Clinical impact of the Warburg effect in gastrointestinal cancer (Review)

International Journal of Oncology

Volumn 45, Issue 4, 2014, Pages 1345-1354

  Sawayama, Hiroshi ^a,b   Ishimoto, Takatsugu ^a   Sugihara, Hidetaka ^a   Miyanari, Nobutomo ^b   Miyamoto, Yuji ^a   Baba, Yoshifumi ^a   Yoshida, Naoya ^a   Baba, Hideo ^a  

^a KUMAMOTO UNIVERSITY   (Japan)

^b NATIONAL HOSPITAL ORGANIZATION KUMAMOTO MEDICAL CENTER   (Japan)

Author keywords

Gastrointestinal cancer; Inhibitor; Prognosis; Small molecule; Warburg effect

Indexed keywords

GLUCOSE TRANSPORTER; GLYCOLYTIC ENZYME; HEXOKINASE; HEXOKINASE 2; HYPOXIA INDUCIBLE FACTOR; LACTATE DEHYDROGENASE; MYC PROTEIN; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PYRUVATE KINASE; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; GLUCOSE; TUMOR MARKER;

ANGIOGENESIS; ANTIPROLIFERATIVE ACTIVITY; CANCER CELL; CANCER PROGNOSIS; CANCER RESISTANCE; CARCINOGENESIS; CELL DIFFERENTIATION; CELL SURVIVAL; CHEMORADIOTHERAPY; COLON CANCER; COLORECTAL CANCER; DIGESTIVE SYSTEM CANCER; ENZYME PHOSPHORYLATION; ESOPHAGEAL SQUAMOUS CELL CARCINOMA; GALLBLADDER CANCER; GENE OVEREXPRESSION; GLUCOSE METABOLISM; GLYCOLYSIS; LIVER CELL CARCINOMA; ONCOLOGICAL PARAMETERS; OXIDATIVE STRESS; PANCREAS CANCER; PATIENT SELECTION; PREDICTION; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN EXPRESSION; REVIEW; STOMACH CANCER; WARBURG EFFECT; DRUG EFFECTS; GASTROINTESTINAL TUMOR; GENE EXPRESSION REGULATION; HUMAN; METABOLISM; PATHOLOGY;

ANTINEOPLASTIC AGENTS; GASTROINTESTINAL NEOPLASMS; GENE EXPRESSION REGULATION, NEOPLASTIC; GLUCOSE; HUMANS; TUMOR MARKERS, BIOLOGICAL;

EID: 84907467704     PISSN: 10196439     EISSN: 17912423     Source Type: Journal    
DOI: 10.3892/ijo.2014.2563     Document Type: Review

References (102)

