Mello FE, Curi R (1998) Regulation of tumour cell fatty acid oxidation by n-6 polyunsaturated fatty acids. Biochem Mol Biol Int 44(1):143–150PubMedGoogle Scholar
  38. 38.
    Qiao L, Kozoni V, Tsioulias GJ, Koutsos MI, Hanif R, Shiff SJ, Rigas B (1995) Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo. Biochim Biophys Acta 1258(2):215–223PubMedGoogle Scholar
  39. 39.
    Chen ZY, Istfan NW (2000) Docosahexaenoic acid is a potent inducer of apoptosis in HT29 colon cancer cells. Prostaglandins Leukot Essent Fat Acids 63(5):301–308Google Scholar
  40. 40.
    Colquhoun A, Ramos KL, Schumacher RI (2001) Eicosapentaenoic acid and docosahexaenoic acid effects on tumour mitochondrial metabolism, acyl CoA metabolism and cell proliferation. Cell Biochem Func 19:97–105Google Scholar
  41. 41.
    Bustamante E, Pedersen PL (1977) High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci U S A 74(9):3735–3739PubMedGoogle Scholar
  42. 42.
    Pedersen PL (2007) Warburg, me and Hexokinase 2: multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr 39(3):211–222PubMedGoogle Scholar
  43. 43.
    Mathupala SP, Ko YH, Pedersen PL (2008) Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol 19(1):17–24PubMedGoogle Scholar
  44. 44.
    Stewart JM, Blakely JA (2000) Long chain fatty acids inhibit and medium chain fatty acids activate mammalian cardiac hexokinase. BiochemBiophys Acta 1484:278–286PubMedGoogle Scholar
  45. 45.
    Arzoine L, Zilberberg N, Ben-Romano R, Shoshan-Barmatz V (2009) Voltage-dependent anion channel 1-based peptides interact with hexokinase to prevent its anti-apoptotic activity. J Biol Chem 284(6):3946–3955PubMedGoogle Scholar
  46. 46.
    Brooks Robey R, Hay N (2009) Is Akt the “Warburg kinase”—Akt-energy interactions and oncogenesis. Semin Cancer Biol 19(1):25–31PubMedGoogle Scholar
  47. 47.
    Kumarswamy R, Chandna S (2009) Putative partners in Bax mediated cytochrome-c release: ANT, CypD, VDAC or none of them? Mitochondrion 9:1–8PubMedGoogle Scholar
  48. 48.
    Colquhoun A, Schumacher RI (2001) Modifications in mitochondrial metabolism and ultrastructure and their relationship to tumour growth inhibition by gamma-linolenic acid. Mol Cell Biochem 218(1–2):13–20PubMedGoogle Scholar
  49. 49.
    Colquhoun A, Schumacher RI (2001) gamma-Linolenic acid and eicosapentaenoic acid induce modifications in mitochondrial metabolism, reactive oxygen species generation, lipid peroxidation and apoptosis in Walker 256 rat carcinosarcoma cells. Biochim Biophys Acta 1533(3):207–219PubMedGoogle Scholar
  50. 50.
    Bartrons R, Caro J (2007) Hypoxia, glucose metabolism and the Warburg’s effect. J Bioenerg Biomembr 39(3):223–229PubMedGoogle Scholar
  51. 51.
    Gogvadze V, Orrenius S, Zhivotovsky B (2009) Mitochondria as targets for chemotherapy. Apoptosis 14:624–640PubMedGoogle Scholar
  52. 52.
    Gogvadze V, Orrenius S, Zhivotovsky B (2009) Mitochondria as targets for cancer chemotherapy. Semin Cancer Biol 19(1):57–66PubMedGoogle Scholar
  53. 53.
    Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12(5):913–922PubMedGoogle Scholar
  54. 54.
    Cocco T, Di Paola M, Papa S, Lorusso M (1999) Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation. Free Radic Biol Med 27(1–2):51–59PubMedGoogle Scholar
  55. 55.
