Skip to main content
SpringerLink
Log in

PI3-Kinase Inhibition

A Target for Therapeutic Intervention

  • Chapter
Protein Tyrosine Kinases

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

The activation of cells by a wide variety of stimuli leads to rapid changes in 3-phosphorylated inositol lipids through the action of a family of enzymes known as phosphoinositide 3-kinases (PI3-Ks). PI3-K activation is central to the coordinated control of multiple cell signaling pathways leading to cell growth, cell proliferation, cell survival, and cell migration. The PI3-Ks have been classified into three groups according to their primary sequence and domain structure, mode of regulation, and substrate specificity in vitro (Fig. 1) (1). The class IA PI3-K subgroup consist of three catalytic subunits, p110α, β, and δ, which form heterodimers with one of five SH2 (Shc homology) domain-containing regulatory subunits, p85α, p85β, p55γ, p55α, and p50α. The class IA heterodimer can be recruited either directly to cell surface receptors, e.g., growth factor receptors, or indirectly by adaptor molecules such as Shc, growth factor receptor bound protein, (Grb2) or insulin receptor substrate (IRS)-1 (2). P110δ was originally identified in leukocytes but is also expressed in other cell types including breast tissue and melanocytes (3). The p110α and p110β isoforms are ubiquitous. Class IB consists of one member, a heterodimer of p110γ and a regulatory subunit termed p101, and is activated by G protein βγ subunits following the stimulation of G protein-coupled receptors (GPCRs). The expression of p110γ is predominantly in leukocytes but this isoform is also found in cardiac tissue. Both class IA and IB catalyze the formation of PtdIns (3,4,5)P3 in vitro and in addition to regulation by cell surface receptors, they can be activated directly by the small GTPase, Ras (4).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Vanhaesebroeck B, Leevers SJ, Ahmadi K, et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 2001; 70:535–602.

    Article  PubMed  CAS  Google Scholar 

  2. Wymann MP, Zvelebil M, Laffargue M. Phosphoinositide 3-kinase signalling—which way to target? TIPS 2003; 34:366–376.

    Google Scholar 

  3. Sawyer C, Sturge J, Bennett DC, et al. Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110δ. Cancer Res 2003; 63:1667–1675.

    PubMed  CAS  Google Scholar 

  4. Rodriguez-Viciana P, Warne PH, Dhand R, et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 1994; 370:527–532.

    Article  PubMed  CAS  Google Scholar 

  5. El Sheikh SS, Domin J, Tomtitchong P, Abel P, Stamp G, Lalani E-N. Topographical expression of class IA and class II phosphoinositide 3-kinase enzymes in normal human tissues is consistent with a role in differentiation. BMC Clin Pathol 2003; 3:4.

    Article  PubMed  Google Scholar 

  6. Arcaro A, Zvelebil MJ, Wallasch C, Ullrich A, Waterfield MD, Domin J. Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol Cell Biol 2000; 20:3817–3830.

    Article  PubMed  CAS  Google Scholar 

  7. Ktori C, Shepard PR, O’Rourke L. TNF-a and leptin activate the a-isoform of class II phosphoinositide 3-kinase. Biochem Biophys Res Commun 2003; 306:139–143.

    Article  PubMed  CAS  Google Scholar 

  8. Turner SJ, Domin J, Waterfield MD, Ward SG, Westwick J. The CC chemokine monocyte chemotactic peptide-1 activates both the class I p85/p110 phosphatidylinositol 3-kinase and the class II PI3-K-C2alpha. J Biol Chem 1998; 273:25987–29595.

    Article  PubMed  CAS  Google Scholar 

  9. Viera OV, Botelho RJ, Rameh L, et al. Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. J Cell Biol 2001; 155:19–25.

    Article  Google Scholar 

  10. Futter CE, Collinson LM, Backer JM, Hopkins CR. Human VPS34 is required for internal vesicle formation within multivesicular endosomes. J Cell Biol 2001; 155:1251–1263.

