Metabolic alterations in cancer cells and therapeutic implications

Chinese Journal of Cancer

Volumn 30, Issue 8, 2011, Pages 508-525

  Hammoudi, Naima ^a,b   Ahmed, Kausar Begam Riaz ^a,b   Garcia Prieto, Celia ^a   Huang, Peng ^a,b  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b UNIVERSITY OF TEXAS   (United States)

Author keywords

Cancer metabolism; Cancer stem cells; Glutamine; Glycolysis; Mitochondria; The warburg effect

Indexed keywords

4 PHENYLBUTYRIC ACID; AMINOOXYACETIC ACID; ANTINEOPLASTIC AGENT; ASPARAGINASE; BROMOPYRUVIC ACID; CISPLATIN; DEOXYGLUCOSE; DICHLOROACETIC ACID; DOXORUBICIN; EVEROLIMUS; GLUTAMINE; HISTONE DEACETYLASE INHIBITOR; HYPOXIA INDUCIBLE FACTOR 1; LONIDAMINE; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOCHONDRIAL DNA; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B INHIBITOR; ROMIDEPSIN; TEMSIROLIMUS; TH 070; TROGLITAZONE; UNCLASSIFIED DRUG; VORINOSTAT;

ACUTE LYMPHOBLASTIC LEUKEMIA; AKT GENE; AMINO ACID METABOLISM; ANAEROBIC GLYCOLYSIS; BREAST CANCER; CANCER CELL; CANCER STEM CELL; CARCINOGENESIS; CELL METABOLISM; DRUG MECHANISM; DRUG SENSITIVITY; ENERGY METABOLISM; ENZYME INHIBITION; ENZYME METABOLISM; GENE FUNCTION; GENE MUTATION; GENE TARGETING; GLIOBLASTOMA; HUMAN; HYPERAMMONEMIA; HYPOXIA INDUCIBLE FACTOR 1 GENE; LACTIC ACIDOSIS; LUNG NON SMALL CELL CANCER; METABOLIC INHIBITION; MITOCHONDRIAL RESPIRATION; MOLECULAR DYNAMICS; MOLECULARLY TARGETED THERAPY; MTOR GENE; MYELOMA; NONHUMAN; ONCOGENE; ONCOGENE C MYC; ONCOGENE RAS; OSTEOSARCOMA; OVARY CANCER; PROSTATE HYPERTROPHY; PROTEIN TARGETING; REVIEW; TARGET CELL; TUMOR SUPPRESSOR GENE;

ANTINEOPLASTIC AGENTS; DRUG RESISTANCE, NEOPLASM; GENES, TUMOR SUPPRESSOR; GLUTAMINE; GLYCOLYSIS; HUMANS; MITOCHONDRIA; MUTATION; NEOPLASMS; NEOPLASTIC STEM CELLS; ONCOGENES; OXIDATIVE PHOSPHORYLATION;

EID: 80051709371     PISSN: 1000467X     EISSN: 1944446X     Source Type: Journal    
DOI: 10.5732/cjc.011.10267     Document Type: Review

References (220)

1. Warburg O. On the origin of cancer cells [J]. Science, 1956,123(3191):309-314.
2. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body [J]. J Gen Physiol, 1927,8(6):519-530.
3. Fantin VR, Berardi MJ, Scorrano L, et al. A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth [J]. Cancer Cell, 2002,2(1):29-42.
4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation [J]. Cell, 2011,144(5):646-674.
5. Weinberg F, Hamanaka R, Wheaton WW, et al. Mitochondrialmetabolism and ROS generation are essential for Kras- mediated tumorigenicity [J]. Proc Natl Acad Sci U S A, 2010,107(19):8788-8793.
6. Shelton LM, Huysentruyt LC, Seyfried TN. Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model [J]. Int J Cancer, 2010,127(10):2478-2485.
7. Aledo JC, Segura JA, Medina MA, et al. Phosphate-activated glutaminase expression d Lett, 1994,341(1):39-42.
8. Brand K. Glutamine and glucose metabolism during thymocyte proliferation. Pathways of glutamine and glutamate metabolism [J]. Biochem J, 1985,228(2):353-361.
9. Medina RA, Owen GI. Glucose transporters: expression, regulation and cancer [J]. Biol Res, 2002,35(1):9-26.
10. Semenza GL. HIF-1: upstream and downstream of cancer metabolism [J]. Curr Opin Genet Dev, 2010,20(1):51-56.
11. Pollard PJ, Briere JJ, Alam NA, et al. Accumulation of Krebs cycle intermediates and over-ex pression of HIF1alpha in tumours which result from germline FH and SDH mutations [J]. Hum Mol Genet, 2005,14(15):2231-2239.
12. Owusu-A nsah E, Yavari A, Mandal S, et al. Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint. Nat Genet, 2008,40(3):356-361.
13. Elstrom RL, Bauer DE, Buzzai M, et al. Akt stimulates aerobic glycolysis in cancer cells [J]. Cancer Res, 2004,64(11):3892-3899.
