Augmentation of chemotherapy-triggered glioma cell apoptosis by blockade of arachidonic acid metabolism-the potential role of ceramide accumulation

Medical Hypotheses

Volumn 77, Issue 5, 2011, Pages 726-733

  Omahen, David A ^a  

^a FOOTHILLS HOSPITAL   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ARACHIDONIC ACID; CERAMIDE; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; CYTOCHROME P450; LEUKOTRIENE; PROSTAGLANDIN; SPHINGOMYELIN PHOSPHODIESTERASE; THROMBOXANE;

ANGIOGENESIS; APOPTOSIS; ARACHIDONIC ACID METABOLISM; ARTICLE; CANCER CHEMOTHERAPY; CANCER GRADING; CANCER INHIBITION; CANCER RADIOTHERAPY; CELL DEATH; GLIOMA CELL; LIPID METABOLISM; PROTEIN EXPRESSION; UPREGULATION;

ANTINEOPLASTIC AGENTS; APOPTOSIS; ARACHIDONIC ACID; BRAIN NEOPLASMS; CELL LINE, TUMOR; CERAMIDES; CYTOCHROME P-450 ENZYME SYSTEM; ENZYME ACTIVATION; GLIOMA; HUMANS; LIPOXYGENASES; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES; SPHINGOMYELIN PHOSPHODIESTERASE;

EID: 80053988207     PISSN: 03069877     EISSN: 15322777     Source Type: Journal    
DOI: 10.1016/j.mehy.2011.07.025     Document Type: Article

References (104)

1. Wrensch M., Minn Y., Chew T., Bondy M., Berger M.S. Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro Oncol 2002, 4(4):278-299.
2. Stupp R., Mason W.P., van den Bent M.J., et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005, 352(10):987-996.
3. Wagemakers M., Van der Wal G.E., Cuberes R., et al. COX-2 inhibition combined with radiation reduces orthotopic glioma outgrowth by targeting the tumor vasculature. Transl Oncol 2009, 2(1):1-7.
4. Van Nifterik K.A., Van Den Berg J., Slotman B.J., Van Rijn J. Anti-tumour effects by a trimodal combination of temozolomide, meloxicam and X-rays in cultures of human glioma cells. Int J Radiat Biol 2011, 87(2):192-201.
5. Kuipers G.K., Slotman B.J., Wedekind L.E., et al. Radiosensitization of human glioma cells by cyclooxygenase-2 (COX-2) inhibition: independent on COX-2 expression and dependent on the COX-2 inhibitor and sequence of administration. Int J Radiat Biol 2007, 83(10):677-685.
6. Marchesini N., Hannun Y.A. Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol 2004, 82(1):27-44.
7. Goldsmith M., Daka A., Lamour N.F., et al. A ceramide analog inhibits cPLA(2) activity and consequent PGE(2) formation in LPS-stimulated macrophages. Immunol Lett 2011, 135(1-2):136-143.
8. Chen J.K., Capdevila J., Harris R.C. Cytochrome p450 epoxygenase metabolism of arachidonic acid inhibits apoptosis. Mol Cell Biol 2001, 21(18):6322-6331.
9. Cipollone F., Patrono C. Cyclooxygenase-2 polymorphism: putting a brake on the inflammatory response to vascular injury?. Arterioscler Thromb Vasc Biol 2002, 22(10):1516-1518.
10. Kwon K.J., Jung Y.S., Lee S.H., Moon C.H., Baik E.J. Arachidonic acid induces neuronal death through lipoxygenase and cytochrome P450 rather than cyclooxygenase. J Neurosci Res 2005, 81(1):73-84.
11. Zagorac D., Jakovcevic D., Gebremedhin D., Harder D.R. Antiangiogenic effect of inhibitors of cytochrome P450 on rats with glioblastoma multiforme. J Cereb Blood Flow Metab 2008, 28(8):1431-1439.