1. Warburg O: On respiratory impairment in cancer cells. Science 124: 269-270, 1956.
2. Younes M, Lechago LV, Somoano JR, Mosharaf M and Lechago J: Wide expression of the human erythrocyte glucose transporter Glut1 in human cancers. Cancer Res 56: 1164-1167, 1996. (Pubitemid 26065417)
3. Warburg O: On the origin of cancer cells. Science 123: 309-314, 1956.
4. Plathow C and Weber WA: Tumor cell metabolism imaging. J Nucl Med 49 (Suppl 2): S43-S63, 2008.
5. Plas DR and Thompson CB: Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24: 7435-7442, 2005. (Pubitemid 41637983)
6. Elstrom RL, Bauer DE, Buzzai M, et al: Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64: 3892-3899, 2004. (Pubitemid 38697301)
7. Vousden KH and Ryan KM: p53 and metabolism. Nat Rev Cancer 9: 691-700, 2009.
8. Stambolic V, MacPherson D, Sas D, et al: Regulation of PTEN transcription by p53. Mol Cell 8: 317-325, 2001. (Pubitemid 32831549)
9. Jones RG, Plas DR, Kubek S, et al: AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18: 283-293, 2005. (Pubitemid 41350534)
10. Shackelford DB and Shaw RJ: The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9: 563-575, 2009.
11. Lu H, Forbes RA and Verma A: Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277: 23111-23115, 2002. (Pubitemid 34952134)
12. Zhong H, De Marzo AM, Laughner E, et al: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59: 5830-5835, 1999.
13. Talks KL, Turley H, Gatter KC, et al: The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157: 411-421, 2000. (Pubitemid 30626905)
14. Matsuyama T, Nakanishi K, Hayashi T, et al: Expression of hypoxia-inducible factor-1alpha in esophageal squamous cell carcinoma. Cancer Sci 96: 176-182, 2005. (Pubitemid 40575919)
15. Ogane N, Yasuda M, Shimizu M, et al: Clinicopathological implications of expressions of hypoxia-related molecules in esophageal superficial squamous cell carcinoma. Ann Diagn Pathol 14: 23-29, 2010.
16. Zhang ZG, Zhang QN, Wang XH and Tian JH: Hypoxia-inducible factor 1 alpha (HIF-1alpha) as a prognostic indicator in patients with gastric tumors: a meta-analysis. Asian Pac J Cancer Prev 14: 4195-4198, 2013.
17. Lin S, Ma R, Zheng XY, et al: Meta-analysis of immunohistochemical expression of hypoxia inducible factor-1alpha as a prognostic role in gastric cancer. World J Gastroenterol 20: 1107-1113, 2014.
18. Baba Y, Nosho K, Shima K, et al: HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol 176: 2292-2301, 2010.
19. Zheng SS, Chen XH, Yin X and Zhang BH: Prognostic significance of HIF-1alpha expression in hepatocellular carcinoma: a meta-analysis. PloS One 8: e65753, 2013.
20. Nakamura J, Kitajima Y, Kai K, et al: Hypoxia-inducible factor-1alpha expression predicts the response to 5-fluorouracil-based adjuvant chemotherapy in advanced gastric cancer. Oncol Rep 22: 693-699, 2009.
21. Nakamura J, Kitajima Y, Kai K, et al: HIF-1alpha is an unfavorable determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy. Int J Cancer 127: 1158-1171, 2010.
22. Griffiths EA, Pritchard SA, McGrath SM, et al: Hypoxia-associated markers in gastric carcinogenesis and HIF-2alpha in gastric and gastro-oesophageal cancer prognosis. Br J Cancer 98: 965-973, 2008. (Pubitemid 351341598)
23. Rasheed S, Harris AL, Tekkis PP, et al: Hypoxia-inducible factor-1alpha and -2alpha are expressed in most rectal cancers but only hypoxia-inducible factor-1alpha is associated with prognosis. Br J Cancer 100: 1666-1673, 2009.
24. Dang CV, Le A and Gao P: MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res 15: 6479-6483, 2009.
25. Calcagno DQ, Leal MF, Assumpcao PP, Smith MA and Burbano RR: MYC and gastric adenocarcinoma carcinogenesis. World J Gastroenterol 14: 5962-5968, 2008.
26. Liu Y, Gong LP, Dong XL and Liu HG: Detection of C-MYC oncogene translocation and copy number change in the normal-dysplasia-carcinoma sequence of the larynx by fluorescence in situ hybridization. Diagn Cytopathol 41: 515-519, 2013.
27. Tuupanen S, Yan J, Turunen M, et al: Characterization of the colorectal cancer-associated enhancer MYC-335 at 8q24: the role of rs67491583. Cancer Genet 205: 25-33, 2012.