14. Hara K, Yonezawa K, Weng QP, et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effect or mechanism [J]. J Biol Chem, 1998,273(23): 14484-14494.
15. Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action [J]. Cell, 2002,110(2):177-189.
16. Hay N. The Akt-mTOR tango and its relevance to cancer [J]. Cancer Cell, 2005,8(3): 179-183.
17. Chapuis N, Tamburini J, Green AS, et al. Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies [J]. Leukemia, 2010,24(10):1686- 1699.
18. Ruderman N, Prentki M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome [J]. Nat Rev Drug Discov, 2004,3(4):340-351.
19. Luo Z, Saha AK, Xiang X, et al. AMPK, the metabolic syndrome and cancer [J]. Trends Pharmacol Sci, 2005,26(2): 69-76.
20. Dang CV, Le A, Gao P. MYC-in duced cancer cell energy metabolism and therapeutic opportunities [J]. Clin Cancer Res, 2009,15(21):6479-6483.
21. Bensaad K, Tsuruta A, Selak MA, et al. TIGAR, a p53- inducible regulator of glycolysis and apoptosis [J]. Cell, 2006,126(1):107-120.
22. Matoba S, Kang JG, Patino WD, et al. p53 regulates mitochondrial respiration [J]. Science, 2006,312 (5780):1650-1653.
23. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer's Achilles' heel [J]. Cancer Cell, 2008,13(6):472-482.
24. Bustamante E, Pedersen PL. High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase [J]. Proc Natl Acad Sci U S A, 1977,74(9):3735-3739.
25. Warburg O. On respiratory impairment in cancer cells [J]. Science, 1956,124(3215):269-270.
26. Roos D, Loos JA. Changes in the carbohydrate metabolism of mitogenically stimulated human peripheral lymphocytes. II. Relative importance of glycolysis and oxidative phosphorylation on phytohaemagglutinin stimulation [J]. Exp Cell Res, 1973,77 (1):127-135.
27. Wang T, Marquardt C, Foker J. Aerobic glycolysis during lymphocyte proliferation [J]. Nature, 1976,261 (5562):702-705.
28. Guppy M, Greiner E, Brand K. The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes [J]. Eur J Biochem, 1993,212(1): 95-99.
29. Berardi MJ, Fantin VR. Survival of the fittest: metabolic adaptations in cancer [J]. Curr Opin Genet Dev, 2011,21(1): 59-66.
30. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, et al. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation [J]. Cell Metab, 2008,7(1):11-20.
31. Izumi H, Torigoe T, Ishiguchi H, et al. Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy [J]. Cancer Treat Rev, 2003,29(6):541-549.
32. Dang CV. Rethinking the Warburg effect with Myc micromanaging glutamine metabolism [J]. Cancer Res, 2010,70 (3):859-862.
33. Nicklin P, Bergman P, Zhang B, et al. Bidirectional transport of amino acids regulates mTOR and autophagy [J]. Cell, 2009,136(3):521-534.
34. Lobo C, Ruiz-B ellido MA, Aledo JC, et al. Inhibition of glutaminase expression by antisense mRNA decreases growth and tumourigenicity of tumour cells [J]. Biochem J, 2000,348 (Pt 2):257-261.
35. DeBerardinis RJ, Mancuso A, Daikhin E, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis [J]. Proc Natl Acad Sci U S A, 2007,104 (49):19345-19350.
36. Mazurek S, Boschek CB, Hugo F, et al. Pyruvate kinase type M2 and its role in tumor growth and spreading [J]. Semin Cancer Biol, 2005,15(4):300-308.
37. Deberardinis RJ, Sayed N, Ditsworth D, et al. Brick by brick: metabolism and tumor cell growth [J]. Curr Opin Genet Dev, 2008,18(1):54-61.
38. Wise DR, DeBerardinis RJ, Mancuso A, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction [J]. Proc Natl Acad Sci U S A, 2008,105(48):18782-18787.
39. Gao P, Tchernyshyov I, Chang TC, et al. C-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism [J]. Nature, 2009,458(7239):762-765.
40. Wang JB, Erickson JW, Fuji R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation [J]. Cancer Cell, 2010,18(3):207-219.
41. Pastorino JG, Shulga N, Hoek JB. Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis [J]. J Biol Chem, 2002,277(9):7610-7618.
42. Pedersen PL, Mathupala S, Rempel A, et al. Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention [J]. Biochim Biophys Acta, 2002,1555(1-3):14-20.
43. Christofk HR, Vander Heiden MG, Harris MH, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth [J]. Nature, 2008,452(7184): 230-233.
44. Schneider J, Neu K, Grimm H, et al. Tumor M2-pyruvate kinase in lung cancer patients: immunohistochemical detection and disease monitoring [J]. Anticancer Res, 2002,22(1A):311-318.