12. Nathoo N., Barnett G.H., Golubic M. The eicosanoid cascade: possible role in gliomas and meningiomas. J Clin Pathol 2004, 57(1):6-13.
13. Roman R.J. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 2002, 82(1):131-185.
14. Zeidan Y.H., Wu B.X., Jenkins R.W., Obeid L.M., Hannun Y.A. A novel role for protein kinase Cdelta-mediated phosphorylation of acid sphingomyelinase in UV light-induced mitochondrial injury. FASEB J 2008, 22(1):183-193.
15. Chien C.C., Shen S.C., Yang L.Y., Wu C.Y., Liau J.S., Chen Y.C. Activation of telomerase and cyclooxygenase-2 in PDGF and FGF inhibition of C2-ceramide-induced apoptosis. J Cell Physiol 2009, 218(2):405-415.
16. Carpinteiro A., Dumitru C., Schenck M., Gulbins E. Ceramide-induced cell death in malignant cells. Cancer Lett 2008, 264(1):1-10.
17. Huwiler A., Johansen B., Skarstad A., Pfeilschifter J. Ceramide binds to the CaLB domain of cytosolic phospholipase A2 and facilitates its membrane docking and arachidonic acid release. FASEB J 2001, 15(1):7-9.
18. Nakamura H., Hirabayashi T., Shimizu M., Murayama T. Ceramide-1-phosphate activates cytosolic phospholipase A2alpha directly and by PKC pathway. Biochem Pharmacol 2006, 71(6):850-857.
19. Shimizu M., Tada E., Makiyama T., et al. Effects of ceramide, ceramidase inhibition and expression of ceramide kinase on cytosolic phospholipase A2alpha; additional role of ceramide-1-phosphate in phosphorylation and Ca2+ signaling. Cell Signal 2009, 21(3):440-447.
20. Zhao S., Du X.Y., Chai M.Q., Chen J.S., Zhou Y.C., Song J.G. Secretory phospholipase A(2) induces apoptosis via a mechanism involving ceramide generation. Biochim Biophys Acta 2002, 1581(3):75-88.
21. Schiffmann S., Ziebell S., Sandner J., et al. Activation of ceramide synthase 6 by celecoxib leads to a selective induction of C16:0-ceramide. Biochem Pharmacol 2010, 80(11):1632-1640.
22. Pettus B.J., Chalfant C.E., Hannun Y.A. Ceramide in apoptosis: an overview and current perspectives. Biochim Biophys Acta 2002, 1585(2-3):114-125.
23. Lahiri S., Futerman A.H. The metabolism and function of sphingolipids and glycosphingolipids. Cell Mol Life Sci 2007, 64(17):2270-2284.
24. Gomez-Munoz A. Ceramide 1-phosphate/ceramide, a switch between life and death. Biochim Biophys Acta 2006, 1758(12):2049-2056.
25. Bornancin F. Ceramide kinase: The first decade. Cell Signal 2011, 23(6):999-1008.
26. Lamour N.F., Chalfant C.E. Ceramide kinase and the ceramide-1-phosphate/cPLA2alpha interaction as a therapeutic target. Curr Drug Targets 2008, 9(8):674-682.
27. Ogretmen B., Hannun Y.A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 2004, 4(8):604-616.
28. Radin N.S. Killing cancer cells by poly-drug elevation of ceramide levels: a hypothesis whose time has come?. Eur J Biochem 2001, 268(2):193-204.
29. Saddoughi S.A., Song P., Ogretmen B. Roles of bioactive sphingolipids in cancer biology and therapeutics. Subcell Biochem 2008, 49:413-440.
30. Billich A., Baumruker T. Sphingolipid metabolizing enzymes as novel therapeutic targets. Subcell Biochem 2008, 49:487-522.
31. Van Brocklyn J.R. Sphingolipid signaling pathways as potential therapeutic targets in gliomas. Mini Rev Med Chem 2007, 7(10):984-990.
