A metabolic perturbation by U0126 identifies a role for glutamine in resveratrol-induced cell death

Cancer Biology and Therapy

Volumn 12, Issue 11, 2011, Pages 966-977

  Freeman, Michael R ^a,b,c,d   Kim, Jayoung ^a,b,c   Lisanti, Michael P ^d   Di Vizio, Dolores ^a,b,c  

^a BOSTON CHILDREN S HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c CEDARS SINAI MEDICAL CENTER   (United States)

^d THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Aerobic glycolysis; Cancer metabolism; Mitochondrial function; Prostate cancer; Therapeutic targets

Indexed keywords

1,4 DIAMINO 1,4 BIS(2 AMINOPHENYLTHIO) 2,3 DICYANOBUTADIENE; 2 OXOGLUTARIC ACID; CYANIDE; GLUTAMINE; MITOGEN ACTIVATED PROTEIN KINASE; RESVERATROL;

AMINO ACID METABOLISM; APOPTOSIS; ARTICLE; CANCER CELL; CITRIC ACID CYCLE; CONTROLLED STUDY; DRUG ANTAGONISM; FEMALE; FLUORESCENCE; GLYCOLYSIS; HUMAN; HUMAN CELL; HUMAN CELL CULTURE; MALE; METABOLIC DISORDER; MITOCHONDRION; PROSTATE CANCER;

ANIMALS; ANTINEOPLASTIC AGENTS, PHYTOGENIC; APOPTOSIS; BUTADIENES; CELL DEATH; CELL LINE, TUMOR; CERCOPITHECUS AETHIOPS; ENZYME INHIBITORS; GLUTAMINE; HUMANS; MALE; MITOCHONDRIA; NITRILES; PROSTATIC NEOPLASMS; STILBENES;

EID: 82755195735     PISSN: 15384047     EISSN: 15558576     Source Type: Journal    
DOI: 10.4161/cbt.12.11.18136     Document Type: Article

References (78)

1. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 2007; 104:19345-50; PMID:18032601; http://dx.doi.org/10. 1073/pnas. 0709747104
2. Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 2010; 329:1492-9; PMID:20847263; http://dx.doi.org/10.1126/science.1188015
3. Chhipa RR, Wu Y, Mohler JL, Ip C. Survival advantage of AMPK activation to androgen-independent prostate cancer cells during energy stress. Cell Signal 2010; 22:1554-61; PMID:20570728; http://dx.doi.org/10.1016/j.cellsig.2010.05.024
4. Flavin R, Zadra G, Loda M. Metabolic alterations and targeted therapies in prostate cancer. J Pathol 2011; 223:283-94; PMID:21125681; http://dx.doi.org/10.1002/path.2809
5. Cao Y, Ma J. Body-mass index, prostate cancer-specific mortality and biochemical recurrence:A systematic review and meta-analysis. Cancer Prev Res (Phila). Jan 13.
6. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52:1766-77; PMID: 19572116; http://dx.doi.org/10.1007/s00125-009-1440-6
7. Monami M, Colombi C, Balzi D, Dicembrini I, Giannini S, Melani C, et al. Metformin and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care 2011; 34:129-31; PMID:20980415; http://dx.doi.org/10.2337/dc10- 1287
8. Jacobs EJ, Newton CC, Thun MJ, Gapstur SM. Long-term use of cholesterol-lowering drugs and cancer incidence in a large united states cohort. Cancer Res. Feb 22.
9. Breau RH, Karnes RJ, Jacobson DJ, McGree ME, Jacobsen SJ, Nehra A, et al. The association between statin use and the diagnosis of prostate cancer in a population based cohort. J Urol 2010; 184:494-9; PMID:20620405; http://dx.doi.org/10.1016/j.juro.2010.03.149
10. Porstmann T, Griffiths B, Chung YL, Delpuech O, Griffiths JR, Downward J, et al. PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 2005; 24:6465-81; PMID:16007182
11. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 2008; 105:18782-7; PMID: 19033189; http://dx.doi.org/10.1073/pnas.0810199105
12. Palmada M, Speil A, Jeyaraj S, Bohmer C, Lang F. The serine/threonine kinases SGK1, 3 and PKB stimulate the amino acid transporter ASCT2. Biochem Biophys Res Commun 2005; 331:272-7; PMID:15845389; http://dx.doi.org/10.1016/j. bbrc.2005.03.159
13. Heemers H, Vanderhoydonc F, Roskams T, Shechter I, Heyns W, Verhoeven G, et al. Androgens stimulate coordinated lipogenic gene expression in normal target tissues in vivo. Mol Cell Endocrinol 2003; 205:21-31; PMID:12890564; http://dx.doi.org/10.1016/S0303-7207(03)00205-3
14. Wieman HL, Wofford JA, Rathmell JC. Cytokine stimulation promotes glucose uptake via phosphatidylinositol- 3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell 2007; 18:1437-46; PMID: 17301289; http://dx.doi.org/10.1091/mbc.E06-07-0593
15. Shanware NP, Mullen AR, Deberardinis RJ, Abraham RT. Glutamine: Pleiotropic roles in tumor growth and stress resistance. J Mol Med 2011; 89:229-36; PMID:21301794; http://dx.doi.org/10.1007/s00109-011-0731-9
16. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009; 458:762-5; PMID:19219026; http://dx.doi.org/10.1038/nature07823
17. Molavian HR, Kohandel M, Milosevic M, Sivaloganathan S. Fingerprint of cell metabolism in the experimentally observed interstitial pH and pO2 in solid tumors. Cancer Res 2009; 69:9141-7; PMID: 19920192; http://dx.doi.org/10.1158/ 0008-5472.CAN-09-2112
18. Qin JZ, Xin H, Nickoloff BJ. 2-deoxyglucose sensitizes melanoma cells to TRAIL-induced apoptosis which is reduced by mannose. Biochem Biophys Res Commun 2010; 401:293-9; PMID:20851102; http://dx.doi.org/10.1016/j.bbrc.2010.09.054
19. Stein M, Lin H, Jeyamohan C, Dvorzhinski D, Gounder M, Bray K, et al. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate 2010; 70:1388-94; PMID:20687211; http://dx.doi.org/10.1002/pros.21172
20. Shelton LM, Huysentruyt LC, Seyfried TN. Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model. Int J Cancer 2010; 127:2478-85; PMID:20473919; http://dx.doi.org/10.1002/ijc.25431
21. Lynch G, Kemeny N, Casper E. Phase II evaluation of DON (6-diazo-5-oxo-L-norleucine) in patients with advanced colorectal carcinoma. Am J Clin Oncol 1982; 5:541-3; PMID:7180833