45. Luftner D, Mesterharm J, Akrivakis C, et al. Tumor type M2 pyruvate kinase expression in advanced breast cancer [J]. Anticancer Res, 2000,20(6D):5077-5082.
46. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism [J]. Nat Rev Cancer, 2011,11(2):85-95.
47. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome [J]. N Engl J Med, 2009,361(11):1058-1066.
48. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas [J]. N Engl J Med, 2009,360(8):765-773.
49. Gross S, Cairns RA, Minden MD, et al. Cancer-as sociated metabolite 2-hy droxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations [J]. J Exp Med, 2010,207(2):339-344.
50. Dang L, White DW, Gross S, et al. Cancer-as sociated IDH1 mutations produce 2-hy droxyglutarate [J]. Nature, 2009,462 (7274):739-744.
51. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-as sociated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate [J]. Cancer Cell, 2010,17(3):225-234.
52. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation [J]. Cancer Cell, 2010,18(6):553-567.
53. Horbinski C, Kofler J, Kelly LM, et al. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fix ed, paraffin-em bedded glioma tissues [J]. J Neuropathol Exp Neurol, 2009,68(12):1319-1325.
54. Gill AJ, Chou A, Vilain R, et al. Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types [J]. Am J Surg Pathol, 2010,34(5):636-644.
55. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer [J]. Nat Genet, 2002,30(4):406-410.
56. Baysal BE, Ferrell RE, Willett-B rozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma [J]. Science, 2000,287(5454):848-851.
57. Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-al pha prolyl hydroxylase [J]. Cancer Cell, 2005,7(1):77-85.
58. Loenarz C, Schofield CJ. Expanding chemical biology of 2-oxoglutarate oxygenases [J]. Nat Chem Biol, 2008,4(3):152-156.
59. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions [J]. Nat Rev Cancer, 2008,8(10):755-768.
60. Fan X, Khaki L, Zhu TS, et al. NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts [J]. Stem Cells, 2010,28 (1):5-16.
61. Zheng H, Ying H, Yan H, et al. P53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation [J]. Nature, 2008,455(7216):1129-1133.
62. Chen C, Liu Y, Liu R, et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species [J]. J Exp Med, 2008,205(10):2397-2408.
63. Li Z, Bao S, Wu Q, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells [J]. Cancer Cell, 2009,15(6):501-513.
64. Soeda A, Park M, Lee D, et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha [J]. Oncogene, 2009,28(45):3949-3959.
65. Xie Z. Brain tumor stem cells [J]. Neurochem Res, 2009,34 (12):2055-2066.
66. Vasiliou V, Nebert DW. Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family [J]. Hum Genomics, 2005,2(2):138-143.
67. Morimoto K, Kim SJ, Tanei T, et al. Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression [J]. Cancer Sci, 2009,100(6):1062-1068.
68. Hwang-Verslues WW, Kuo WH, Chang PH, et al. Multiple lineages of human breast cancer stem/progenitor cells identified by profiling with stem cell markers [J]. PLoS One, 2009,4(12):e8377.
69. Charafe-Jauffret E, Ginestier C, Iovino F, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature [J]. Cancer Res, 2009,69(4):1302-1313.
70. Sullivan JP, Spinola M, Dodge M, et al. Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling [J]. Cancer Res, 2010,70 (23):9937-9948.
71. Chute JP, Muramoto GG, Whitesides J, et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells [J]. Proc Natl Acad Sci U S A, 2006,103(31):11707-11712.
72. Korkaya H, Paulson A, Charafe-Jauffret E, et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling [J]. PLoS Biol, 2009,7(6):e1000121.
73. + tumor initiating cells under hypoxic microenvironment [M]. Proc Am Assoc Cancer Res, 2007.
74. Varum S, Rodrigues AS, Moura MB, et al. Energy metabolism in human pluripotent stem cells and their differentiated counterparts [J]. PLoS One, 2011,6(6):e20914.
75. + leukemic cells acquiring stem-lik e characteristics in a hypoxic environment [J]. Cell Death Differ, 2010,17(7):1211-1220.
76. Singh KK, Russell J, Sigala B, et al. Mitochondrial DNA determines the cellular response to cancer therapeutic agents [J]. Oncogene, 1999,18(48):6641-6646.
77. Cai J, Wallace DC, Zhivotovsky B, et al. Separation of cytochrome c-dependent caspase activation from thiol-disulfide redox change in cells lacking mitochondrial DNA [J]. Free Radic Biol Med, 2000,29(3-4):334-342.
78. Park SY, Chang I, Kim JY, et al. Resistance of mitochondrial DNA-depleted cells against cell death: role of mitochondrial superoxide dismutase [J]. J Biol Chem, 2004,279(9):7512-7520.
79. Hail N Jr, Chen P, Kepa JJ. Selective apoptosis induction by the cancer chemopreventive agent N-(4 -hy droxyphenyl) retinamide is achieved by modulating mitochondrial bioenergetics in premalignant and malignant human prostate epithelial cells [J]. Apoptosis, 2009,14(7):849-863.