28. Amente S, Lania L and Majello B: Epigenetic reprogramming of Myc target genes. Am J Cancer Res 1: 413-418, 2011.
29. de Souza CR, Leal MF, Calcagno DQ, et al: MYC deregulation in gastric cancer and its clinicopathological implications. PloS One 8: e64420, 2013.
30. He C, Jiang H, Geng S, et al: Expression and prognostic value of c-Myc and Fas (CD95/APO1) in patients with pancreatic cancer. Int J Clin Exp Pathol 7: 742-750, 2014.
31. Mueckler M, Caruso C, Baldwin SA, et al: Sequence and structure of a human glucose transporter. Science 229: 941-945, 1985. (Pubitemid 16248486)
32. Joost HG and Thorens B: The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review). Mol Membr Biol 18: 247-256, 2001.
33. Younes M, Lechago LV, Somoano JR, Mosharaf M and Lechago J: Immunohistochemical detection of Glut3 in human tumors and normal tissues. Anticancer Res 17: 2747-2750, 1997. (Pubitemid 27352681)
34. Ayala FR, Rocha RM, Carvalho KC, et al: GLUT1 and GLUT3 as potential prognostic markers for oral squamous cell carcinoma. Molecules 15: 2374-2387, 2010.
35. Fonteyne P, Casneuf V, Pauwels P, et al: Expression of hexokinases and glucose transporters in treated and untreated oesophageal adenocarcinoma. Histol Histopathol 24: 971-977, 2009.
36. Carvalho KC, Cunha IW, Rocha RM, et al: GLUT1 expression in malignant tumors and its use as an immunodiagnostic marker. Clinics (Sao Paulo) 66: 965-972, 2011.
37. Griffiths EA, Pritchard SA, Welch IM, Price PM and West CM: Is the hypoxia-inducible factor pathway important in gastric cancer? Eur J Cancer 41: 2792-2805, 2005. (Pubitemid 41713116)
38. Yun J, Rago C, Cheong I, et al: Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325: 1555-1559, 2009.
39. Kawada K, Nakamoto Y, Kawada M, et al: Relationship between 18F-fluorodeoxyglucose accumulation and KRAS/BRAF mutations in colorectal cancer. Clin Cancer Res 18: 1696-1703, 2012.
40. Yang W, Zheng Y, Xia Y, et al: ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 14: 1295-1304, 2012.
41. Young CD, Lewis AS, Rudolph MC, et al: Modulation of glucose transporter 1 (GLUT1) expression levels alters mouse mammary tumor cell growth in vitro and in vivo. PloS One 6: e23205, 2011.
42. Sawayama H, Ishimoto T, Watanabe M, et al: High expression of glucose transporter 1 on primary lesions of esophageal squamous cell carcinoma is associated with hematogenous recurrence. Ann Surg Oncol 21: 1756-1762, 2014.
43. Tohma T, Okazumi S, Makino H, et al: Overexpression of glucose transporter 1 in esophageal squamous cell carcinomas: a marker for poor prognosis. Dis Esophagus 18: 185-189, 2005. (Pubitemid 41801114)
44. Kawamura T, Kusakabe T, Sugino T, et al: Expression of glucose transporter-1 in human gastric carcinoma: association with tumor aggressiveness, metastasis, and patient survival. Cancer 92: 634-641, 2001. (Pubitemid 32735200)
45. Jung JH, Im S, Jung ES and Kang CS: Clinicopathological implications of the expression of hypoxia-related proteins in gastric cancer. Int J Med Sci 10: 1217-1223, 2013.
46. Haber RS, Rathan A, Weiser KR, et al: GLUT1 glucose transporter expression in colorectal carcinoma: a marker for poor prognosis. Cancer 83: 34-40, 1998. (Pubitemid 28299626)
47. Korkeila E, Jaakkola PM, Syrjanen K, Pyrhonen S and Sundstrom J: Pronounced tumour regression after radiotherapy is associated with negative/weak glucose transporter-1 expression in rectal cancer. Anticancer Res 31: 311-315, 2011.
48. Kitamura K, Hatano E, Higashi T, et al: Proliferative activity in hepatocellular carcinoma is closely correlated with glucose metabolism but not angiogenesis. J Hepatol 55: 846-857, 2011.
49. Legan M, Tevzic S, Tolar A, Luzar B and Marolt VF: Glucose transporter-1 (GLUT-1) immunoreactivity in benign, premalignant and malignant lesions of the gallbladder. Pathol Oncol Res 17: 61-66, 2011.
50. Kim YW, Park YK, Yoon TY and Lee SM: Expression of the GLUT1 glucose transporter in gallbladder carcinomas. Hepatogastroenterology 49: 907-911, 2002.
51. Sattler UG and Mueller-Klieser W: The anti-oxidant capacity of tumour glycolysis. Int J Radiat Biol 85: 963-971, 2009.