    Article  PubMed  CAS  Google Scholar 

  11. Sulis ML, Parsons R. PTEN: from pathology to biology. Trends Cell Biol 2003; 13:478–483.

    Article  PubMed  CAS  Google Scholar 

  12. Krystal G. Lipid phosphatases in the immune system. Semin Immunol 2000; 12:397–403.

    Article  PubMed  CAS  Google Scholar 

  13. Cozier GE, Carlton J, Bouyoucef D, Cullen PJ. Membrane targeting by pleckstrin homology domains. Curr Top Microbiol Immunol 2004; 282:49–88.

    PubMed  CAS  Google Scholar 

  14. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296:1655–1657.

    Article  PubMed  CAS  Google Scholar 

  15. Chan TO, Rittenhouse SE, Tsichlis PN. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 1999; 68:965–1014.

    Article  PubMed  CAS  Google Scholar 

  16. Arcaro A, Wymann MP. Wortmannin is a potent phosphatidylimositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem J 1993; 269:297–301.

    Google Scholar 

  17. Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, et al. Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol 1996; 16:1722–1733.

    PubMed  CAS  Google Scholar 

  18. Vlahos CJ, Matter MF, Hui KY, Brown RF. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(-4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 1994; 269:5241–5248.

    PubMed  CAS  Google Scholar 

  19. Walker EH, Pacold ME, Perisic O, et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 2000; 6:909–919.

    Article  PubMed  CAS  Google Scholar 

  20. Domin J, Pages F, Volinia S, et al. Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin. Biochem J 1997; 326:139–147.

    PubMed  CAS  Google Scholar 

  21. El-Kholy W, MacDonald PE, Lin JH, et al. The phosphatidylinositol 3-kinase inhibitor LY294002 potently blocks Kv currents via a direct mechanism. FASEB J 2003; 17:720–722.

    PubMed  CAS  Google Scholar 

  22. Foukas LC, Daniele N, Ktori C, Anderson KE, Jensen J, Shepherd P. Direct effects of caffeine and theophylline on p110δ and other phosphoinositide 3-kinases. J Biol Chem 2002; 277:37124–37130.

    Article  PubMed  CAS  Google Scholar 

  23. Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE. Essential role of phosphatinositide 3-kinase in neutrophil directional movement. J Immunol 2003; 170:2647–2654.

    PubMed  CAS  Google Scholar 

  24. Foukas LC, Okkenhaug K. Gene-targeting reveals physiological roles and complaex regulation of the phosphoinositide 3-kinases. Arch Biochem Biophys 2003; 414:13–18.

    Article  PubMed  CAS  Google Scholar 

  25. Sasaki T, Suzuki A, Sasaki J, Penninger JM. Phosphoinositide 3-kinases in immunity: lessons from knockout mice. J Biochem (Tokyo) 2002; 131:495–501.

    CAS  Google Scholar 

  26. Bi L, Okabe I, Bernard DJ, Wynshaw-Boris A, Nussbaum RL. Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem 1999; 274:10963–10968.

    Article  PubMed  CAS  Google Scholar 

  27. Bi L, Okabe I, Bernard DJ, Nussbaum RL. Early embryonic lethality in mice deficient in the p110beta catalytic subunit of PI3-K. Mamm Genome 2002; 13:169–172.

    PubMed  CAS  Google Scholar 

  28. Clayton E, Bardi G, Bell SE, et al. A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med 2002; 196:753–763.

    Article  PubMed  CAS  Google Scholar 

  29. Jou ST, Carpino N, Takahashi Y, et al. Essential, non-redundant role for the phosphoinositide 3-kinase p110delta in signalling by the B cell receptor complex. Mol Cell Biol 2002; 22:8580–8591.

    Article  PubMed  CAS  Google Scholar 

  30. Okkenhaug K, Bilanchio A, Farjot G, et al. Impaired B and T cell antigen receptor signalling in p110δ PI3-kinase mutant mice. Science 2002; 297:1031–1034.

