Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling

Molecular Cancer Therapeutics

Volumn 3, Issue 7, 2004, Pages 763-772

  Ihle, Nathan T ^a   Williams, Ryan ^a   Chow, Sherry ^a   Chew, Wade ^a   Berggren, Margareta I ^a   Paine Mrrieta, Gillian ^a   Minion, Daniel J ^b   Halter, Robert J ^b   Wipf, Peter ^b   Abraham, Robert ^c   Kirkpatrick, Lynn ^d   Powis, Garth ^a  

^a UNIVERSITY OF ARIZONA   (United States)

^b UNIVERSITY OF PITTSBURGH   (United States)

^c BURNHAM INSTITUTE   (United States)

^d Biomira Inc   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

CISPLATIN; DRUG METABOLITE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHOSERINE; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN KINASE B; PX 866; PX 867; PX 868; PX 870; PX 871; PX 880; PX 881; PX 882; PX 889; PX 890; UNCLASSIFIED DRUG; WORTMANNIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL; CANCER RADIOTHERAPY; COLON CANCER; CONCENTRATION RESPONSE; CONTROLLED STUDY; CYTOTOXICITY; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG ELIMINATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENTIATION; DRUG STRUCTURE; ENZYME INHIBITION; ENZYME PURIFICATION; FIRST PASS EFFECT; HUMAN; HUMAN CELL; IC 50; IMMUNE DEFICIENCY; IN VIVO STUDY; LIVER TOXICITY; LUNG CANCER; MALE; MAXIMUM TOLERATED DOSE; MOUSE; NONHUMAN; OVARY CANCER; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; TUMOR XENOGRAFT;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANDROSTADIENES; ANDROSTENES; ANIMALS; ANTIBODIES, PHOSPHO-SPECIFIC; ANTINEOPLASTIC AGENTS; BACTERIOCINS; CELL LINE, TUMOR; CISPLATIN; COLONIC NEOPLASMS; ENZYME INHIBITORS; FEMALE; GONANES; HUMANS; LUNG NEOPLASMS; MICE; MICE, SCID; OVARIAN NEOPLASMS; PROTEIN-SERINE-THREONINE KINASES; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-AKT; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 4444223702     PISSN: 15357163     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (48)

