This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bondar, V. M. Articles by McConkey, D. J. Search for Related Content PubMed PubMed Citation Articles by Bondar, V. M. Articles by McConkey, D. J.

Departments of Surgical Oncology [V. M. B.], Cancer Biology [V. M. B., B. S-G., D. J. M.], Molecular Hematology [M. A.], and Molecular Therapeutics [G. B. M.], University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030

The phosphatidylinositol 3'-kinase (PI3k)-AKT survival pathway is activated in many malignancies. We observed constitutive AKT phosphorylation (on S473) consistent with pathway activation in seven of nine human pancreatic carcinoma cell lines in vitro. Exposure of the cells to two structurally distinct inhibitors of PI3k (wortmannin and LY294002) resulted in a dose-dependent induction of apoptosis in six of seven of the cell lines that displayed constitutive AKT phosphorylation but not in either of the cell lines that did not. The mitogen-activated protein/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase inhibitor PD98059 also induced apoptosis in two of the cell lines, including one of the LY294002-insensitive lines (AsPC-1). Exposure of orthotopic L3.6pl pancreatic tumors to LY294002 resulted in dose-dependent inhibition of tumor growth, and decreased peritoneal and liver metastases, effects that were associated with an inhibition of AKT phosphorylation and increased terminal deoxynucleotidyl transferase-mediated nick end labeling staining characteristic of apoptosis. Furthermore, a suboptimal dose of LY294002 (25 mg/kg) produced additive inhibition of tumor growth when combined with a suboptimal dose of gemcitabine (62 mg/kg). Together, our results establish that the PI3k/AKT pathway is constitutively activated in a majority of human pancreatic cancer cell lines and establish that the pathway is a promising target for therapeutic intervention.

This article has been cited by other articles:

				S. A. Danovi, H. H. Wong, and N. R. Lemoine Targeted therapies for pancreatic cancer Br. Med. Bull., September 1, 2008; 87(1): 97 - 130. [Abstract] [Full Text] [PDF]

				Y. Woo, K. J. Kelly, M. M. Stanford, C. Galanis, Y. S. Chun, Y. Fong, and G. McFadden Myxoma Virus Is Oncolytic for Human Pancreatic Adenocarcinoma Cells Ann. Surg. Oncol., August 1, 2008; 15(8): 2329 - 2335. [Abstract] [Full Text] [PDF]

				S.-M. Maira, F. Stauffer, J. Brueggen, P. Furet, C. Schnell, C. Fritsch, S. Brachmann, P. Chene, A. De Pover, K. Schoemaker, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity Mol. Cancer Ther., July 1, 2008; 7(7): 1851 - 1863. [Abstract] [Full Text] [PDF]

				M. P. Kim and G. E. Gallick Gemcitabine Resistance in Pancreatic Cancer: Picking the Key Players Clin. Cancer Res., March 1, 2008; 14(5): 1284 - 1285. [Full Text] [PDF]

				S.-S. Liau and E. Whang HMGA1 Is a Molecular Determinant of Chemoresistance to Gemcitabine in Pancreatic Adenocarcinoma Clin. Cancer Res., March 1, 2008; 14(5): 1470 - 1477. [Abstract] [Full Text] [PDF]

				M. Reichert, D. Saur, R. Hamacher, R. M. Schmid, and G. Schneider Phosphoinositide-3-Kinase Signaling Controls S-Phase Kinase-Associated Protein 2 Transcription via E2F1 in Pancreatic Ductal Adenocarcinoma Cells Cancer Res., May 1, 2007; 67(9): 4149 - 4156. [Abstract] [Full Text] [PDF]

				V. Giroux, J. Iovanna, and J.-C. Dagorn Probing the human kinome for kinases involved in pancreatic cancer cell survival and gemcitabine resistance FASEB J, October 1, 2006; 20(12): 1982 - 1991. [Abstract] [Full Text] [PDF]

				E. Giovannetti, V. Mey, S. Nannizzi, G. Pasqualetti, M. Del Tacca, and R. Danesi Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer. Mol. Cancer Ther., June 1, 2006; 5(6): 1387 - 1395. [Abstract] [Full Text] [PDF]

				S.-i. Yaguchi, Y. Fukui, I. Koshimizu, H. Yoshimi, T. Matsuno, H. Gouda, S. Hirono, K. Yamazaki, and T. Yamori Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst, April 19, 2006; 98(8): 545 - 556. [Abstract] [Full Text] [PDF]

				T. Ohta, M. Ohmichi, T. Hayasaka, S. Mabuchi, M. Saitoh, J. Kawagoe, K. Takahashi, H. Igarashi, B. Du, M. Doshida, et al. Inhibition of Phosphatidylinositol 3-Kinase Increases Efficacy of Cisplatin in in Vivo Ovarian Cancer Models Endocrinology, April 1, 2006; 147(4): 1761 - 1769. [Abstract] [Full Text] [PDF]

				C. A. Granville, R. M. Memmott, J. J. Gills, and P. A. Dennis Handicapping the Race to Develop Inhibitors of the Phosphoinositide 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway Clin. Cancer Res., February 1, 2006; 12(3): 679 - 689. [Abstract] [Full Text] [PDF]

				T. Asano, Y. Yao, S. Shin, J. McCubrey, J. L. Abbruzzese, and S. A.G. Reddy Insulin Receptor Substrate Is a Mediator of Phosphoinositide 3-Kinase Activation in Quiescent Pancreatic Cancer Cells Cancer Res., October 15, 2005; 65(20): 9164 - 9168. [Abstract] [Full Text] [PDF]