80. Hayashi J, Takemitsu M, Nonaka I. Recovery of the missing tumorigenicity in mitochondrial DNA-less HeLa cells by introduction of mitochondrial DNA from normal human cells [J]. Somat Cell Mol Genet, 1992,18(2):123-129.
81. Kong Q, Beel JA, Lillehei KO. A threshold concept for cancer therapy [J]. Med Hypotheses, 2000,55(1):29-35.
82. Zamzami N, Marchetti P, Castedo M, et al. Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death [J]. J Exp Med, 1995,182(2):367-377.
83. Davis W Jr, Ronai Z, Tew KD. Cellular thiols and reactive oxygen species in drug-induced apoptosis [J]. J Pharmacol Exp Ther, 2001,296(1):1-6.
84. Benhar M, Dalyot I, Engelberg D, et al. Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-ac tivated protein kinase activation and sensitization to genotoxic stress [J]. Mol Cell Biol, 2001,21(20):6913-6926.
85. Zhou P, Kalakonda N, Comenzo RL. Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo [J]. Br J Haematol, 2005,128(5):636-644.
86. Hour TC, Huang CY, Lin CC, et al. Characterization of molecular events in a series of bladder urothelial carcinoma cell lines with progressive resistance to arsenic trioxide [J]. Anticancer Drugs, 2004,15(8):779-785.
87. Hoshida Y, Moriyama M, Otsuka M, et al. Gene expressions associated with chemosensitivity in human hepatoma cells [J]. Hepatogastroenterology, 2007,54(74):489-492.
88. Ramanathan B, Jan KY, Chen CH, et al. Resistance to paclitaxel is proportional to cellular total antioxidant capacity [J]. Cancer Res, 2005,65(18):8455-8460.
89. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? [J]. Nat Rev Drug Discov, 2009,8(7):579-591.
90. Trachootham D, Zhou Y, Zhang H, et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate [J]. Cancer Cell, 2006,10(3):241-252.
91. Trachootham D, Zhang H, Zhang W, et al. Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox- mediated mechanism [J]. Blood, 2008,112(5):1912-1922.
92. Xu RH, Pelicano H, Zhou Y, et al. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia [J]. Cancer Res, 2005,65(2):613-621.
93. Weinhouse S. On respiratory impairment in cancer cells [J]. Science, 1956,124(3215):267-269.
94. Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-H ernandez A, et al. Energy metabolism in tumor cells [J]. FEBS J, 2007,274 (6):1393-1418.
95. Compton S, Kim C, Griner NB, et al. Mitochondrial dysfunction impairs tumor suppressor p53 expression/function [J]. J Biol Chem, 2010,286(23):20297-20312.
96. Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-os motic type of mechanism [J]. Nature, 1961,191:144-148.
97. Anderson S, Bankier AT, Barrell BG, et al. Sequence and organization of the human mitochondrial genome [J]. Nature, 1981,290(5806):457-465.
98. Attardi G. Animal mitochondrial DNA: an extreme example of genetic economy [J]. Int Rev Cytol, 1985,93:93-145.
99. Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications [J]. Drug Resist Updat, 2004,7(2): 97-110.
100. Carew JS, Huang P. Mitochondrial defects in cancer [J]. Mol Cancer, 2002,1:9.
101. Attardi G, Yoneda M, Chomyn A. Complementation and segregation behavior of disease-causing mitochondrial DNA mutations in cellular model systems [J]. Biochim Biophys Acta, 1995,1271(1):241-248.
102. Hayashi J, Ohta S, Kikuchi A, et al. Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction [J]. Proc Natl Acad Sci U S A, 1991,88(23): 10614-10618.
103. Fliss MS, Usadel H, Caballero OL, et al. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids [J]. Science, 2000,287(5460):2017-2019.
104. Zhou S, Kassauei K, Cutler DJ, et al. An oligonucleotide microarray for high-th roughput sequencing of the mitochondrial genome [J]. J Mol Diagn, 2006,8(4):476-482.
105. Tan DJ, Bai RK, Wong LJ. Comprehensive scanning of somatic mitochondrial DNA mutations in breast cancer [J]. Cancer Res, 2002,62(4):972-976.
106. Parrella P, Xiao Y, Fliss M, et al. Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates [J]. Cancer Res, 2001,61(20):7623-7626.
107. Polyak K, Li Y, Zhu H, et al. Somatic mutations of the mitochondrial genome in human colorectal tumours [J]. Nat Genet, 1998,20(3):291-293.
108. Alonso A, Martin P, Albarran C, et al. Detection of somatic mutations in the mitochondrial DNA control region of colorectal and gastric tumors by heteroduplex and single-strand conformation analysis [J]. Electrophoresis, 1997,18 (5):682-685.
109. Taylor RW, Barron MJ, Borthwick GM, et al. Mitochondrial DNA mutations in human colonic crypt stem cells [J]. J Clin Invest, 2003,112(9):1351-1360.