52. Hirschhaeuser F, Sattler UG and Mueller-Klieser W: Lactate: a metabolic key player in cancer. Cancer Res 71: 6921-6925, 2011.
53. Brophy S, Sheehan KM, McNamara DA, Deasy J, Bouchier-Hayes DJ and Kay EW: GLUT-1 expression and response to chemoradiotherapy in rectal cancer. Int J Cancer 125: 2778-2782, 2009.
54. Cao X, Fang L, Gibbs S, et al: Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia. Cancer Chemother Pharmacol 59: 495-505, 2007. (Pubitemid 46122328)
55. Wu CH, Ho YS, Tsai CY, et al: In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter. Int J Cancer 124: 2210-2219, 2009.
56. Liu Y, Cao Y, Zhang W, et al: A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther 11: 1672-1682, 2012.
57. Mathupala SP, Ko YH and Pedersen PL: Hexokinase-2 bound to mitochondria: cancer's stygian link to the 'Warburg Effect' and a pivotal target for effective therapy. Semin Cancer Biol 19: 17-24, 2009.
58. Kwee SA, Hernandez B, Chan O and Wong L: Choline kinase alpha and hexokinase-2 protein expression in hepatocellular carcinoma: association with survival. PloS One 7: e46591, 2012.
59. Paudyal B, Paudyal P, Oriuchi N, Tsushima Y, Nakajima T and Endo K: Clinical implication of glucose transport and metabolism evaluated by 18F-FDG PET in hepatocellular carcinoma. Int J Oncol 33: 1047-1054, 2008.
60. Seo S, Hatano E, Higashi T, et al: Fluorine-18 fluorodeoxyglucose positron emission tomography predicts tumor differentiation, P-glycoprotein expression, and outcome after resection in hepatocellular carcinoma. Clin Cancer Res 13: 427-433, 2007. (Pubitemid 46225346)
61. Ganapathy-Kanniappan S, Vali M, Kunjithapatham R, et al: 3-bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy. Curr Pharm Biotechnol 11: 510-517, 2010.
62. David CJ, Chen M, Assanah M, Canoll P and Manley JL: HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463: 364-368, 2010.
63. Clower CV, Chatterjee D, Wang Z, Cantley LC, Vander Heiden MG and Krainer AR: The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci USA 107: 1894-1899, 2010.
64. Christofk HR, Vander Heiden MG, Harris MH, et al: The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452: 230-233, 2008. (Pubitemid 351380249)
65. Christofk HR, Vander Heiden MG, Wu N, Asara JM and Cantley LC: Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452: 181-186, 2008. (Pubitemid 351380242)
66. Anastasiou D, Yu Y, Israelsen WJ, et al: Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 8: 839-847, 2012.
67. Yang W and Lu Z: Regulation and function of pyruvate kinase M2 in cancer. Cancer Lett 339: 153-158, 2013.
68. Tamada M, Suematsu M and Saya H: Pyruvate kinase M2: multiple faces for conferring benefits on cancer cells. Clin Cancer Res 18: 5554-5561, 2012.
69. Kaplon J, Zheng L, Meissl K, et al: A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498: 109-112, 2013.
70. Hur H, Xuan Y, Kim YB, et al: Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a potential therapeutic target. Int J Oncol 42: 44-54, 2013.
71. Lu CW, Lin SC, Chien CW, et al: Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer. Am J Pathol 179: 1405-1414, 2011.
72. Peifer C and Alessi DR: Small-molecule inhibitors of PDK1. Chem Med Chem 3: 1810-1838, 2008.
73. Tong J, Xie G, He J, Li J, Pan F and Liang H: Synergistic antitumor effect of dichloroacetate in combination with 5-fluorouracil in colorectal cancer. J Biomed Biotechnol 2011: 740564, 2011.
74. Shen YC, Ou DL, Hsu C, et al: Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma. Br J Cancer 108: 72-81, 2013.
75. Fantin VR, St-Pierre J and Leder P: Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9: 425-434, 2006. (Pubitemid 43832190)
76. Goldman RD, Kaplan NO and Hall TC: Lactic dehydrogenase in human neoplastic tissues. Cancer Res 24: 389-399, 1964.
77. Fan J, Hitosugi T, Chung TW, et al: Tyrosine phosphorylation of lactate dehydrogenase A is important for NADH/NAD(+) redox homeostasis in cancer cells. Mol Cell Biol 31: 4938-4950, 2011.
78. Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC and Harris AL: Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway - a report of the Tumour Angiogenesis Research Group. J Clin Oncol 24: 4301-4308, 2006. (Pubitemid 46630788)