    PubMed  CAS  Google Scholar 

  31. Hirsch E, Katanaev VL, Garlanda C, et al. Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 2000; 287:1049–1053.

    Article  PubMed  CAS  Google Scholar 

  32. Sasaki T, Irie-Sasaki J, Jones RG, et al. Function of PI3-Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 2000; 287:1040–1046.

    Article  PubMed  CAS  Google Scholar 

  33. Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D. Roles of PLC-β2 and −β3 and PI3-Kγ in chemoattractant-mediated signal transduction. Science 2000; 287:1046–1049.

    Article  PubMed  CAS  Google Scholar 

  34. Hannigan M, Zhan L, Li Z, Ai Y, Wu D, Huang C-K. Neutrophils lacking phosphoinositide 3-kinase γ show loss of directionality during N-formyl-Met-Leu-Phe-induced chemotaxis. Proc Natl Acad Sci USA 2002; 99:3603–3608.

    Article  PubMed  CAS  Google Scholar 

  35. Laffargue M, Calvez R, Finan P, et al. Phosphoinositide 3-kinase gamma is an essential amplifier of mast cell function. Immunity 2002; 16:441–451.

    Article  PubMed  CAS  Google Scholar 

  36. Hirsch E, Bosco O, Tropel P, et al. Resistance to thromboembolism in PI3-Kγ-deficient mice. FASEB J 2001; 15:2019–2021.

    PubMed  CAS  Google Scholar 

  37. Crackower MA, Oudit GY, Kozieradzki I, et al. Regulation of myocardial contractility and cell size by distinct PI3-K-PTEN signaling pathways. Cell 2002; 110:737–749.

    Article  PubMed  CAS  Google Scholar 

  38. Vlahos CJ, McDowell SA, Clerk A. Kinases as therapeutic targets for heart failure. Nat Rev Drug Discov 2003; 2:99–113.

    Article  PubMed  CAS  Google Scholar 

  39. Susuki H, Terauchi Y, Fujiwara M, et al. Xid-like immunodefiency in mice and disruption of the p85α subunit of phosphoinositide 3-kinase. Science 1999; 283:390–392.

    Article  Google Scholar 

  40. Fruman DA, Snapper SB, Yballe CM, et al. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85α. Science 1999; 283:393–397.

    Article  PubMed  CAS  Google Scholar 

  41. Ueki K, Yballe CM, Brachmann SM, et al. Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 2002; 99:419–424.

    Article  PubMed  CAS  Google Scholar 

  42. Luo J, Manning BD, Cantley LC. Targeting the PI3-K-Akt pathway in human cancer: rationale and promise. Cancer Cell 2003; 4:257–262.

    Article  PubMed  CAS  Google Scholar 

  43. Roymans D, Slegers H. Phosphatidylinositol 3-kinases in tumor progression. Eur J Biochem 2001; 268:487–498.

    Article  PubMed  CAS  Google Scholar 

  44. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-Akt pathway in human cancer. Nat Rev Cancer 2002; 2:489–501.

    Article  PubMed  CAS  Google Scholar 

  45. Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 1985; 315:239–242.

    Article  PubMed  CAS  Google Scholar 

  46. Courtneidge SA, Heber A. An 81 kd protein complexed with middle T antigen and pp60c-src: a possible phosphatidylinositol kinase. Cell 1987; 50:1031–1037.

    Article  PubMed  CAS  Google Scholar 

  47. Chang HW, Aoki M, Fruman D, et al. Transformation of chicken cells by the gene encoding the catalytic subunit of PI3-K. Science 1997; 276:1848–1850.

    Article  PubMed  CAS  Google Scholar 

  48. Jimenez C, Jones DR, Rodriguez-Viciana P, et al. Identification and characterisation of a new oncogene derived form the regulatory subunit of phosphoinositide 3-kinase. EMBO J 1998; 17:743–753.

    Article  PubMed  CAS  Google Scholar 

  49. Borlado RL, Redondo C, Alvarez B, et al. Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. FASEB J 2000; 14:895–903.

    PubMed  CAS  Google Scholar 

  50. Jucker M, Sudel K, Horn S, et al. Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin’s lymphoma-derived cell line (CO). Leukemia 2002; 16:894–901.

