© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 4, 291-302,
February 19, 2003
© 2003 Oxford University Press
ARTICLE |
Effects of Deguelin on the Phosphatidylinositol 3-Kinase/Akt Pathway and Apoptosis in Premalignant Human Bronchial Epithelial Cells
Affiliations of authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston; J. W. Kosmeder II, J. M. Pezzuto, College of Pharmacy, Department of Medicinal Chemistry and Pharmacognosy, Program for Collaborative Research in the Pharmaceutical Sciences, University of Illinois at Chicago.
Correspondence to: Ho-Young Lee, Ph.D., Box 432, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: hlee{at}mdanderson.org).
Background: Because lung cancer is the leading cause of cancer-related death, new approaches for preventing and controlling the disease are needed. Chemoprevention approaches are both feasible and effective. We evaluated the potential of deguelin, a natural plant product, as a lung cancer chemopreventive agent and investigated its mechanism of action. Methods: The effects of deguelin on proliferation and apoptosis of normal, premalignant, and malignant human bronchial epithelial (HBE) cells were assessed by using the MTT assay, a flow cytometry-based TUNEL assay, and western blot analyses. The effects of deguelin on the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways were assessed by western blot analyses and with adenoviral vectors that expressed constitutively active Akt. Results: Deguelin treatment in vitro at doses attainable in vivo inhibited the growth of and induced apoptosis of premalignant and malignant HBE cells but had minimal effects on normal HBE cells. Levels of phosphorylated Akt (pAkt) were higher in premalignant HBE cells than in normal HBE cells. In premalignant HBE cells, deguelin inhibited PI3K activity and reduced pAkt levels and activity but had mimimal effects on the MAPK pathway. Although overexpression of a constitutively active Akt in premalignant and malignant HBE cells had no effect on growth inhibition mediated by N-(4-hydroxyphenyl)retinamide (4-HPR), a novel chemopreventive retinoid, it blocked deguelin-induced growth arrest and apoptosis. Conclusions: The ability of deguelin to inhibit PI3K/Akt-mediated signaling pathways may contribute to the potency and specificity of this pro-apoptotic drug. Because both premalignant and malignant HBE cells are more sensitive to deguelin than normal HBE cells, deguelin may have potential as both a chemopreventive agent for early stages of lung carcinogenesis and a therapeutic agent against lung cancer.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. R. Fay, V. Steele, and J. A. Crowell Energy Homeostasis and Cancer Prevention: The AMP-Activated Protein Kinase Cancer Prevention Research, April 1, 2009; 2(4): 301 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Woo, D. S. Choi, H. T. Tran, B. E. Gilbert, W. K. Hong, and H.-Y. Lee Liposomal Encapsulation of Deguelin: Evidence for Enhanced Antitumor Activity in Tobacco Carcinogen-Induced and Oncogenic K-ras-Induced Lung Tumorigenesis Cancer Prevention Research, April 1, 2009; 2(4): 361 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-Y. Kim, D. J. Chang, B. Hennessy, H. J. Kang, J. Yoo, S.-H. Han, Y.-S. Kim, H.-J. Park, S.-Y. Geo, G. Mills, et al. A Novel Derivative of the Natural Agent Deguelin for Cancer Chemoprevention and Therapy Cancer Prevention Research, December 1, 2008; 1(7): 577 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Jin, D. G. Menter, L. Mao, W. K. Hong, and H.-Y. Lee Survivin expression in normal human bronchial epithelial cells: an early and critical step in tumorigenesis induced by tobacco exposure Carcinogenesis, August 1, 2008; 29(8): 1614 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Johnson, M. B. Lai, J. C. K. Lai, and A. Bhushan Inhibition of Cell Proliferation and MAP Kinase and Akt Pathways in Oral Squamous cell Carcinoma by Genistein and Biochanin A Evid. Based Complement. Altern. Med., February 29, 2008; (2008) nen011v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Kim, J. H. Kim, Y. S. Yu, K. H. Park, H. J. Kang, H.-Y. Lee, and K.-W. Kim Antiangiogenic Effect of Deguelin on Choroidal Neovascularization J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 643 - 647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Jin, L. Feng, C. Behrens, B. N. Bekele, I. I. Wistuba, W.-K. Hong, and H.