1. Cantley LC. The phosphoinositide-3-kinase pathway. Science 2000; 296:1655-7.
2. Van Haesebroeck B, Waterfield MD. Signaling by distinct classes of phosphoinositide-kinases. Exp Cell Res 1999;253:239-54.
3. Stein RC. Prospects for phosphoinositide-3-kinase inhibition as a cancer treatment. Endocr Relat Cancer 2001;8:237-48.
4. Carpenter CL, Cantley LC. Phosphoinositide kinases. Biochemistry 1990;29:11147-55.
5. ras with phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 1991; 88:7908-47.
6. Laffargue M, Calvez R, Finan P, et al. Phosphoinositide-3-kinase γ is an essential amplifier of mast cell function. Immunity 2002;16:441-51.
7. Abraham RT. Phosphatidylinositol-3-kinase related kinases. Curr Opin Immunol 1996;8:412-8.
8. Jimenez C, Jones DR, Rodriguez-Viciana P, et al. Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide-3-kinase. EMBO J 1998;17:743-53.
9. Moore SM, Rintoul RC, Walker TR, Chilvers ER, Haslett C, Sethi T. The presence of a constitutively active phosphoinositide-3-kinase in small cell lung cancer cells mediates anchorage-independent proliferation via a protein kinase B and p70s6k-dependent pathway. Cancer Res 1998; 58:5239-47.
10. Shayesteh L, Lu Y, Kuo WL, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 1999;21:99-102.
11. Toker A, Cantley LC. Signaling through the lipid products of phosphoinositide-3-OH kinase. Nature 1997;387:673-6.
12. Lin J, Adam RM, Santiestevan E, Freeman MR. The phosphatidylinositol-3′-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells. Cancer Res 1999; 59:2891-7.
13. Marte BM, Downward J. PKB/Akt: connecting phosphoinositide-3-kinase to cell survival and beyond. Trends Biochem Sci 1997;22:355-8.
14. Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol-3-kinase activation. Biochem J 1998;335:1-13.
15. Alessi DR, Cohen P. Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev 1998;8:55-62.
16. Alessi DR, Andjelkovic M, Caudwell B, et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 1996;15:6541-51.
17. Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr Biol 1997;7:261-9.
18. Meier R, Alessi DR, Cron P, Andjelkovic M, Hemmings BA. Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bβ. J Biol Chem 1997;272:30491-7.
19. Nicholson KM, Anderson NG. The protein kinase B/Akt signaling pathway in human malignancy. Cell Signal 2002;14:381-95.
20. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91:231-41.
21. Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 2001;21:893-901.
22. Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998;282:1318-21.
23. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-κB activation by tumor necrosis factor requires the Akt serine-threonine kinase. Nature 1999;401:82-5.
24. Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 1998;273:32377-9.
25. Bellacosa A, de Feo D, Godwin AK, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 1995;64: 280-5.
26. Cheng JQ, Ruggeri B, Klein WM, et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 1996;93:3636-41.
27. Nakatani K, Thompson DA, Barthel A, et al. Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J Biol Chem 1999;274:21525-32.
28. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4, 5-trisphosphate. J Biol Chem 1998;273:13375-8.
29. Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide-3-kinase/Akt pathway. Proc Natl Acad Sci USA 1998;95:15587-91.
30. Cantley L, Neel BG. New insights into tumor suppression: PTEN suppress tumor formation by restraining the phosphoinositide-3-kinase/AKT pathways. Proc Natl Acad Sci USA 1999;96:4240-5.
31. Powis G, Bonjouklian R, Berggren MM, et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 1994;54:2419-23.
32. Wymann MP, Bulgarelli-Ieva 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;16:1722-33.
33. Walker EH, Williams RL. Structural determinants of phosphoinositide-3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 2000;6:909-19.
34. Schultz RM, Merriman RL, Andis SL, et al. In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res 1995;15:1135-40.
35. Paine GD, Taylor CW, Curtis RA, et al. Human tumor models in the severe combined immune deficient scid mouse. Cancer Chemother Pharmacol 1997;40:209-14.
36. Teicher B. In vivo tumor response end points. In: Teicher BA, editor. Tumor models in cancer research. Totowa: Humana Press, Inc.; 2002. p. 593-616.
37. Snedecor GW, Cochran WG. The comparison of two samples. In: Statistical methods. 6th ed. Ames (IA): Iowa State University; 1967. p. 91-119.
38. Wymann MP, Zvelebil M, Laffargue M. Phosphoinositide-3-kinase signaling-which way to target? Trends Pharmacol Sci 2003;24:366-9.
39. Berrie CP. Phosphoinositide-3-kinase inhibition in cancer treatment. Exp Opin Invest Drugs 2001;10:1085-98.
40. 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;1:989-97.
41. Su JD, Mayo LD, Donner DB, Durden DL. PTEN and phosphatidylinositol-3-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment. Cancer Res 2003;63:3585-92.
42. Bonomi P. Clinical studies with non-Iressa EGFR tyrosine kinase inhibitors. Lung Cancer 2003;41:S43-8.
43. Drevs J, Medinger M, Schmidt-Gersbach C, Weber R, Unger C. Receptor tyrosine kinases: the main targets for new anticancer therapy. Curr Drug Targets 2003;4:113-21.
44. Ng S, Tsao MS, Chow S, Hadley DW. Inhibition of phosphatidylinositide-3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res 2003;60:5451-5.
45. 2-M delay. Clin Cancer Res 1997;3: 1149-56.
46. Ng S, Tsao MS, Nicklee T, Hedley D. Wortmannin Inhibits PKB/Akt Phosphorylation and promotes Gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin Cancer Res 2001;7:3269-75.
47. Edwards E, Geng L, Tan J, Onishko H, Donnelly E, Hallahan DE. Phosphatidylinositol-3-kinase/AKT signaling in the response of vascular endothelium to ionizing radiation. Cancer Res 2002;62:4671-7.
48. Sarkaria JN, Tibbets RS, Busby EC, Kennedy AP, Hill DE, Abraham RT. Inhibition of phosphoinositide-3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res 1998;58:4375-82.