    Article  PubMed  CAS  Google Scholar 

  51. Shayesteh L, Lu Y, Kuo WL, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nature Genetics 1999; 21:99–102.

    Article  PubMed  CAS  Google Scholar 

  52. Ma YY, Wei S-J, Lin Y-C, et al. PIK3CA as an oncogene in cervical cancer. Oncogene 2000; 19:2739–2744.

    Article  PubMed  CAS  Google Scholar 

  53. Woenckhaus J, Steger K, Werner E, et al. Genomic gain of PI3-KCA and increased expression of p110alpha are associated with progression of dysplasia into invasive squamous cell carcinoma. J Pathol 2002; 198:335–342.

    Article  PubMed  CAS  Google Scholar 

  54. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304:554.

    Article  PubMed  CAS  Google Scholar 

  55. Bachman KE, Argani P, Samuels Y, et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther. 2004; 8:772–775.

    Google Scholar 

  56. Campbell IG, Russell SE, Choong DY, et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004; 64:7678–7681.

    Article  PubMed  CAS  Google Scholar 

  57. Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-K mutations identified in human cancer are oncogenic. Proc. Natl. Acad. Sci. USA 2005; 102:802–807.

    Article  PubMed  CAS  Google Scholar 

  58. Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA 2002; 98:10983–10985.

    Article  Google Scholar 

  59. Bonneau D, Longy M. Mutations of the human PTEN gene. J Med Genet 2000; 16:109–122.

    CAS  Google Scholar 

  60. Zhou X-P, Gimm O, Hampel H, Niemann T, Walker MJ, Eng C. Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am J Pathol 2000; 157:1123–1128.

    PubMed  CAS  Google Scholar 

  61. Soria JC, Lee HY, Lee JL, et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res 2002; 8:1178–1184.

    PubMed  CAS  Google Scholar 

  62. Roche S, Koegl M, Courtneidge SA. The phosphatidylinositol 3-kinase alpha is required for DNA synthesis induced by some but not all growth factors. Proc Natl Acad Sci USA 1994; 91:9185–9189.

    Article  PubMed  CAS  Google Scholar 

  63. Liang J, Zubovitz J, Petrocelli T, et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 2002; 8:1153–1160.

    Article  PubMed  CAS  Google Scholar 

  64. Shin I, Yakes FM, Rojo F, et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 2002; 8:1145–1152.

    Article  PubMed  CAS  Google Scholar 

  65. Viglietto G, Motti ML, Bruni P, et al. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 2002; 8:1136–1144.

    Article  PubMed  CAS  Google Scholar 

  66. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localisation. Genes Dev 1998; 12:3499–3511.

    PubMed  CAS  Google Scholar 

  67. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 2000; 14:2501–2514.

    Article  PubMed  CAS  Google Scholar 

  68. Burgering BM, Medema RH. Decisions on life and death: FOXO forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol 2003; 73:689–701.

    Article  PubMed  CAS  Google Scholar 

  69. Dudek H, Datta SR, Franke TF, et al. Regulation of neuronal survival by the serine-threonine kinase Akt. Science 1997; 275:661–665.

    Article  PubMed  CAS  Google Scholar 

  70. Philpott KL, McCarthy MJ, Klippel A, Rubin LL. Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons. J Cell Biol 1997; 139:809–815.

    Article  PubMed  CAS  Google Scholar 

  71. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91:231–241.

    Article  PubMed  CAS  Google Scholar 

  72. Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282:1318–1321.

    Article  PubMed  CAS  Google Scholar 

  73. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 1999; 96:857–868.

    Article  PubMed  CAS  Google Scholar 

  74. Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem Sci 2002; 27:462–467.

    Article  PubMed  CAS  Google Scholar 

  75. Fingar DC, Salama S, Tsou C, Harlow E, Blenis J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 2002; 16: 1472–1487.