79. Sheng SL, Liu JJ, Dai YH, Sun XG, Xiong XP and Huang G: Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma. FEBS J 279: 3898-3910, 2012.
80. Zhang Y, Zhang X, Wang X, et al: Inhibition of LDH-A by lentivirus-mediated small interfering RNA suppresses intestinal-type gastric cancer tumorigenicity through the downregulation of Oct4. Cancer Lett 321: 45-54, 2012.
81. Le A, Cooper CR, Gouw AM, et al: Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA 107: 2037-2042, 2010.
82. Miskimins WK, Ahn HJ, Kim JY, Ryu S, Jung YS and Choi JY: Synergistic anti-cancer effect of phenformin and oxamate. PloS One 9: e85576, 2014.
83. Zhou M, Zhao Y, Ding Y, et al: Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol. Mol Cancer 9: 33, 2010.
84. Sumiyoshi Y, Kakeji Y, Egashira A, Mizokami K, Orita H and Maehara Y: Overexpression of hypoxia-inducible factor 1alpha and p53 is a marker for an unfavorable prognosis in gastric cancer. Clin Cancer Res 12: 5112-5117, 2006. (Pubitemid 44453338)
85. Isobe T, Aoyagi K, Koufuji K, et al: Clinicopathological significance of hypoxia-inducible factor-1 alpha (HIF-1alpha) expression in gastric cancer. Int J Clin Oncol 18: 293-304, 2013.
86. Theodoropoulos GE, Lazaris AC, Theodoropoulos VE, et al: Hypoxia, angiogenesis and apoptosis markers in locally advanced rectal cancer. Int J Colorectal Dis 21: 248-257, 2006. (Pubitemid 43280332)
87. Dai CX, Gao Q, Qiu SJ, et al: Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery. BMC Cancer 9: 418, 2009.
88. Liu L, Zhu XD, Wang WQ, et al: Activation of beta-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis. Clin Cancer Res 16: 2740-2750, 2010.
89. Couvelard A, O'Toole D, Leek R, et al: Expression of hypoxia-inducible factors is correlated with the presence of a fibrotic focus and angiogenesis in pancreatic ductal adenocarcinomas. Histopathology 46: 668-676, 2005. (Pubitemid 40834826)
90. Shen YM, Arbman G, Olsson B and Sun XF: Overexpression of GLUT1 in colorectal cancer is independently associated with poor prognosis. Int J Biol Markers 26: 166-172, 2011.
91. Pizzi S, Porzionato A, Pasquali C, et al: Glucose transporter-1 expression and prognostic significance in pancreatic carcinogenesis. Histol Histopathol 24: 175-185, 2009.
92. Rho M, Kim J, Jee CD, et al: Expression of type 2 hexokinase and mitochondria-related genes in gastric carcinoma tissues and cell lines. Anticancer Res 27: 251-258, 2007. (Pubitemid 46363339)
93. Qiu MZ, Han B, Luo HY, et al: Expressions of hypoxia-inducible factor-1alpha and hexokinase-II in gastric adenocarcinoma: the impact on prognosis and correlation to clinicopathologic features. Tumour Biol 32: 159-166, 2011.
94. Gong L, Cui Z, Chen P, Han H, Peng J and Leng X: Reduced survival of patients with hepatocellular carcinoma expressing hexokinase II. Med Oncol 29: 909-914, 2012.
95. Zhan C, Shi Y, Lu C and Wang Q: Pyruvate kinase M2 is highly correlated with the differentiation and the prognosis of esophageal squamous cell cancer. Dis Esophagus 26: 746-753, 2013.
96. Lim JY, Yoon SO, Seol SY, et al: Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer. World J Gastroenterol 18: 4037-4043, 2012.
97. Li J, Yang Z, Zou Q, et al: PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer. Clin Transl Oncol 16: 200-207, 2014.
98. Kolev Y, Uetake H, Takagi Y and Sugihara K: Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. Ann Surg Oncol 15: 2336-2344, 2008.
99. Yu SJ, Yoon JH, Yang JI, et al: Enhancement of hexokinase II inhibitor-induced apoptosis in hepatocellular carcinoma cells via augmenting ER stress and anti-angiogenesis by protein disulfide isomerase inhibition. J Bioenerg Biomembr 44: 101-115, 2012.
100. Zhou Y, Tozzi F, Chen J, et al: Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res 72: 304-314, 2012.
101. Vander Heiden MG, Christofk HR, Schuman E, et al: Identification of small molecule inhibitors of pyruvate kinase M2. Biochem Pharmacol 79: 1118-1124, 2010.
102. Feldman RI, Wu JM, Polokoff MA, et al: Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem 280: 19867-19874, 2005. (Pubitemid 41379514)