32. Riboni L., Campanella R., Bassi R., et al. Ceramide levels are inversely associated with malignant progression of human glial tumors. Glia 2002, 39(2):105-113.
33. Pettus B.J., Bielawski J., Porcelli A.M., et al. The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-alpha. FASEB J 2003, 17(11):1411-1421.
34. Farooqui A.A., Horrocks L.A., Farooqui T. Interactions between neural membrane glycerophospholipid and sphingolipid mediators: a recipe for neural cell survival or suicide. J Neurosci Res 2007, 85(9):1834-1850.
35. Van Brocklyn J.R., Young N., Roof R. Sphingosine-1-phosphate stimulates motility and invasiveness of human glioblastoma multiforme cells. Cancer Lett 2003, 199(1):53-60.
36. Kapitonov D., Allegood J.C., Mitchell C., et al. Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res 2009, 69(17):6915-6923.
37. Luberto C., Hassler D.F., Signorelli P., et al. Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase. J Biol Chem 2002, 277(43):41128-41139.
38. Clarke C.J., Hannun Y.A. Neutral sphingomyelinases and nSMase2: bridging the gaps. Biochim Biophys Acta 2006, 1758(12):1893-1901.
39. Radin N.S. Killing tumours by ceramide-induced apoptosis: a critique of available drugs. Biochem J 2003, 371(Pt 2):243-256.
40. Wolf L.A., Laster S.M. Characterization of arachidonic acid-induced apoptosis. Cell Biochem Biophys 1999, 30(3):353-368.
41. Schenck M., Carpinteiro A., Grassme H., Lang F., Gulbins E. Ceramide: physiological and pathophysiological aspects. Arch Biochem Biophys 2007, 462(2):171-175.
42. Dumitru C.A., Gulbins E. TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene 2006, 25(41):5612-5625.
43. Grassme H., Jekle A., Riehle A., et al. CD95 signaling via ceramide-rich membrane rafts. J Biol Chem 2001, 276(23):20589-20596.
44. Martin S., Phillips D.C., Szekely-Szucs K., Elghazi L., Desmots F., Houghton J.A. Cyclooxygenase-2 inhibition sensitizes human colon carcinoma cells to TRAIL-induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae. Cancer Res 2005, 65(24):11447-11458.
45. Heinrich M., Wickel M., Schneider-Brachert W., et al. Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J 1999, 18(19):5252-5263.
46. Taha T.A., Mullen T.D., Obeid L.M. A house divided: ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death. Biochim Biophys Acta 2006, 1758(12):2027-2036.
47. Arboleda G., Morales L.C., Benitez B., Arboleda H. Regulation of ceramide-induced neuronal death: cell metabolism meets neurodegeneration. Brain Res Rev 2009, 59(2):333-346.
48. Castillo S.S., Levy M., Wang C., Thaikoottathil J.V., Khan E., Goldkorn T. Nitric oxide-enhanced caspase-3 and acidic sphingomyelinase interaction: a novel mechanism by which airway epithelial cells escape ceramide-induced apoptosis. Exp Cell Res 2007, 313(4):816-823.
49. Kurzel F., Hagel C., Zapf S., Meissner H., Westphal M., Giese A. Cyclo-oxygenase inhibitors and thromboxane synthase inhibitors differentially regulate migration arrest, growth inhibition and apoptosis in human glioma cells. Acta Neurochir (Wien) 2002, 144(1):71-87.
50. Deininger M.H., Meyermann R., Trautmann K., et al. Cyclooxygenase (COX)-1 expressing macrophages/microglial cells and COX-2 expressing astrocytes accumulate during oligodendroglioma progression. Brain Res 2000, 885(1):111-116.
51. Schwab J.M., Nguyen T.D., Postler E., Meyermann R., Schluesener H.J. Selective accumulation of cyclooxygenase-1-expressing microglial cells/macrophages in lesions of human focal cerebral ischemia. Acta Neuropathol 2000, 99(6):609-614.