    Article  PubMed  CAS  Google Scholar 

  76. Manning BD, Cantley LC. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem Soc Trans 2003; 31:573–578.

    Article  PubMed  CAS  Google Scholar 

  77. Manning BD, Cantley LC. Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 2003; 28:573–576.

    Article  PubMed  CAS  Google Scholar 

  78. Shi Y, Gera J, Hu L, Hsu JH, Bookstein R, Li W, Lichtenstein A. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002; 62:5027–5034.

    PubMed  CAS  Google Scholar 

  79. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 2001; 98:10314–10319.

    Article  PubMed  CAS  Google Scholar 

  80. Wang D, Huang HJ, Kazlauskas A, Cavenee WK. Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res 1999; 59:1464–1472.

    PubMed  CAS  Google Scholar 

  81. Jiang BH, Zheng JZ, Aoki M, Vogt PK. Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc Natl Acad Sci USA 2000; 97:1749–1753.

    Article  PubMed  CAS  Google Scholar 

  82. Rak J, Mitsuhashi Y, Sheenan C, et al. Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in Ras-transformed epithelial cells and fibroblasts. Cancer Res 2000; 60:490–498.

    PubMed  CAS  Google Scholar 

  83. Shiojima I, Walsh K. Role of Akt signalling in vascular homeostasis and angiogenesis. Circ Res 2002; 90:1243–1250.

    Article  PubMed  CAS  Google Scholar 

  84. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/Akt/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000; 60:1541–1545.

    PubMed  CAS  Google Scholar 

  85. Semenza GL. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 2002; 64:993–998.

    Article  PubMed  CAS  Google Scholar 

  86. Giaccia A, Siim B, Johnson RS. HIF-1 as a target for drug development. Nat Rev Drug Discov 2003; 2:803–811.

    Article  PubMed  CAS  Google Scholar 

  87. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 2003; 425:307–311.

    Article  PubMed  CAS  Google Scholar 

  88. Stephens L, Ellson C, Hawkins P. Roles of PI3-Ks in leucocyte chemotaxis and phagocytosis. Curr Opin Cell Biol 2002; 14:203–213.

    Article  PubMed  CAS  Google Scholar 

  89. Bourne HR, Weiner O. A chemical compass. Nature 2002; 419:21.

    Article  PubMed  CAS  Google Scholar 

  90. Price JT, Tiganis T, Agarwal A, Djakiew D, Thompson EW. Epidermal growth factor promotes MDA-MB-231 breast cancer cell migration through a phosphatidylinositol 3′-kinase and phospholipase C-dependent mechanism. Cancer Res 1999; 59:5475–5478.

    PubMed  CAS  Google Scholar 

  91. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410:50–56.

    Article  PubMed  CAS  Google Scholar 

  92. Curnock AP, Sotsios Y, Wright KL, Ward SG. Optimal chemotactic responses of leukemic T cells to stromal cell-derived factor-1 requires the activation of both class IA and IB phosphoinositide 3-kinases. J Immunol 2003; 170(8):4021–4030.

    PubMed  CAS  Google Scholar 

  93. West KA, Castillo S, Dennis PA. Activation of the PI3-K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat 2002; 5:234–248.

    Article  PubMed  CAS  Google Scholar 

  94. Schultz RM, Merriman RL, Andis SL, et al. In-vitro and in-vivo anti-tumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res 1995; 15:1135–1139.

    PubMed  CAS  Google Scholar 

  95. Lemke LE, Paine-Murrieta GD, Taylor CW, Powis G. Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase. Cancer Chemother Pharmacol 1999; 44:491–497.

    Article  PubMed  CAS  Google Scholar 

  96. Boehle AS, Kurdow R, Boenicke L, et al. Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo. Langenbeck’s Arch Surg 2002; 387:234–239.

    Article  Google Scholar 

  97. Hosoi Y, Miyachi H, Matsumoto Y, et al. A phosphatidylinositol 3-kinase inhibitor wortmannin induces radioresistant DNA synthesis and sensitizes cells to bleomycin and ionizing radiation. Int J Cancer 1998; 78:642–647.