110. Wu CW, Yin PH, Hung WY, et al. Mitochondrial DNA mutations and mitochondrial DNA depletion in gastric cancer [J]. Genes Chromosomes Cancer, 2005,44(1):19-28.
111. Liu VW, Shi HH, Cheung AN, et al. High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas [J]. Cancer Res, 2001,61(16):5998-6001.
112. Nishikawa M, Nishiguchi S, Shiomi S, et al. Somatic mutation of mitochondrial DNA in cancerous and noncancerous liver tissue in individuals with hepatocellular carcinoma [J]. Cancer Res, 2001,61(5):1843-1845.
113. Wheelhouse NM, Lai PB, Wigmore SJ, et al. Mitochondrial D- loop mutations and deletion profiles of cancerous and noncancerous liver tissue in hepatitis B virus-infected liver [J]. Br J Cancer, 2005,92(7):1268-1272.
114. Jones JB, Song JJ, Hempen PM, et al. Detection of mitochondrial DNA mutations in pancreatic cancer offers a massive advantage over detection of nuclear DNA mutations [J]. Cancer Res, 2001,61 (4): 1299-1304.
115. Jessie BC, Sun CQ, Irons HR, et al. Accumulation of mitochondrial DNA deletions in the malignant prostate of patients of different ages [J]. Exp Gerontol, 2001,37(1):169-174.
116. Maximo V, Soares P, Lima J, et al. Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hurthle cell tumors [J]. Am J Pathol, 2002,160(5):1857-1865.
117. Montanini L, Regna-G ladin C, Eoli M, et al. Instability of mitochondrial DNA and MRI and clinical correlations in malignant gliomas [J]. J Neurooncol, 2005,74(1):87-89.
118. Sanchez-Cespedes M, Parrella P, Nomoto S, et al. Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors [J]. Cancer Res, 2001,61(19):7015-7019.
119. Testa JR, Tsichlis PN. AKT signaling in normal and malignant cells [J]. Oncogene, 2005,24(50):7391-7393.
120. Pastorino JG, Hoek JB, Shulga N. Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-in duced cytotoxicity [J]. Cancer Res, 2005,65(22): 10545-10554.
121. Lum JJ, Bui T, Gruber M, et al. The transcription factor HIF- 1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis [J]. Genes Dev, 2007,21 (9): 1037-1049.
122. Kim DH, Sarbassov DD, Ali SM, et al. MTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery [J]. Cell, 2002,110(2):163-175.
123. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex [J]. N Engl J Med, 2006,355(13):1345-1356.
124. Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling [J]. Nat Cell Biol, 2002,4(9):648-657.
125. Duvel K, Yecies JL, Menon S, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1 [J]. Mol Cell, 2010,39(2):171-183.
126. Green AS, Chapuis N, Lacombe C, et al. LKB1/AMPK/mTOR signaling pathway in hematological malignancies: from metabolism to cancer cell biology [J]. Cell Cycle, 2011,10(13). [Epub ahead of print]
127. Carling D, Sanders MJ, Woods A. The regulation of AMP-activated protein kinase by upstream kinases [J]. Int J Obes, 2008,32(Suppl 4):S55-S59.
128. Luo Z, Zang M, Guo W. AMPK as a metabolic tumorsuppressor: control of metabolism and cell growth [J]. Future Oncol, 2010,6(3):457-470.
129. Shackelford DB, Shaw RJ. The LKB1-A MPK pathway: metabolism and growth control in tumour suppression [J]. Nat Rev Cancer, 2009,9(8):563-575.
130. Scholl C, Gilliland DG, Frohling S. Deregulation of signaling pathways in acute myeloid leukemia [J]. Semin Oncol, 2008,35 (4):336-345.
131. Patiar S, Harris AL. Role of hypoxia-inducible factor-1alpha as a cancer therapy target [J]. Endocr Relat Cancer, 2006,13 (Suppl 1):S61-S75.
132. Brunelle JK, Bell EL, Quesada NM, et al. Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation [J]. Cell Metab, 2005,1(6):409-414.
133. Mansfield KD, Guzy RD, Pan Y, et al. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-al pha activation [J]. Cell Metab, 2005,1(6):393-399.
134. Semenza GL. Targeting HIF-1 for cancer therapy [J]. Nat Rev Cancer, 2003,3(10):721-732.
135. Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer [J]. J Cell Physiol, 2005,202(3):654-662.
136. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression [J]. Nature, 2006,441 (7092):437-443.
137. Semenza GL. Hypoxia-in ducible factor 1 (HIF-1) pathway [J]. Sci STKE, 2007,2007(407):cm8.
138. Papandreou I, Cairns RA, Fontana L, et al. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption [J]. Cell Metab, 2006,3(3):187-197.
139. Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update [J]. Nat Rev Cancer, 2005,5 (11):857-866.