22. Ratan HL, Steward WP, Gescher AJ, Mellon JK. Resveratrol-a prostate cancer chemopreventive agent? Urol Oncol 2002; 7:223-7; PMID:12504842; http://dx.doi.org/10.1016/S1078-1439(02)00194-1
23. Shih A, Zhang S, Cao HJ, Boswell S, Wu YH, Tang HY, et al. Inhibitory effect of epidermal growth factor on resveratrol-induced apoptosis in prostate cancer cells is mediated by protein kinase C-alpha. Mol Cancer Ther 2004; 3:1355-64; PMID:15542774
24. Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997; 275:218-20; PMID:8985016; http://dx.doi.org/10.1126/ science.275.5297.218
25. Subbaramaiah K, Chung WJ, Michaluart P, Telang N, Tanabe T, Inoue H, et al. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J Biol Chem 1998; 273:21875-82; PMID:9705326; http://dx.doi.org/10.1074/jbc.273.34.21875
26. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006; 127:1109-22; PMID:17112576; http://dx.doi.org/10.1016/j.cell.2006.11.013
27. Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 2010; 59:554-63; PMID: 19934007; http://dx.doi.org/10.2337/db09-0482
28. Gatz SA, Keimling M, Baumann C, Dork T, Debatin KM, Fulda S, et al. Resveratrol modulates DNA double-strand break repair pathways in an ATM/ATR-p53- and -Nbs1-dependent manner. Carcinogenesis 2008; 29:519-27; PMID:18174244; http://dx.doi.org/10.1093/carcin/bgm283
29. Ahmad N, Adhami VM, Afaq F, Feyes DK, Mukhtar H. Resveratrol causes WAF-1/p21-mediated G(1)-phase arrest of cell cycle and induction of apoptosis in human epidermoid carcinoma A431 cells. Clin Cancer Res 2001; 7:1466-73; PMID:11350919
30. Ajmo JM, Liang X, Rogers CQ, Pennock B, You M. Resveratrol alleviates alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 2008; 295:G833-42; PMID:18755807; http://dx.doi.org/10.1152/ajpgi. 90358.2008
31. Wang TT, Hudson TS, Wang TC, Remsberg CM, Davies NM, Takahashi Y, et al. Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis 2008; 29:2001-10; PMID:18586690; http://dx.doi.org/10.1093/carcin/bgn131
32. Niles RM, Cook CP, Meadows GG, Fu YM, McLaughlin JL, Rankin GO. Resveratrol is rapidly metabolized in athymic (nu/nu) mice and does not inhibit human melanoma xenograft tumor growth. J Nutr 2006; 136:2542-6; PMID:16988123
33. Sakamoto T, Horiguchi H, Oguma E, Kayama F. Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor- positive breast cancer cells. J Nutr Biochem 2010; 21:856-64; PMID:19800779; http://dx.doi.org/10.1016/j.jnutbio.2009.06.010
34. Opipari AW, Jr., Tan L, Boitano AE, Sorenson DR, Aurora A, Liu JR. Resveratrol-induced autophagocytosis in ovarian cancer cells. Cancer Res 2004; 64:696-703; PMID:14744787; http://dx.doi.org/10.1158/0008-5472.CAN-03-2404
35. Juan ME, Wenzel U, Daniel H, Planas JM. Resveratrol induces apoptosis through ROS-dependent mitochondria pathway in HT-29 human colorectal carcinoma cells. J Agric Food Chem 2008; 56:4813-8; PMID: 18522405; http://dx.doi.org/10. 1021/jf800175a
36. Kim YA, Lee WH, Choi TH, Rhee SH, Park KY, Choi YH. Involvement of p21WAF1/CIP1, pRB, bax and NF-kappaB in induction of growth arrest and apoptosis by resveratrol in human lung carcinoma A549 cells. Int J Oncol 2003; 23:1143-9; PMID:12963997
37. Michels G, Watjen W, Weber N, Niering P, Chovolou Y, Kampkotter A, et al. Resveratrol induces apoptotic cell death in rat H4IIE hepatoma cells but necrosis in C6 glioma cells. Toxicology 2006; 225:173-82; PMID: 16843582; http://dx.doi.org/10.1016/j.tox.2006.05.014
38. Simopoulos AP. The mediterranean diets: What is so special about the diet of greece? the scientific evidence. J Nutr 2001; 131(Suppl):3065S-73S; PMID:11694649
39. Wu HC, Hsieh JT, Gleave ME, Brown NM, Pathak S, Chung LW. Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: Role of bone stromal cells. Int J Cancer 1994; 57:406-12; PMID:8169003; http://dx.doi.org/10. 1002/ijc. 2910570319
40. Thalmann GN, Anezinis PE, Chang SM, Zhau HE, Kim EE, Hopwood VL, et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res 1994; 54:2577-81; PMID:8168083
41. Kim AL, Zhu Y, Zhu H, Han L, Kopelovich L, Bickers DR, et al. Resveratrol inhibits proliferation of human epidermoid carcinoma A431 cells by modulating MEK1 and AP-1 signalling pathways. Exp Dermatol 2006; 15:538-46; PMID:16761963; http://dx.doi.org/10.1111/j.1600-0625.2006.00445.x
42. Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, Gao H, et al. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 2008; 118:3051-64; PMID:18725989
43. Trombly R, Tappel A. Fractionation and analysis of fluorescent products of lipid peroxidation. Lipids 1975; 10:441-7; PMID:1160518; http://dx.doi.org/ 10.1007/BF02532426
44. Arun P, Moffett JR, Ives JA, Todorov TI, Centeno JA, Namboodiri MA, et al. Rapid sodium cyanide depletion in cell culture media: Outgassing of hydrogen cyanide at physiological pH. Anal Biochem 2005; 339:282-9; PMID:15797569; http://dx.doi.org/10.1016/j.ab.2005.01.015
45. Griffiths M, Keast D, Patrick G, Crawford M, Palmer TN. The role of glutamine and glucose analogues in metabolic inhibition of human myeloid leukaemia in vitro. Int J Biochem 1993; 25:1749-55; PMID: 8138012; http://dx.doi.org/10.1016/0020-711X(88) 90303-5
46. Fischmann TO, Smith CK, Mayhood TW, Myers JE, Reichert P, Mannarino A, et al. Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors. Biochemistry 2009; 48:2661-74; PMID: 19161339; http://dx.doi.org/10.1021/bi801898e
47. Barrett SD, Bridges AJ, Dudley DT, Saltiel AR, Fergus JH, Flamme CM, et al. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD Bioorg Med Chem Lett 2008; 18:6501-4; PMID:18952427; http://dx.doi.org/10.1016/j.bmcl. 2008.10.054
48. Wong DT, Fuller RW, Molloy BB. Inhibition of amino acid transaminases by L-cycloserine. Adv Enzyme Regul 1973; 11:139-54; PMID:4150977; http://dx.doi.org/10.1016/0065-2571(73)90013-7
49. Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 1998; 273:18623-32; PMID:9660836; http://dx.doi.org/10.1074/ jbc.273.29.18623
50. Bachleda P, Dvorak Z. Pharmacological inhibitors of JNK and ERK kinases SP600125 and U0126 are not appropriate tools for studies of drug metabolism because they activate aryl hydrocarbon receptor. Gen Physiol Biophys 2008; 27:143-5; PMID:18645229
51. Dokladda K, Green KA, Pan DA, Hardie DG. PD98059 and U0126 activate AMP-activated protein kinase by increasing the cellular AMP:ATP ratio and not via inhibition of the MAP kinase pathway. FEBS Lett 2005; 579:236-40; PMID:15620719; http://dx. doi.org/10.1016/j.febslet.2004.11.084
52. LaRosa C, Downs SM. MEK inhibitors block AICAR-induced maturation in mouse oocytes by a MAPK-independent mechanism. Mol Reprod Dev 2005; 70: 235-45; PMID:15570612; http://dx.doi.org/10.1002/mrd.20200
53. Yung HW, Wyttenbach A, Tolkovsky AM. Aggravation of necrotic death of glucose-deprived cells by the MEK1 inhibitors U0126 and PD184161 through depletion of ATP. Biochem Pharmacol 2004; 68:351- 60; PMID:15194007; http://dx.doi.org/10.1016/j.bcp.2004.03.030
54. Blank N, Burger R, Duerr B, Bakker F, Wohlfarth A, Dumitriu I, et al. MEK inhibitor U0126 interferes with immunofluorescence analysis of apoptotic cell death. Cytometry 2002; 48:179-84; PMID:12210141; http://dx.doi.org/10.1002/cyto. 10127
55. Wang ZQ, Chen XC, Yang GY, Zhou LF. U0126 prevents ERK pathway phosphorylation and interleukin- 1beta mRNA production after cerebral ischemia. Chin Med Sci J 2004; 19:270-5; PMID:15669185
56. Maddahi A, Edvinsson L. Cerebral ischemia induces microvascular pro-inflammatory cytokine expression via the MEK/ERK pathway. J Neuroinflammation 2010; 7:14; PMID:20187933; http://dx.doi.org/10.1186/1742- 2094-7-14
57. Maddahi A, Edvinsson L. Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway. BMC Neurosci 2008; 9:85; PMID: 18793415; http://dx.doi.org/10.1186/ 1471-2202-9-85
58. Korde AS, Pettigrew LC, Craddock SD, Maragos WF. The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia. J Neurochem 2005; 94:1676-84; PMID:16045446; http://dx.doi.org/10.1111/j.1471-4159.2005.03328.x
59. Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol 2007; 25:1035- 44; PMID:17721511; http://dx.doi.org/10.1038/nbt1328
60. Schubbert S, Shannon K, Bollag G. Hyperactive ras in developmental disorders and cancer. Nat Rev Cancer 2007; 7:295-308; PMID:17384584; http://dx.doi.org/10.1038/nrc2109
61. Gioeli D, Mandell JW, Petroni GR, Frierson HF, Jr., Weber MJ. Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res 1999; 59:279-84; PMID:9927031