    Article  PubMed  CAS  Google Scholar 

  98. Edwards E, Geng L, Tan J, Onishko H, Donnelly E, Hallahan, DE Phosphatidylinositol 3-kinase/Akt signalling in the response of vascular endothelium to ionizing radiation. Cancer Res 2002; 62:4671–4677.

    PubMed  CAS  Google Scholar 

  99. Semba S, Itoh N, Ito M, Harada M, Yamakawa M. The in vitro and in vivo effects of 2-(4-Morpholinyl)-8-phenyl-chromone (LY294002), a specific inhibitor of phosphatidylinositol 3′-kinase, in human colon cancer cells. Clin Cancer Res 2002; 8:1957–1963.

    PubMed  CAS  Google Scholar 

  100. Bondar VM, Sweeney-Gotsch B, Andreeff M, Mills GB, McConkey DJ. Inhibition of the phosphatidylinositol 3′-kinase-Akt pathway induces apoptosis in pancreatic carcinoma cells in vitro and in vivo. Mol Cancer Ther 2002; 1:989–997.

    PubMed  CAS  Google Scholar 

  101. Brognard J, Clark AS, Ni Y, Dennis PA. Akt/protein kinase b is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 2001; 61:3986–3997.

    PubMed  CAS  Google Scholar 

  102. Clark AE, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab and tamoxifen in breast cancer cells. Mol Cancer Ther 2002; 1:707–717.

    PubMed  CAS  Google Scholar 

  103. Gupta AK, Cerniglia GJ, Mick R, et al. Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3-K using LY294002. Int J Radiat Oncol Biol Phys 2003; 56:846–853.

    Article  PubMed  CAS  Google Scholar 

  104. Davies MA, Kim SJ, Parikh NU, Dong Z, Bucana CD, Gallick GE. Adenoviral-mediated expression of MMAC/PTEN inihibits proliferation and metastasis of human prostate cancer cells. Clin Cancer Res 2002; 8:1695–1698.

    Google Scholar 

  105. Saito Y, Swanson X, Mhashikar AM, et al. Adenoviral-mediated transfer of the PTEN gene inihibits human colorectal cancer growth in vitro and in vivo. Gene Ther 2003; 10:1961–1969.

    Article  PubMed  CAS  Google Scholar 

  106. Tanaka M, Grossman HB. In vivo gene therapy of human bladder cancer with PTEN suppresses tumor growth, downregulates phosphorylated Akt, and increases sensitivity to doxorubicin. Gene Ther 2003; 10:1636–1642.

    Article  PubMed  CAS  Google Scholar 

  107. Czauderna F, Fechtner M, Aygun H, et al. Functional studies of the PI(3)-kinase signalling pathway employing synthetic and expressed siRNA. Nucleic Acids Res 2003; 31:670–682.

    Article  PubMed  CAS  Google Scholar 

  108. Czauderna F, Santel A, Hinz M, et al. Inducible shRNA expression for application in a prostate cancer model. Nucleic Acids Res 2003; 31:e127.

    Article  PubMed  CAS  Google Scholar 

  109. Ward S, Sotsios Y, Dowden J, Bruce I, Finan P. Therapeutic potential of PI3-K inhibitors. Chem Biol 2003; 10:207–213.

    Article  PubMed  CAS  Google Scholar 

  110. Fry MJ. Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play? Breast Cancer Res 2001; 3:304–312.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Novartis Horsham Research Centre, Horsham, UK

    Peter M. Finan PhD

  2. Department of Pharmacy and Pharmacology, University of Bath, Bath, UK

    Stephen G. Ward PhD

Authors
  1. Peter M. Finan PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen G. Ward PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Novartis Institutes for BioMedical Research Basel, Novartis Pharma AG, Basel, Switzerland

    Doriano Fabbro PhD

  2. UCSF Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA

    Frank McCormick MD, PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Finan, P.M., Ward, S.G. (2006). PI3-Kinase Inhibition. In: Fabbro, D., McCormick, F. (eds) Protein Tyrosine Kinases. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-962-1:053

Download citation

Publish with us

Policies and ethics

Search

Navigation