52. Loh J.K., Hwang S.L., Lieu A.S., Huang T.Y., Howng S.L. The alteration of prostaglandin E2 levels in patients with brain tumors before and after tumor removal. J Neurooncol 2002, 57(2):147-150.
53. Shono T., Tofilon P.J., Bruner J.M., Owolabi O., Lang F.F. Cyclooxygenase-2 expression in human gliomas: prognostic significance and molecular correlations. Cancer Res 2001, 61(11):4375-4381.
54. Constantini S., Tamir J., Gomori M.J., Shohami E. Tumor prostaglandin levels correlate with edema around supratentorial meningiomas. Neurosurgery 1993, 33(2):204-210. [discussion 211].
55. Joki T., Heese O., Nikas D.C., et al. Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398. Cancer Res 2000, 60(17):4926-4931.
56. Blomgren H., Kling-Andersson G. Growth inhibition of human malignant glioma cells in vitro by agents which interfere with biosynthesis of eicosanoids. Anticancer Res 1992, 12(3):981-986.
57. Kundu N., Smyth M.J., Samsel L., Fulton A.M. Cyclooxygenase inhibitors block cell growth, increase ceramide and inhibit cell cycle. Breast Cancer Res Treat 2002, 76(1):57-64.
58. Tuettenberg J., Grobholz R., Korn T., Wenz F., Erber R., Vajkoczy P. Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. J Cancer Res Clin Oncol 2005, 131(1):31-40.
59. Pannullo S., Balmaceda C., Serventi J. Temozolomide plus celecoxib for treatment of malignant gliomas [abstract]. Neuro-oncology 2002, 4:A239.
60. Kesari S., Schiff D., Henson J.W., et al. Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults. Neuro Oncol 2008, 10(3):300-308.
61. Gilbert M.R., Gonzalez J., Hunter K., et al. A phase I factorial design study of dose-dense temozolomide alone and in combination with thalidomide, isotretinoin, and/or celecoxib as postchemoradiation adjuvant therapy for newly diagnosed glioblastoma. Neuro Oncol 2010, 12(11):1167-1172.
62. Hau P., Kunz-Schughart L., Bogdahn U., et al. Low-dose chemotherapy in combination with COX-2 inhibitors and PPAR-gamma agonists in recurrent high-grade gliomas-a phase II study. Oncology 2007, 73(1-2):21-25.
63. Petersen C., Petersen S., Milas L., Lang F.F., Tofilon P.J. Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor. Clin Cancer Res 2000, 6(6):2513-2520.
64. Milas L., Kishi K., Hunter N., Mason K., Masferrer J.L., Tofilon P.J. Enhancement of tumor response to gamma-radiation by an inhibitor of cyclooxygenase-2 enzyme. J Natl Cancer Inst 1999, 91(17):1501-1504.
65. Ma H.I., Chiou S.H., Hueng D.Y., et al. Celecoxib and radioresistant glioblastoma-derived CD133(+) cells: improvement in radiotherapeutic effects. J Neurosurg 2011, 114(3):651-662.
66. Simmet T., Luck W., Winking M., Delank W.K., Peskar B.A. Identification and characterization of cysteinyl-leukotriene formation in tissue slices from human intracranial tumors: evidence for their biosynthesis under in vivo conditions. J Neurochem 1990, 54(6):2091-2099.
67. Black K.L., Hoff J.T., McGillicuddy J.E., Gebarski S.S. Increased leukotriene C4 and vasogenic edema surrounding brain tumors in humans. Ann Neurol 1986, 19(6):592-595.
68. Gati I., Bergstrom M., Muhr C., Carlsson J. Leukotriene and 5-lipoxygenase inhibitor induced variations in thymidine uptake in a human glioma cell line cultured as monolayers or as multicellular spheroids. Anticancer Res 1994, 14(2A):453-459.