    Colquhoun A (2009) Mechanisms of action of eicosapentaenoic acid in bladder cancer cells in vitro: alterations in mitochondrial metabolism, reactive oxygen species generation and apoptosis induction. J Urol 181(4):1885–1893PubMedGoogle Scholar
  56. 56.
    Kantrow SP, Tatro LG, Piantadosi CA (2000) Oxidative stress and adenine nucleotide control of mitochondrial permeability transition. Free Radic Biol Med 28(2):251–260PubMedGoogle Scholar
  57. 57.
    Gendron MC, Schrantz N, Métivier D, Kroemer G, Maciorowska Z, Sureau F, Koester S, Petit PX (2001) Oxidation of pyridine nucleotides during Fas- and ceramide-induced apoptosis in Jurkat cells: correlation with changes in mitochondria, glutathione depletion, intracellular acidification and caspase 3 activation. Biochem J 353(Pt 2):357–367PubMedGoogle Scholar
  58. 58.
    Cao Y, Pearman AT, Zimmerman GA, McIntyre TM, Prescott SM (2000) Intracellular unesterified arachidonic acid signals apoptosis. Proc Natl Acad Sci U S A 97(21):11280–11285PubMedGoogle Scholar
  59. 59.
    Neuzil J, Dyason JC, Freeman R, Dong LF, Prochazka L, Wang XF, Scheffler I (2007) Ralph SJ Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II. J Bioenerg Biomembr 39(1):65–72PubMedGoogle Scholar
  60. 60.
    Jones RG, Thompson CB (2009) Tumor suppressor and cell metabolism: a recipe for cancer growth. Genes Dev 23:537–548PubMedGoogle Scholar
  61. 61.
    Watkins SM, Carter LC, German JB (1998) Docosahexaenoic acid accumulates in cardiolipin and enhances HT-29 cell oxidant production. J Lipid Res 39(8):1583–1588PubMedGoogle Scholar
  62. 62.
    Gonzalez B, Iturralde M, Alava MA, Anel A, Piñeiro A (2000) Metabolism of n -9, n -6 and n -3 fatty acids in hepatoma Morris 7777 cells. Preferential accumulation of linoleic acid in cardiolipin. Prostaglandins Leukot Essent Fat Acids 62(5):299–306Google Scholar
  63. 63.
    Nomura K, Imai H, Koumura T, Kobayashi T, Nakagawa Y (2000) Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis. Biochem J 351(Pt 1):183–193PubMedGoogle Scholar
  64. 64.
    Brdiczka D (1991) Contact sites between mitochondrial envelope membranes. Structure and function in energy- and protein-transfer. Biochim Biophys Acta 1071(3):291–312PubMedGoogle Scholar
  65. 65.
    Jacob WA, Bakker A, Hertsens RC, Biermans W (1994) Mitochondrial matrix granules: their behavior during changing metabolic situations and their relationship to contact sites between inner and outer mitochondrial membranes. Microsc Res Tech 27(4):307–318PubMedGoogle Scholar
  66. 66.
    Denis-Pouxviel C, Riesinger I, Bühler C, Brdiczka D, Murat JC (1987) Regulation of mitochondrial hexokinase in cultured HT 29 human cancer cells. Na ultrastructural and biochemical study. Biochim Biophys Acta 902(3):335–348PubMedGoogle Scholar
  67. 67.
    Kryvi H, Aarsland A, Berge RK (1990) Morphologic effects of sulfur-substituted fatty acids on rat hepatocytes with special reference to proliferation of peroxisomes and mitochondria. J Struct Biol 103(3):257–265PubMedGoogle Scholar
  68. 68.
    Fraser F, Zammit VA (1998) Enrichment of carnitine palmitoyltransferases I and II in the contact sites of rat liver mitochondria. Biochem J 329(Pt 2):225–229PubMedGoogle Scholar
  69. 69.