				S. Banerjee, Y. Zhang, S. Ali, M. Bhuiyan, Z. Wang, P. J. Chiao, P. A. Philip, J. Abbruzzese, and F. H. Sarkar Molecular Evidence for Increased Antitumor Activity of Gemcitabine by Genistein In vitro and In vivo Using an Orthotopic Model of Pancreatic Cancer Cancer Res., October 1, 2005; 65(19): 9064 - 9072. [Abstract] [Full Text] [PDF]

				T. B. Brunner, K. A. Cengel, S. M. Hahn, J. Wu, D. L. Fraker, W. G. McKenna, and E. J. Bernhard Pancreatic Cancer Cell Radiation Survival and Prenyltransferase Inhibition: The Role of K-Ras Cancer Res., September 15, 2005; 65(18): 8433 - 8441. [Abstract] [Full Text] [PDF]

				I.-A. Kim, S.-S. Bae, A. Fernandes, J. Wu, R. J. Muschel, W. G. McKenna, M. J. Birnbaum, and E. J. Bernhard Selective Inhibition of Ras, Phosphoinositide 3 Kinase, and Akt Isoforms Increases the Radiosensitivity of Human Carcinoma Cell Lines Cancer Res., September 1, 2005; 65(17): 7902 - 7910. [Abstract] [Full Text] [PDF]

				Y. Luo, A. R. Shoemaker, X. Liu, K. W. Woods, S. A. Thomas, R. de Jong, E. K. Han, T. Li, V. S. Stoll, J. A. Powlas, et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo Mol. Cancer Ther., June 1, 2005; 4(6): 977 - 986. [Abstract] [Full Text] [PDF]

				V. Pinho, D. G. Souza, M. M. Barsante, F. P. Hamer, M. S. De Freitas, A. G. Rossi, and M. M. Teixeira Phosphoinositide-3 kinases critically regulate the recruitment and survival of eosinophils in vivo: importance for the resolution of allergic inflammation J. Leukoc. Biol., May 1, 2005; 77(5): 800 - 810. [Abstract] [Full Text] [PDF]

				M. S. Duxbury, H. Ito, E. Benoit, T. Waseem, S. W. Ashley, and E. E. Whang RNA Interference Demonstrates a Novel Role for Integrin-Linked Kinase as a Determinant of Pancreatic Adenocarcinoma Cell Gemcitabine Chemoresistance Clin. Cancer Res., May 1, 2005; 11(9): 3433 - 3438. [Abstract] [Full Text] [PDF]

				V Stoll, V Calleja, G Vassaux, J Downward, and N R Lemoine Dominant negative inhibitors of signalling through the phosphoinositol 3-kinase pathway for gene therapy of pancreatic cancer Gut, January 1, 2005; 54(1): 109 - 116. [Abstract] [Full Text] [PDF]

				N. T. Ihle, R. Williams, S. Chow, W. Chew, M. I. Berggren, G. Paine-Murrieta, D. J. Minion, R. J. Halter, P. Wipf, R. Abraham, et al. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling Mol. Cancer Ther., July 1, 2004; 3(7): 763 - 772. [Abstract] [Full Text] [PDF]

				M. S. Duxbury, H. Ito, E. Benoit, T. Waseem, S. W. Ashley, and E. E. Whang A Novel Role for Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6 as a Determinant of Gemcitabine Chemoresistance in Pancreatic Adenocarcinoma Cells Cancer Res., June 1, 2004; 64(11): 3987 - 3993. [Abstract] [Full Text] [PDF]

				M. Esfandiarei, H. Luo, B. Yanagawa, A. Suarez, D. Dabiri, J. Zhang, and B. M. McManus Protein Kinase B/Akt Regulates Coxsackievirus B3 Replication through a Mechanism Which Is Not Caspase Dependent J. Virol., April 15, 2004; 78(8): 4289 - 4298. [Abstract] [Full Text] [PDF]

				S. S. Castillo, J. Brognard, P. A. Petukhov, C. Zhang, J. Tsurutani, C. A. Granville, M. Li, M. Jung, K. A. West, J. G. Gills, et al. Preferential Inhibition of Akt and Killing of Akt-Dependent Cancer Cells by Rationally Designed Phosphatidylinositol Ether Lipid Analogues Cancer Res., April 15, 2004; 64(8): 2782 - 2792. [Abstract] [Full Text] [PDF]

				S. Yamamoto, Y. Tomita, Y. Hoshida, T. Morooka, H. Nagano, K. Dono, K. Umeshita, M. Sakon, O. Ishikawa, H. Ohigashi, et al. Prognostic Significance of Activated Akt Expression in Pancreatic Ductal Adenocarcinoma Clin. Cancer Res., April 15, 2004; 10(8): 2846 - 2850. [Abstract] [Full Text] [PDF]

				K. Yokoi and I. J. Fidler Hypoxia Increases Resistance of Human Pancreatic Cancer Cells to Apoptosis Induced by Gemcitabine Clin. Cancer Res., April 1, 2004; 10(7): 2299 - 2306. [Abstract] [Full Text] [PDF]

				M. S. Duxbury, H. Ito, M. J. Zinner, S. W. Ashley, and E. E. Whang Inhibition of Src Tyrosine Kinase Impairs Inherent and Acquired Gemcitabine Resistance in Human Pancreatic Adenocarcinoma Cells Clin. Cancer Res., April 1, 2004; 10(7): 2307 - 2318. [Abstract] [Full Text] [PDF]