140. Wokolorczyk D, Gliniewicz B, Sikorski A, et al. A range of cancers is associated with the rs6983267 marker on chromosome 8 [J]. Cancer Res, 2008,68(23):9982-9986.
141. Aylon Y, Oren M. Living with p53, dying of p53 [J]. Cell, 2007,130(4):597-600.
142. Chesney J, Mitchell R, Benigni F, et al. An inducible gene product for 6-phosphofructo-2- ki nase with an AU-ric h instability element: role in tumor cell glycolysis and the Warburg effect [J]. Proc Natl Acad Sci U S A, 1999,96(6):3047-3052.
143. Feng Z, Levine AJ. The regulation of energy metabolism and the IGF-1/ mTOR pathways by the p53 protein [J]. Trends Cell Biol, 2010,20(7):427-434.
144. Bos JL. Ras oncogenes in human cancer: a review [J]. Cancer Res, 1989,49(17):4682-4689.
145. Friday BB, Adjei AA. K-ras as a target for cancer therapy [J]. Biochim Biophys Acta, 2005,1756(2):127-144.
146. Chiaradonna F, Gaglio D, Vanoni M, et al. Expression of transforming K-R as oncogene affects mitochondrial function and morphology in mouse fibroblasts [J]. Biochim Biophys Acta, 2006,1757(9-10):1338-1356.
147. Baracca A, Chiaradonna F, Sgarbi G, et al. Mitochondrial Complex I decrease is responsible for bioenergetic dysfunction in K-ras transformed cells [J]. Biochim Biophys Acta, 2010,1797(2):314-323.
148. Yang D, Wang MT, Tang Y, et al. Impairment of mitochondrial respiration in mouse fibroblasts by oncogenic H-R AS (Q61L) [J]. Cancer Biol Ther, 2010,9(2):122-133.
149. Chun SY, Johnson C, Washburn JG, et al. Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1alpha and HIF-2alpha target genes [J]. Mol Cancer, 2010,9:293.
150. Rose IA, Warms JV. Mitochondrial hexokinase. Release, rebinding, and location [J]. J Biol Chem, 1967,242(7):1635-1645.
151. Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions [J]. J Biol Chem, 2001,276(46):43407-43412.
152. Maher JC, Wangpaichitr M, Savaraj N, et al. Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D -glucose [J]. Mol Cancer Ther, 2007,6(2):732-741.
153. Simons AL, Ahmad IM, Mattson DM, et al. 2-Deoxy-D -glucose combined with cisplatin enhances cytotoxicity via metabolic oxidative stress in human head and neck cancer cells [J]. Cancer Res, 2007,67(7):3364-3370.
154. Singh D, Banerji AK, Dwarakanath BS, et al. Optimizing cancer radiotherapy with 2-deoxy-d -glucose dose escalation studies in patients with glioblastoma multiforme [J]. Strahlenther Onkol, 2005,181(8):507-514.
155. Liu H, Hu YP, Savaraj N, et al. Hypersensitization of tumor cells to glycolytic inhibitors [J]. Biochemistry, 2001,40(18): 5542-5547.
156. Liu H, Savaraj N, Priebe W, et al. Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy (Model C) [J]. Biochem Pharmacol, 2002,64(12):1745-1751.
157. Maher JC, Krishan A, Lampidis TJ. Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D -glucose in tumor cells treated under hypoxic vs aerobic conditions [J]. Cancer Chemother Pharmacol, 2004,53(2):116-122.
158. Maschek G, Savaraj N, Priebe W, et al. 2-deoxy-D -glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-sm all cell lung cancers in vivo [J]. Cancer Res, 2004,64(1):31-34.
159. Chen Z, Zhang H, Lu W, et al. Role of mitochondria-as sociated hexokinase II in cancer cell death induced by 3-bromopyruvate [J]. Biochim Biophys Acta, 2009,1787(5):553-560.
160. Chiara F, Castellaro D, Marin O, et al. Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels [J]. PLoS One, 2008,3(3):e1852.
161. Goldin N, Arzoine L, Heyfets A, et al. Methyl jasmonate binds to and detaches mitochondria-bound hexokinase [J]. Oncogene, 2008,27(34):4636-4643.
162. Elia U, Flescher E. PI3K/Akt pathway activation attenuates the cytotoxic effect of methyl jasmonate toward sarcoma cells [J]. Neoplasia, 2008,10(11): 1303-1313.
163. Floridi A, Paggi MG, Marcante ML, et al. Lonidamine, a selective inhibitor of aerobic glycolysis of murine tumor cells [J]. J Natl Cancer Inst, 1981,66(3):497-499.
164. Floridi A, Bruno T, Miccadei S, et al. Enhancement of doxorubicin content by the antitumor drug lonidamine in resistant Ehrlich ascites tumor cells through modulation of energy metabolism [J]. Biochem Pharmacol, 1998,56(7):841-849.
165. Floridi A, Paggi MG, D'Atri S, et al. Effect of lonidamine on the energy metabolism of Ehrlich ascites tumor cells [J]. Cancer Res, 1981,41(11 Pt 1):4661-4666.