    Fraser F, Padovese R, Zammit VA (2001) Distinct kinetics of carnitine palmitoyltransferase I in contact sites and outer membranes of rat liver mitochondria. J Biol Chem 276(23):20182–20185PubMedGoogle Scholar
  70. 70.
    Hoppel CL, Kerner J, Turkaly P, Tandler B (2001) Distinct kinetics of carnitine palmitoyltransferase I in contact sites and outer membranes of rat liver mitochondria. Arch Biochem Biophys 392:321–325PubMedGoogle Scholar
  71. 71.
    Seegers JC, de Kock M, Lottering ML, Grobler CJ, van Papendorp DH, Shou Y, Habbersett R, Lehnert BE (1997) Effects of gamma-linolenic acid and arachidonic acid on cell cycle progression and apoptosis induction in normal and transformed cells. Prostaglandins Leukot Essent Fat Acids 56(4):271–280Google Scholar
  72. 72.
    Seegers JC, Lottering ML, Panzer A, Bianchi P, Stark JH (1998) Comparative anti-mitotic effects of lithium gamma-linolenate, gamma-linolenic acid and arachidonic acid, on transformed and embryonic cells. Prostaglandins Leukot Essent Fat Acids 59(4):285–291Google Scholar
  73. 73.
    de Kock M, Lottering ML, Grobler CJ, Viljoen TC, le Roux M, Seegers JC (1996) The induction of apoptosis in human cervical carcinoma (HeLa) cells by gamma-linolenic acid. Prostaglandins Leukot Essent Fat Acids 55(6):403–411Google Scholar
  74. 74.
    Siddiqui RA, Jenski LJ, Neff K, Harvey K, Kovacs RJ, Stillwell W, Siddiqui EA (2001) Docosahexaenoic acid induces apoptosis in Jurkat cells by a protein phosphatase-mediated process. Biochim Biophys Acta 1499(3):265–275PubMedGoogle Scholar
  75. 75.
    Siddiqui RA, Jenski LJ, Harvey KA, Wiesehan JD, Stillwell W, Zaloga GP (2003) Cell-cycle arrest in Jurkat leukaemic cells: a possible role for docosahexaenoic acid. Biochem J 371(Pt 2):621–629PubMedGoogle Scholar
  76. 76.
    Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N (2001) Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 15(11):1406–1418PubMedGoogle Scholar
  77. 77.
    Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341(Pt 2):233–249PubMedGoogle Scholar
  78. 78.
    Desagher S, Martinou JC (2000) Mitochondria as the central control point of apoptosis. Trends Cell Biol 10(9):369–377PubMedGoogle Scholar
  79. 79.
    Lena A, Rechichi M, Salvetti A, Bartoli B, Vecchio D, Scarcelli V, Amoroso R, Benvenuti L, Gagliardi R, Gremigni V, Rossi L (2009) Drugs targeting the mitochondrial pore act as citotoxic and cytostatic agents in temozolomide-resistant glioma cells. J Transl Med 7:13PubMedGoogle Scholar
  80. 80.
    Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, Unterman T, Hay N (2008) Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14(6):458–470PubMedGoogle Scholar
  81. 81.
    Paumen MB, Ishida Y, Muramatsu M, Yamamoto M, Honjo T (1997) Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis. J Biol Chem 272(6):3324–3329PubMedGoogle Scholar
  82. 82.
    Paumen MB, Ishida Y, Han H, Muramatsu M, Eguchi Y, Tsujimoto Y, Honjo T (1997) Direct interaction of the mitochondrial membrane protein carnitine palmitoyltransferase I with Bcl-2. Biochem Biophys Res Commun 231(3):523–525PubMedGoogle Scholar
  83. 83.
    Sparagna GC, Hickson-Bick DL, Buja LM, McMillin JB (2000) A metabolic role for mitochondria in palmitate-induced cardiac myocyte apoptosis. Am J Physiol Heart Circ Physiol 279(5):H2124–H2132PubMedGoogle Scholar
  84. 84.