69. Glaser T., Winter S., Groscurth P., et al. Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity. Br J Cancer 1999, 80(5-6):756-765.
70. Winking M., Sarikaya S., Rahmanian A., Jodicke A., Boker D.K. Boswellic acids inhibit glioma growth: a new treatment option?. J Neurooncol 2000, 46(2):97-103.
71. Streffer J.R., Bitzer M., Schabet M., Dichgans J., Weller M. Response of radiochemotherapy-associated cerebral edema to a phytotherapeutic agent, H15. Neurology 2001, 56(9):1219-1221.
72. Maier T.J., Tausch L., Hoernig M., et al. Celecoxib inhibits 5-lipoxygenase. Biochem Pharmacol 2008, 76(7):862-872.
73. Guo A.M., Sheng J., Scicli G.M., et al. Expression of CYP4A1 in U251 human glioma cell induces hyperproliferative phenotype in vitro and rapidly growing tumors in vivo. J Pharmacol Exp Ther 2008, 327(1):10-19.
74. Malaplate-Armand C., Ferrari L., Masson C., Siest G., Batt A.M. Astroglial CYP1B1 up-regulation in inflammatory/oxidative toxic conditions: IL-1beta effect and protection by N-acetylcysteine. Toxicol Lett 2003, 138(3):243-251.
75. Guo M., Roman R.J., Fenstermacher J.D., et al. 9L gliosarcoma cell proliferation and tumor growth in rats are suppressed by N-hydroxy-N'-(4-butyl-2-methylphenol) formamidine (HET0016), a selective inhibitor of CYP4A. J Pharmacol Exp Ther 2006, 317(1):97-108.
76. Guo M., Roman R.J., Falck J.R., Edwards P.A., Scicli A.G. Human U251 glioma cell proliferation is suppressed by HET0016 [N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine], a selective inhibitor of CYP4A. J Pharmacol Exp Ther 2005, 315(2):526-533.
77. Jeng J.Y., Lee W.H., Tsai Y.H., Chen C.Y., Chao S.Y., Hsieh R.H. Functional modulation of mitochondria by eicosapentaenoic acid provides protection against ceramide toxicity to C6 glioma cells. J Agric Food Chem 2009, 57(24):11455-11462.
78. Young N., Van Brocklyn J.R. Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P2 on cell migration and invasiveness. Exp Cell Res 2007, 313(8):1615-1627.
79. Van Brocklyn J.R., Jackson C.A., Pearl D.K., Kotur M.S., Snyder P.J., Prior T.W. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol 2005, 64(8):695-705.
80. Yoshida Y., Nakada M., Sugimoto N., et al. Sphingosine-1-phosphate receptor type 1 regulates glioma cell proliferation and correlates with patient survival. Int J Cancer 2010, 126(10):2341-2352.
81. Hara S., Nakashima S., Kiyono T., et al. P53-Independent ceramide formation in human glioma cells during gamma-radiation-induced apoptosis. Cell Death Differ 2004, 11(8):853-861.
82. Senchenkov A., Litvak D.A., Cabot M.C. Targeting ceramide metabolism-a strategy for overcoming drug resistance. J Natl Cancer Inst 2001, 93(5):347-357.
83. Lacour S., Hammann A., Grazide S., et al. Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells. Cancer Res 2004, 64(10):3593-3598.
84. Sumitomo M., Ohba M., Asakuma J., Asano T., Kuroki T., Hayakawa M. Protein kinase Cdelta amplifies ceramide formation via mitochondrial signaling in prostate cancer cells. J Clin Invest 2002, 109(6):827-836.
85. Modrak D.E., Cardillo T.M., Newsome G.A., Goldenberg D.M., Gold D.V. Synergistic interaction between sphingomyelin and gemcitabine potentiates ceramide-mediated apoptosis in pancreatic cancer. Cancer Res 2004, 64(22):8405-8410.