166. Berruti A, Bitossi R, Gorzegno G, et al. Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design [J]. J Clin Oncol, 2002,20(20):4150-4159.
167. De Lena M, Lorusso V, Latorre A, et al. Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study [J]. Eur J Cancer, 2001,37(3):364-368.
168. Oudard S, Carpentier A, Banu E, et al. Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme [J]. J Neurooncol, 2003,63(1):81-86.
169. De Marinis F, Rinaldi M, Ardizzoni A, et al. The role of vindesine and lonidamine in the treatment of elderly patients with advanced non-small cell lung cancer: a phase III randomized FONICAP trial [J]. Italian Lung Cancer Task Force Tumori, 1999,85(3):177-182.
170. Wang F, Ogasawara MA, Huang P. Small mitochondria- targeting molecules as anti-ca ncer agents [J]. Mol Aspects Med, 2010,31(1):75-92.
171. Goldberg EB, Colowick SP. The role of glycolysis in the growth of tumor cells. 3. Lactic dehydrogenase as the site of action of oxamate on the growth of cultured cells [J]. J Biol Chem, 1965,240:2786-2790.
172. Hamilton E, Fennell M, Stafford DM. Modification of tumour glucose metabolism for therapeutic benefit [J]. Acta Oncol, 1995,34(3):429-433.
173. Pedersen PL. The cancer cell's power plants as promising therapeutic targets: an overview [J]. J Bioenerg Biomembr, 2007,39(1):1-12.
174. Mathupala SP, Colen CB, Parajuli P, et al. Lactate and malignant tumors: a therapeutic target at the end stage of glycolysis [J]. J Bioenerg Biomembr, 2007,39(1):73-77.
175. Ohta S. Contribution of somatic mutations in the mitochondrial genome to the development of cancer and tolerance against anticancer drugs [J]. Oncogene, 2006,25(34):4768-4776.
176. Bonnet S, Archer SL, Allalunis-Turner J, et al. A mitochondria- K + channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth [J]. Cancer Cell, 2007,11(1):37-51.
177. Cao X, Fang L, Gibbs S, et al. Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia [J]. Cancer Chemother Pharmacol, 2007,59(4):495-505.
178. Chesney J. 6-phosphofructo-2- ki nase/fructose-2, 6- bisphosphatase and tumor cell glycolysis [J]. Curr Opin Clin Nutr Metab Care, 2006,9(5):535-539.
179. Clem B, Telang S, Clem A, et al. Small-molecule inhibition of 6-phosphofructo-2- ki nase activity suppresses glycolytic flux and tumor growth [J]. Mol Cancer Ther, 2008,7(1):110-120.
180. Eagle H. Nutrition needs of mammalian cells in tissue culture [J]. Science, 1955,122(3168):501-514.
181. Wu MC, Arimura GK, Yunis AA. Mechanism of sensitivity of cultured pancreatic carcinoma to asparaginase [J]. Int J Cancer, 1978,22(6):728-733.
182. Ahluwalia GS, Grem JL, Hao Z, et al. Metabolism and action of amino acid analog anti-ca ncer agents [J]. Pharmacol Ther, 1990,46(2):243-271.
183. Ovejera AA, Houchens DP, Catane R, et al. Efficacy of 6- diazo-5- ox o-L- norleucine and N-[N -gamma-glutamyl-6- diazo-5- oxo-norleucinyl]-6- di azo-5- ox o-no rleucine against experimental tumors in conventional and nude mice [J]. Cancer Res,1979,39(8):3220-3224.
184. Griffiths M, Keast D, Patrick G, et al. The role of glutamine and glucose analogues in metabolic inhibition of human myeloid leukaemia in vitro [J]. Int J Biochem, 1993,25(12):1749-1755.
185. Narta UK, Kanwar SS, Azmi W. Pharmacological and clinical evaluation of L-as paraginase in the treatment of leukemia [J]. Crit Rev Oncol Hematol, 2007,61 (3):208-221.
186. Avramis VI, Panosyan EH. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future [J]. Clin Pharmacokinet, 2005,44(4):367-393.
187. Enns GM, Berry SA, Berry GT, et al. Survival after treatment with phenylacetate and benzoate for urea-cy cle disorders [J]. N Engl J Med, 2007,356(22):2282-2292.
188. Thibault A, Samid D, Cooper MR, et al. Phase I study of phenylacetate administered twice daily to patients with cancer [J]. Cancer, 1995,75(12):2932-2938.
189. Mitchell RB, Wagner JE, Karp JE, et al. Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases [J]. Am J Med, 1988,85(5):662-667.
190. Fuchs BC, Bode BP. Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? [J]. Semin Cancer Biol, 2005,15 (4):254-266.
191. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer [J]. Trends Biochem Sci, 2010,35 (8):427-433.