    Colquhoun A (1998) Induction of apoptosis by polyunsaturated fatty acids and its relationship to fatty acid inhibition of carnitine palmitoyltransferase I activity in Hep2 cells. Biochem Mol Biol Int 45(2):331–336PubMedGoogle Scholar
  85. 85.
    Gonzalvez F, Gottlieb E (2007) Cardiolipin: setting the beat of apoptosis. Apotosis 12:877–885Google Scholar
  86. 86.
    Mynatt RL, Greenhaw JJ, Cook GA (1994) Cholate extracts of mitochondrial outer membranes increase inhibition by malonyl-CoA of carnitine palmitoyltransferase-I by a mechanism involving phospholipids. Biochem J 299(Pt 3):761–767PubMedGoogle Scholar
  87. 87.
    Serini S, Piccioni E, Merendino N, Calviello G (2009) Dietary polyunsaturated fatty acids as inducers of apoptosis: implications for cancer. Apoptosis 14(2):135–152PubMedGoogle Scholar
  88. 88.
    Liepkalns VA, Icard-Liepkalns C, Cornwell DG (1982) Regulation of cell division in a human glioma cell clone by arachidonic acid and alpha-tocopherolquinone. Cancer Lett 15(2):173–178PubMedGoogle Scholar
  89. 89.
    Williams JR, Leaver HA, Ironside JW, Miller EP, Whittle IR, Gregor A (1998) Apoptosis in human primary brain tumours: actions of arachidonic acid. Prostaglandins Leukot Essent Fat Acids 58(3):193–200Google Scholar
  90. 90.
    Martin DD, Robbins ME, Spector AA, Wen BC, Hussey DH (1996) The fatty acid composition of human gliomas differs from that found in nonmalignant brain tissue. Lipids 31(12):1283–1288PubMedGoogle Scholar
  91. 91.
    Kokoglu E, Tüter Y, Yazici Z, Sandikci KS, Sönmez H, Ulakoğlu EZ, Ozyurt E (1998) Profiles of the fatty acids in the plasma membrane of human brain tumors. Cancer Biochem Biophys 16(4):301–312PubMedGoogle Scholar
  92. 92.
    Leaver HA, Williams JR, Ironside JW, Miller EP, Gregor A, Su BH, Prescott RJ, Whittle IR (1999) Dynamics of reactive oxygen intermediate production in human glioma: n-6 essential fatty acid effects. Eur J Clin Invest 29(3):220–231, Comment in: Eur J Clin Invest 1999 Mar; 29(3):185-8PubMedGoogle Scholar
  93. 93.
    Leaver HA, Williams JR, Smith C, Whittle IR (2004) Intracellular oxidation by human glioma cell populations: effect of arachidonic acid. Prostaglandins Leukot Essent Fat Acids 70(5):449–453Google Scholar
  94. 94.
    Naidu MR, Das UN, Kishan A (1992) Intratumoral gamma-linoleic acid therapy of human gliomas. Prostaglandins Leukot Essent Fat Acids 45(3):181–184Google Scholar
  95. 95.
    Das UN, Prasad VV, Reddy DR (1995) Local application of gamma-linolenic acid in the treatment of human gliomas. Cancer Lett 94(2):147–155PubMedGoogle Scholar
  96. 96.
    Bakshi A, Mukherjee D, Bakshi A, Banerji AK, Das UN (2003) Gamma-linolenic acid therapy of human gliomas. Nutrition 19(4):305–309, Comment on: Nutrition. 2003 Apr; 19(4):386-8PubMedGoogle Scholar
  97. 97.
    Das UN (2004) From bench to the clinic: gamma-linolenic acid therapy of human gliomas. Prostaglandins Leukot Essent Fat Acids 70(6):539–552Google Scholar
  98. 98.
    Das UN (2007) Gamma-linolenic acid therapy of human glioma-a review of in vitro, in vivo, and clinical studies. Med Sci Monit 13(7):RA119–RA131PubMedGoogle Scholar
  99. 99.