62. Kueck A, Opipari AW, Jr., Griffith KA, Tan L, Choi M, Huang J, et al. Resveratrol inhibits glucose metabolism in human ovarian cancer cells. Gynecol Oncol 2007; 107:450-7; PMID:17825886; http://dx.doi.org/10.1016/j.ygyno.2007.07. 065
63. Park JB. Inhibition of glucose and dehydroascorbic acid uptakes by resveratrol in human transformed myelocytic cells. J Nat Prod 2001; 64:381-4; PMID:11277764; http://dx.doi.org/10.1021/np000411t
64. Faber AC, Dufort FJ, Blair D, Wagner D, Roberts MF, Chiles TC. Inhibition of phosphatidylinositol 3-kinase-mediated glucose metabolism coincides with resveratrol-induced cell cycle arrest in human diffuse large B-cell lymphomas. Biochem Pharmacol 2006; 72:1246-56; PMID:16979140; http://dx.doi.org/10.1016/j. bcp.2006.08.009
65. Haider UG, Sorescu D, Griendling KK, Vollmar AM, Dirsch VM. Resveratrol suppresses angiotensin II-induced Akt/protein kinase B and p70 S6 kinase phosphorylation and subsequent hypertrophy in rat aortic smooth muscle cells. Mol Pharmacol 2002; 62:772-7; PMID:12237323; http://dx.doi.org/10.1124/mol.62.4. 772
66. Wellen KE, Lu C, Mancuso A, Lemons JM, Ryczko M, Dennis JW, et al. The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev 2010; 24:2784- 99; PMID:21106670; http://dx.doi.org/10.1101/gad.1985910
67. Sidoryk M, Matyja E, Dybel A, Zielinska M, Bogucki J, Jaskolski DJ, et al. Increased expression of a glutamine transporter SNAT3 is a marker of malignant gliomas. Neuroreport 2004; 15:575-8; PMID:15094455; http://dx.doi.org/10.1097/00001756-200403220-00001
68. Witte D, Ali N, Carlson N, Younes M. Overexpression of the neutral amino acid transporter ASCT2 in human colorectal adenocarcinoma. Anticancer Res 2002; 22:2555-7; PMID:12529963
69. Avissar NE, Sax HC, Toia L. In human entrocytes, GLN transport and ASCT2 surface expression induced by short-term EGF are MAPK, PI3K, and rhodependent. Dig Dis Sci 2008; 53:2113-25; PMID: 18157695; http://dx.doi.org/10.1007/s10620- 007-0120-y
70. Hwang SO, Lee GM. Nutrient deprivation induces autophagy as well as apoptosis in chinese hamster ovary cell culture. Biotechnol Bioeng 2008; 99:678-85; PMID:17680685; http://dx.doi.org/10.1002/bit. 21589
71. Lee MH, Choi BY, Kundu JK, Shin YK, Na HK, Surh YJ. Resveratrol suppresses growth of human ovarian cancer cells in culture and in a murine xenograft model: Eukaryotic elongation factor 1A2 as a potential target. Cancer Res 2009; 69:7449-58; PMID:19738051; http://dx.doi.org/10.1158/0008-5472.CAN-09- 1266
72. Bode B, Tamarappoo BK, Mailliard M, Kilberg MS. Characteristics and regulation of hepatic glutamine transport. JPEN J Parenter Enteral Nutr 1990; 14 (Suppl):51S-5S; PMID:2402055; http://dx.doi.org/10.1177/014860719001400404
73. Wasa M, Bode BP, Abcouwer SF, Collins CL, Tanabe KK, Souba WW. Glutamine as a regulator of DNA and protein biosynthesis in human solid tumor cell lines. Ann Surg 1996; 224:189-97; PMID:8757383; http://dx.doi.org/10.1097/00000658- 199608000-00012
74. Kallinowski F, Runkel S, Fortmeyer HP, Forster H, Vaupel P. L-glutamine: A major substrate for tumor cells in vivo?. J Cancer Res Clin Oncol 1987; 113: 209-15; PMID:3584211; http://dx.doi.org/10.1007/BF00396375
75. Lefauconnier JM, Portemer C, Chatagner F. Free amino acids and related substances in human glial tumours and in fetal brain: Comparison with normal adult brain. Brain Res 1976; 117:105-13; PMID: 186155; http://dx.doi.org/10. 1016/0006-8993(76)90559-X
76. de Almeida LM, Pineiro CC, Leite MC, Brolese G, Tramontina F, Feoli AM, et al. Resveratrol increases glutamate uptake, glutathione content, and S100B secretion in cortical astrocyte cultures. Cell Mol Neurobiol 2007; 27:661-8; PMID:17554623; http://dx.doi.org/10.1007/s10571-007-9152-2
77. Rayalam S, Yang JY, Ambati S, Della-Fera MA, Baile CA. Resveratrol induces apoptosis and inhibits adipogenesis in 3T3-L1 adipocytes. Phytother Res 2008; 22:1367-71; PMID:18688788; http://dx.doi.org/10.1002/ptr.2503
78. Ballard FJ, Hanson RW. The citrate cleavage pathway and lipogenesis in rat adipose tissue: Replenishment of oxaloacetate. J Lipid Res 1967; 8:73-9; PMID: 14564711