192. Esslinger CS, Cybulski KA, Rhoderick JF. Ngamma-ar yl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site [J]. Bioorg Med Chem, 2005,13 (4):1111-1118.
193. Erickson JW, Cerione RA. Glutaminase: a hot spot for regulation of cancer cell metabolism? [J]. Oncotarget, 2010,1 (8):734-740.
194. + -dependent malic enzyme [J]. J Biol Chem, 1984,259(10):6215-621.
195. Thornburg JM, Nelson KK, Clem BF, et al. Targeting aspartate aminotransferase in breast cancer [J]. Breast Cancer Res, 2008,10(5):R84.
196. Qin JZ, Xin H, Nickoloff BJ. Targeting glutamine metabolism sensitizes melanoma cells to TRAIL-induced death [J]. Biochem Biophys Res Commun, 2010,398(1): 146-152.
197. Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth [J]. Future Oncol, 2010,6(3):457-470.
198. Hadad SM, Baker L, Quinlan PR, et al. Histological evaluation of AMPK signalling in primary breast cancer [J]. BMC Cancer, 2009,9:307.
199. Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer [J]. J Clin Oncol, 2009,27 (20):3297-3302.
200. Sarraf P, Mueller E, Jones D, et al. Differentiation and reversal of malignant changes in colon cancer through PPARgamma [J]. Nat Med, 1998,4(9):1046-1052.
201. Lehrke M, Lazar MA. The many faces of PPARgamma [J]. Cell, 2005,123(6):993-999.
202. Buzzai M, Bauer DE, Jones RG, et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-ox idation [J]. Oncogene, 2005,24(26):4165-4173.
203. Motoshima H, Goldstein BJ, Igata M, et al. AMPK and cell proliferation-AMPK as a therapeutic target for atherosclerosis and cancer [J]. J Physiol, 2006,574(Pt 1):63-71.
204. Bruserud O, Stapnes C, Tronstad KJ, et al. Protein lysine acetylation in normal and leukaemic haematopoiesis: HDACs as possible therapeutic targets in adult AML [J]. Expert Opin Ther Targets, 2006,10(1):51-68.
205. Carew JS, Nawrocki ST, Kahue CN, et al. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-A bl-mediated drug resistance [J]. Blood, 2007,110(1):313-322.
206. Stiehl DP, Fath DM, Liang D, et al. Histone deacetylase inhibitors synergize p300 autoacetylation that regulates its transactivation activity and complex formation [J]. Cancer Res, 2007,67(5):2256-2264.
207. Nelson EC, Evans CP, Mack PC, et al. Inhibition of Akt pathways in the treatment of prostate cancer [J]. Prostate Cancer Prostatic Dis, 2007,10(4):331-339.
208. Shin I, Edl J, Biswas S, et al. Proapoptotic activity of cell-permeable anti-A kt single-chain antibodies [J]. Cancer Res, 2005,65(7):2815-2824.
209. Kong D, Yamori T. Phosphatidylinositol 3-kinase inhibitors: promising drug candidates for cancer therapy [J]. Cancer Sci, 2008,99(9):1734-1740.
210. Wu M, Neilson A, Swift AL, et al. Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells [J]. Am J Physiol Cell Physiol, 2007,292(1): C125-C136.
211. Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition [J]. Sci Signal, 2009,2(67):pe24.
212. Dancey JE. Inhibitors of the mammalian target of rapamycin [J]. Expert Opin Investig Drugs, 2005,14(3):313-328.
213. Shor B, Zhang WG, Toral-B arza L, et al. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis [J]. Cancer Res, 2008,68(8):2934-2943.
214. Shim H, Dolde C, Lewis BC, et al. C-Myc transactivation of LDH-A: implications for tumor metabolism and growth [J]. Proc Natl Acad Sci U S A, 1997,94(13):6658-6663.
215. Kim JW, Gao P, Liu YC, et al. Hypoxia-in ducible factor 1 and dysregulated c-M yc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1 [J]. Mol Cell Biol, 2007,27 (21):7381-7393.
216. Osthus RC, Shim H, Kim S, et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc [J]. J Biol Chem, 2000,275(29):21797-21800.
217. Scatena R, Bottoni P, Pontoglio A, et al. Glycolytic enzyme inhibitors in cancer treatment [J]. Expert Opin Investig Drugs, 2008,17(10):1533-1545.
218. Pelicano H, Martin DS, Xu RH, et al. Glycolysis inhibition for anticancer treatment [J]. Oncogene, 2006,25(34):4633-4646.
219. Zancan P, Rosas AO, Marcondes MC, et al. Clotrimazole inhibits and modulates heterologous association of the key glycolytic enzyme 6-phosphofructo-1 -kinase [J]. Biochem Pharmacol, 2007,73(10):1520-1527.
220. Hagland H, Nikolaisen J, Hodneland LI, et al. Targeting mitochondria in the treatment of human cancer: a coordinated attack against cancer cell energy metabolism and signalling [J]. Expert Opin Ther Targets, 2007,11(8):1055-1069.