    Bell HS, Wharton SB, Leaver HA, Whittle IR (1999) Effects of N-6 essential fatty acids on glioma invasion and growth: experimental studies with glioma spheroids in collagen gels. J Neurosurg 91(6):989–996PubMedGoogle Scholar
  100. 100.
    Ramos KL, Colquhoun A (2003) Protective role of glucose-6-phosphate dehydrogenase activity in the metabolic response of C6 rat glioma cells to polyunsaturated fatty acid exposure. Glia 43(2):149–166PubMedGoogle Scholar
  101. 101.
    Farin A, Suzuki SO, Weiker M, Goldman JE, Bruce JN, Canoll P (2006) Transplanted glioma cells migrate and proliferate on host brain vasculature: a dynamic analysis. Glia 53(8):799–808PubMedGoogle Scholar
  102. 102.
    Benadiba M, Miyake JA, Colquhoun A (2009) Gamma-linolenic acid alters Ku80, E2F1, and bax expression and induces micronucleus formation in C6 glioma cells in vitro. IUBMB Life 61(3):244–251PubMedGoogle Scholar
  103. 103.
    Chen ZY, Istfan NW (2001) Docosahexaenoic acid, a major constituent of fish oil diets, prevents activation of cyclin-dependent kinases and S-phase entry by serum stimulation in HT29 cells. Prostaglandins Leukot Essent Fat Acids 64(1):67–73Google Scholar
  104. 104.
    Kim R, Emi M, Tanabe K (2005) Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol 57(5):545–553PubMedGoogle Scholar
  105. 105.
    Susnow N, Zeng L, Margineantu D, Hockenbery DM (2009) Bcl-2 family proteins as regulators of oxidative stress. Semin Cancer Biol 19(1):42–49PubMedGoogle Scholar
  106. 106.
    Subramanian C, Opipari AW Jr, Bian X, Castle VP, Kwok RP (2005) Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A 102:4842–4847PubMedGoogle Scholar
  107. 107.
    Gullo C, Au M, Feng G, Teoh G (2006) The biology of Ku and its potential oncogenic role in cancer. Biochim Biophys Acta 1765:223–234PubMedGoogle Scholar
  108. 108.
    Pedley J, Pettit A, Parsons PG (1998) Inhibition of Ku autoantigen binding activity to the E2F motif after ultraviolet B irradiation of melanocytic cells. Melanoma Res 8(6):471–481PubMedGoogle Scholar
  109. 109.
    Park SJ, Ciccone SL, Freie B, Kurimasa A, Chen DJ, Li GC, Clapp DW, Lee SH (2004) A positive role for the Ku complex in DNA replication following strand break damage in mammals. J Biol Chem 279(7):6046–6055PubMedGoogle Scholar
  110. 110.
    Song JY, Lim JW, Kim H, Kim KH (2003) Role of NF-kappaB and DNA repair protein Ku on apoptosis in pancreatic acinar cells. Ann N Y Acad Sci 1010:259–263PubMedGoogle Scholar
  111. 111.
    Rampakakis E, Di Paola D, Zannis-Hadjopoulos M (2008) Ku is involved in cell growth, DNA replication and G1-S transition. J Cell Sci 121(Pt 5):590–600PubMedGoogle Scholar
  112. 112.
    Yang QS, Gu JL, DU LQ, Jia LL, Qin LL, Wang Y, Fan FY (2008) ShRNA-mediated Ku80 gene silencing inhibits cell proliferation and sensitizes to gamma-radiation and mitomycin c-induced apoptosis in esophageal squamous cell carcinoma lines. J Radiat Res (Tokyo). 2008 Apr 9Google Scholar
  113. 113.
    Groesser T, Chun E, Rydberg B (2007) Relative biological effectiveness of high-energy iron ions for micronucleus formation at low doses. Radiat Res 168(6):675–682PubMedGoogle Scholar
  114. 114.