-Y. Lee Implication of AMP-Activated Protein Kinase and Akt-Regulated Survivin in Lung Cancer Chemopreventive Activities of Deguelin Cancer Res., December 15, 2007; 67(24): 11630 - 11639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Li, V. Chandrakanthan, M. L Day, and C. O'Neill Direct Evidence for the Action of Phosphatidylinositol (3,4,5)-Trisphosphate-Mediated Signal Transduction in the 2-Cell Mouse Embryo Biol Reprod, November 1, 2007; 77(5): 813 - 821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Crowell, V. E. Steele, and J. R. Fay Targeting the AKT protein kinase for cancer chemoprevention Mol. Cancer Ther., August 1, 2007; 6(8): 2139 - 2148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Kopelovich, J. R. Fay, C. C. Sigman, and J. A. Crowell The Mammalian Target of Rapamycin Pathway as a Potential Target for Cancer Chemoprevention Cancer Epidemiol. Biomarkers Prev., July 1, 2007; 16(7): 1330 - 1340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Oh, J. K. Woo, Y. D. Yazici, J. N. Myers, W.-Y. Kim, Q. Jin, S. S. Hong, H.-J. Park, Y.-G. Suh, K.-W. Kim, et al. Structural Basis for Depletion of Heat Shock Protein 90 Client Proteins by Deguelin J Natl Cancer Inst, June 20, 2007; 99(12): 949 - 961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Morgillo, W.-Y. Kim, E. S. Kim, F. Ciardiello, W. K. Hong, and H.-Y. Lee Implication of the Insulin-like Growth Factor-IR Pathway in the Resistance of Non small Cell Lung Cancer Cells to Treatment with Gefitinib Clin. Cancer Res., May 1, 2007; 13(9): 2795 - 2803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bogush, S. Pedrini, J. Pelta-Heller, T. Chan, Q. Yang, Z. Mao, E. Sluzas, T. Gieringer, and M. E. Ehrlich AKT and CDK5/p35 Mediate Brain-derived Neurotrophic Factor Induction of DARPP-32 in Medium Size Spiny Neurons in Vitro J. Biol. Chem., March 9, 2007; 282(10): 7352 - 7359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Dell'Eva, C. Ambrosini, S. Minghelli, D. M. Noonan, A. Albini, and N. Ferrari The Akt inhibitor deguelin, is an angiopreventive agent also acting on the NF-{kappa}B pathway Carcinogenesis, February 1, 2007; 28(2): 404 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-H. Peng, P. Karna, R. M. O'Regan, X. Liu, R. Naithani, R. M. Moriarty, W. C. Wood, H.-Y. Lee, and L. Yang Down-Regulation of Inhibitor of Apoptosis Proteins by Deguelin Selectively Induces Apoptosis in Breast Cancer Cells Mol. Pharmacol., January 1, 2007; 71(1): 101 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Shen, C. Behrens, I. I. Wistuba, L. Feng, J. J. Lee, W. K. Hong, and R. Lotan Identification and Validation of Differences in Protein Levels in Normal, Premalignant, and Malignant Lung Cells and Tissues Using High-Throughput Western Array and Immunohistochemistry Cancer Res., December 1, 2006; 66(23): 11194 - 11206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-C. Lin, C.-T. Shun, M.-S. Wu, and C.-C. Chen A Novel Anticancer Effect of Thalidomide: Inhibition of Intercellular Adhesion Molecule-1-Mediated Cell Invasion and Metastasis through Suppression of Nuclear Factor-{kappa}B Clin. Cancer Res., December 1, 2006; 12(23): 7165 - 7173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Cunningham, S. C. Artim, C. M. Fornadel, M. C. Sellars, S. G. Edmonson, G. Scott, F. Albino, A. Mathur, and J. A. Punt Immature CD4+CD8+ Thymocytes and Mature T Cells Regulate Nur77 Distinctly in Response to TCR Stimulation J. Immunol., November 15, 2006; 177(10): 6660 - 6666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Morgillo, J. K. Woo, E. S. Kim, W. K. Hong, and H.-Y. Lee Heterodimerization of Insulin-like Growth Factor Receptor/Epidermal Growth Factor Receptor and Induction of Survivin Expression Counteract the Antitumor Action of Erlotinib. Cancer Res., October 15, 2006; 66(20): 10100 - 10111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Nair, S. Shishodia, K. S. Ahn, A. B. Kunnumakkara, G. Sethi, and B. B. Aggarwal Deguelin, an Akt Inhibitor, Suppresses I{kappa}B{alpha} Kinase Activation Leading to Suppression of NF-{kappa}B-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion J. Immunol., October 15, 2006; 177(8): 5612 - 5622. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Schroeder, H. Kadara, D. Lotan, J. K. Woo, H.-Y. Lee, W. K. Hong, and R. Lotan Involvement of Mitochondrial and Akt Signaling Pathways in Augmented Apoptosis Induced by a Combination of Low Doses of Celecoxib and N-(4-Hydroxyphenyl) Retinamide in Premalignant Human Bronchial Epithelial Cells Cancer Res., October 1, 2006; 66(19): 9762 - 9770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Ogunwobi, G. Mutungi, and I. L. P. Beales Leptin Stimulates Proliferation and Inhibits Apoptosis in Barrett's Esophageal Adenocarcinoma Cells by Cyclooxygenase-2-Dependent, Prostaglandin-E2-Mediated Transactivation of the Epidermal Growth Factor Receptor and c-Jun NH2-Terminal Kinase Activation Endocrinology, September 1, 2006; 147(9): 4505 - 4516. [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]