86. Wu G.S., Saftig P., Peters C., El-Deiry W.S. Potential role for cathepsin D in p53-dependent tumor suppression and chemosensitivity. Oncogene 1998, 16(17):2177-2183.
87. Lovat P.E., Corazzari M., Di Sano F., Piacentini M., Redfern C.P. The role of gangliosides in fenretinide-induced apoptosis of neuroblastoma. Cancer Lett 2005, 228(1-2):105-110.
88. Rath G., Schneider C., Langlois B., et al. De novo ceramide synthesis is responsible for the anti-tumor properties of camptothecin and doxorubicin in follicular thyroid carcinoma. Int J Biochem Cell Biol 2009, 41(5):1165-1172.
89. Dumitru C.A., Weller M., Gulbins E. Ceramide metabolism determines glioma cell resistance to chemotherapy. J Cell Physiol 2009, 221(3):688-695.
90. Phillips D.C., Allen K., Griffiths H.R. Synthetic ceramides induce growth arrest or apoptosis by altering cellular redox status. Arch Biochem Biophys 2002, 407(1):15-24.
91. Fillet M., Bentires-Alj M., Deregowski V., et al. Mechanisms involved in exogenous C2- and C6-ceramide-induced cancer cell toxicity. Biochem Pharmacol 2003, 65(10):1633-1642.
92. Chen J.Y., Hwang C.C., Chen W.Y., et al. Additive effects of C(2)-ceramide on paclitaxel-induced premature senescence of human lung cancer cells. Life Sci 2010, 87(11-12):350-357.
93. Zhao S., Du X.Y., Chen J.S., Zhou Y.C., Song J.G. Secretory phospholipase A(2) inhibits epidermal growth factor-induced receptor activation. Exp Cell Res 2002, 279(2):354-364.
94. Jaffrezou J.P., Maestre N., de Mas-Mansat V., Bezombes C., Levade T., Laurent G. Positive feedback control of neutral sphingomyelinase activity by ceramide. FASEB J 1998, 12(11):999-1006.
95. Perry D.K., Carton J., Shah A.K., Meredith F., Uhlinger D.J., Hannun Y.A. Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J Biol Chem 2000, 275(12):9078-9084.
96. Cianchi F., Cortesini C., Magnelli L., et al. Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells. Mol Cancer Ther 2006, 5(11):2716-2726.
97. Luberto C., Kraveka J.M., Hannun Y.A. Ceramide regulation of apoptosis versus differentiation: a walk on a fine line. Lessons from neurobiology. Neurochem Res 2002, 27(7-8):609-617.
98. Sot J., Goni F.M., Alonso A. Molecular associations and surface-active properties of short- and long-N-acyl chain ceramides. Biochim Biophys Acta 2005, 1711(1):12-19.
99. Hannun Y.A., Obeid L.M. The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem 2002, 277(29):25847-25850.
100. Corazzari M., Lovat P.E., Oliverio S., et al. Fenretinide: a p53-independent way to kill cancer cells. Biochem Biophys Res Commun 2005, 331(3):810-815.
101. Schonthal A.H. Exploiting cyclooxygenase-(in)dependent properties of COX-2 inhibitors for malignant glioma therapy. Anticancer Agents Med Chem 2010, 10(6):450-461.
102. Fischer A.S., Metzner J., Steinbrink S.D., et al. 5-Lipoxygenase inhibitors induce potent anti-proliferative and cytotoxic effects in human tumour cells independently of suppression of 5-lipoxygenase activity. Br J Pharmacol 2010, 161(4):936-949.
103. Dbaibo G.S., Pushkareva M.Y., Rachid R.A., et al. P53-dependent ceramide response to genotoxic stress. J Clin Invest 1998, 102(2):329-339.
104. Caro A.A., Cederbaum A.I. Role of cytochrome P450 in phospholipase A2- and arachidonic acid-mediated cytotoxicity. Free Radic Biol Med 2006, 40(3):364-375.