    Zhang F, Zhang T, Gu ZP, Zhou YA, Han Y, Li XF, Wang XP, Cheng QS, Mei QB (2008) Enhancement of radiosensitivity by roscovitine pretreatment in human non-small cell lung cancer A549 cells. J Radiat Res (Tokyo) 49(5):541–548Google Scholar
  115. 115.
    Kinsella JE, Black JM (1993) Effects of polyunsaturated fatty acids on the efficacy of antineoplastic agents toward L5178Y lymphoma cells. Biochem Pharmacol 45(9):1881–1887PubMedGoogle Scholar
  116. 116.
    Vartak S, Robbins ME, Spector AA (1997) Polyunsaturated fatty acids increase the sensitivity of 36B10 rat astrocytoma cells to radiation-induced cell kill. Lipids 32(3):283–292PubMedGoogle Scholar
  117. 117.
    Germain E, Chajès V, Cognault S, Lhuillery C, Bougnoux P (1998) 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 75(4):578–583PubMedGoogle Scholar
  118. 118.
    Madhavi N, Das UN (1994) 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 84(1):31–41PubMedGoogle Scholar
  119. 119.
    Kenny FS, Pinder SE, Ellis IO, Gee JM, Nicholson RI, Bryce RP, Robertson JF (2000) Gamma linolenic acid with tamoxifen as primary therapy in breast cancer. Int J Cancer 85(5):643–648PubMedGoogle Scholar
  120. 120.
    Das UN, Madhavi N, Sravan Kumar G, Padma M, Sangeetha P (1998) Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites? Prostaglandins Leukot Essent Fat Acids 58(1):39–54Google Scholar
  121. 121.
    Leaver HA, Bell HS, Rizzo MT, Ironside JW, Gregor A, Wharton SB, Whittle IR (2002) Antitumour and pro-apoptotic actions of highly unsaturated fatty acids in glioma. Prostaglandins Leukot Essent Fat Acids 66(1):19–29Google Scholar
  122. 122.
    Godinot C, de Laplanche E, Hervouet E, Simonnet H (2007) Actuality of Warburg’s views in our understanding of renal cancer metabolism. J Bioenerg Biomembr 39(3):235–241PubMedGoogle Scholar
  123. 123.
    Leaver HA, Wharton SB, Bell HS, Leaver-Yap IM, Whittle IR (2002) 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 Fat Acids 67(5):283–292Google Scholar
  124. 124.
    Miyake JA, Benadiba M, Colquhoun A (2009) 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 8:8PubMedGoogle Scholar
  125. 125.
    Ma W, Sung HJ, Park JY, Matoba S, Hwang PM (2007) A pivotal role for p53: balancing aerobic respiration and glycolysis. J Bioenerg Biomembr 39(3):243–246PubMedGoogle Scholar
  126. 126.
    Frezza C, Gottlieb E (2009) Mitochondria in cancer: not just innocent bystanders. Semin Cancer Biol 19(1):4–11PubMedGoogle Scholar
  127. 127.
    Olovnikov IA, Kravchenko JE, Chumakov PM (2009) Homeostatic functions of metabolism and antioxidant defense. Semin Cancer Biol 19(1):32–41PubMedGoogle Scholar
  128. 128.
    Khan NA, Nishimura K, Aires V, Yamashita T, Oaxaca-Castillo D, Kashigawa K, Igarashi K (2006) Docosahexaenoic acid inhibits cancer cell growth via p27Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation. J Lipid Res 47(10):2306–2313PubMedGoogle Scholar
  129. 129.
    Schley PD, Jijon HB, Robinson LE, Field CJ (2005) Mechanisms of omega-3 fatty acid-induced growth inhibition in MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat 92:187–195PubMedGoogle Scholar
  130. 130.
    Calviello G, Palozza P, Piccioni E, Maggiano N, Frattucci A, Franceschelli P, Bartoli GM (1998) Dietary supplementation with eicosapentaenoic and docosahexaenoic acid inhibits growth of Morris hepatocarcinoma 3924A in rats: effects on proliferation and apoptosis. Int J Cancer 75(5):699–705PubMedGoogle Scholar
  131. 131.
    Cai J, Jiang WG, Mansel RE (1999) Inhibition of the expression of VE-cadherin/catenin complex by gamma linolenic acid in human vascular endothelial cells, and its impact on angiogenesis. Biochem Biophys Res Commun 258(1):113–8, 29PubMedGoogle Scholar
  132. 132.
    Jiang WG, Bryce RP, Horrobin DF (1998) Essential fatty acids: molecular and cellular basis of their anti-cancer action and clinical implications. Crit Rev Oncol Hematol 27(3):179–209PubMedGoogle Scholar
  133. 133.
    Yamagata K, Tagami M, Takenaga F, Yamori Y, Nara Y, Itoh S (2003) Fatty acids induce tight junctions to form in brain capillary endothelial cells. Neuroscience 116:649–656PubMedGoogle Scholar
  134. 134.
    Schiazza L, Lamari F, Foglietti MJ, Hainque B, Bernard M, Beaudeux JL (2008) Métabolisme énergétique cellulaire du tissue cérébral: spécificités métaboliques des tumeurs gliales. Ann Biol Clin 66(2):131–141Google Scholar
  135. 135.
    Pilkington GJ, Parker K, Murray SA (2008) Approaches to mitochondrially mediated cancer therapy. Sem Cancer Biol 18:226–235Google Scholar
  136. 136.
    Auestad N, Korsak RA, Morrow JW, Edmond J (1991) Fatty acid oxidation and ketogenesis by astrocytes in primary culture. J Neurochem 56(4):1376–1386PubMedGoogle Scholar
  137. 137.
    Blázquez C, Sánchez C, Velasco G, Guzmán M (1998) Role of carnitine palmitoyltransferase I in the control of ketogenesis in primary cultures of rat astrocytes. J Neurochem 71(4):1597–1606PubMedCrossRefGoogle Scholar
  138. 138.
    Blázquez C, Woods A, de Ceballos ML, Carling D, Guzmán M (1999) The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. J Neurochem 73(4):1674–1682PubMedGoogle Scholar
  139. 139.
    Blázquez C, Sánchez C, Daza A, Galve-Roperh I, Guzmán M (1999) The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide-activated enzyme. J Neurochem 72(4):1759–1768PubMedGoogle Scholar
  140. 140.
    Hertz L, Peng L, Dienel GA (2007) Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 27(2):219–249, Epub 2006 Jul 12PubMedGoogle Scholar
  141. 141.
    Oudard S, Miccoli L, Beurdeley-Thomas A, Dutrillaux B, Poupon MF (2004) Homophilic anchorage of brain-hexokinase to mitochondria-porins revealed by specific-peptide antibody cross recognition. Bull Cancer 91(6):E184–E200PubMedGoogle Scholar
  142. 142.
    Abu-Hamad S, Zaid H, Israelson A, Nahon E, Shoshan-Barmatz V (2008) Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding. J Biol Chem 283(19):13482–13490PubMedGoogle Scholar
  143. 143.
    Lewandrowski U, Sickmann A, Cesaro L, Brunati AM, Toninello A, Salvi M (2008) Identification of new tyrosine phosphorylated proteins in rat brain mitochondria. FEBS Lett 582(7):1104–1110PubMedGoogle Scholar
  144. 144.
    Jou MJ (2008) Pathophysiological and pharmacological implications of mitochondria-targeted reactive oxygen species generation in astrocytes. Adv Drug Deliv Rev 60(13-14):1512–1526PubMedGoogle Scholar
  145. 145.
    Hamm-Alvarez S, Cadenas E (2008) Mitochondrial medicine and mitochondrion-based therapeutics. Adv Drug Deliv Rev 60(13-14):1437–1438PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Laboratory of Tumour Cell Metabolism, Department of Cell and Developmental Biology, Biomedical Sciences InstituteUniversity of São PauloSão PauloBrazil

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