|
|
|
|
|
|
S.-H. Oh, W.-Y. Kim, J.-H. Kim, M. N. Younes, A. K. El-Naggar, J. N. Myers, M. Kies, P. Cohen, F. Khuri, W. K. Hong, et al. Identification of Insulin-Like Growth Factor Binding Protein-3 as a Farnesyl Transferase Inhibitor SCH66336-Induced Negative Regulator of Angiogenesis in Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., January 15, 2006; 12(2): 653 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Suzuki, Y. Daigo, N. Ishikawa, T. Kato, S. Hayama, T. Ito, E. Tsuchiya, and Y. Nakamura ANLN Plays a Critical Role in Human Lung Carcinogenesis through the Activation of RHOA and by Involvement in the Phosphoinositide 3-Kinase/AKT Pathway Cancer Res., December 15, 2005; 65(24): 11314 - 11325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-Y. Lee, S.-H. Oh, J. K. Woo, W.-Y. Kim, C. S. Van Pelt, R. E. Price, D. Cody, H. Tran, J. M. Pezzuto, R. M. Moriarty, et al. Chemopreventive Effects of Deguelin, a Novel Akt Inhibitor, on Tobacco-Induced Lung Tumorigenesis J Natl Cancer Inst, November 16, 2005; 97(22): 1695 - 1699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Katsanakis and T. S. Pillay Cross-talk between the Two Divergent Insulin Signaling Pathways Is Revealed by the Protein Kinase B (Akt)-mediated Phosphorylation of Adapter Protein APS on Serine 588 J. Biol. Chem., November 11, 2005; 280(45): 37827 - 37832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Han, S. H. Oh, F. Morgillo, J. N. Myers, E. Kim, W. K. Hong, and H.-Y. Lee Hypoxia-inducible Factor 1{alpha} and Antiangiogenic Activity of Farnesyltransferase Inhibitor SCH66336 in Human Aerodigestive Tract Cancer J Natl Cancer Inst, September 7, 2005; 97(17): 1272 - 1286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-Z. Liu, J. Fang, Q. Zhou, X. Hu, X. Shi, and B.-H. Jiang Apigenin Inhibits Expression of Vascular Endothelial Growth Factor and Angiogenesis in Human Lung Cancer Cells: Implication of Chemoprevention of Lung Cancer Mol. Pharmacol., September 1, 2005; 68(3): 635 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-Y. Lee, S.-H. Oh, Y.-A. Suh, J. H. Baek, V. Papadimitrakopoulou, S. Huang, and W. K. Hong Response of Non-Small Cell Lung Cancer Cells to the Inhibitors of Phosphatidylinositol 3-Kinase/Akt- and MAPK Kinase 4/c-Jun NH2-Terminal Kinase Pathways: An Effective Therapeutic Strategy for Lung Cancer Clin. Cancer Res., August 15, 2005; 11(16): 6065 - 6074. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. R. Hirsch and S. M. Lippman Advances in the Biology of Lung Cancer Chemoprevention J. Clin. Oncol., May 10, 2005; 23(14): 3186 - 3197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Shah, W. A. Swain, D. Richardson, J. Edwards, D. J. Stewart, C. M. Richardson, D. E.B. Swinson, D. Patel, J. L. Jones, and K. J. O'Byrne Phospho-Akt Expression Is Associated with a Favorable Outcome in Non-Small Cell Lung Cancer Clin. Cancer Res., April 15, 2005; 11(8): 2930 - 2936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Ethier, E. Cappelluti, and J. M. Madison Mechanisms of Interleukin-4 Effects on Calcium Signaling in Airway Smooth Muscle Cells J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 127 - 133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Connelly, M. Madhani, and A. J. Hobbs Resistance to Endotoxic Shock in Endothelial Nitric-oxide Synthase (eNOS) Knock-out Mice: A PRO-INFLAMMATORY ROLE FOR eNOS-DERIVED NO IN VIVO J. Biol. Chem., March 18, 2005; 280(11): 10040 - 10046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kempna, E. Reiter, M. Arock, A. Azzi, and J.-M. Zingg Inhibition of HMC-1 Mast Cell Proliferation by Vitamin E: INVOLVEMENT OF THE PROTEIN KINASE B PATHWAY J. Biol. Chem., December 3, 2004; 279(49): 50700 - 50709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. P. Massion, P. M. Taflan, Y. Shyr, S. M. J. Rahman, P. Yildiz, B. Shakthour, M. E. Edgerton, M. Ninan, J. J. Andersen, and A. L. Gonzalez Early Involvement of the Phosphatidylinositol 3-Kinase/Akt Pathway in Lung Cancer Progression Am. J. Respir. Crit. Care Med., November 15, 2004; 170(10): 1088 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. R. Balsara, J. Pei, Y. Mitsuuchi, R. Page, A. Klein-Szanto, H. Wang, M. Unger, and J. R. Testa Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions Carcinogenesis, November 1, 2004; 25(11): 2053 - 2059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-Y. Lee, H. Moon, K.-H. Chun, Y.-S. Chang, K. Hassan, L. Ji, R. Lotan, F. R. Khuri, and W. K. Hong Effects of Insulin-like Growth Factor Binding Protein-3 and Farnesyltransferase Inhibitor SCH66336 on Akt Expression and Apoptosis in Non-Small-Cell Lung Cancer Cells J Natl Cancer Inst, October 20, 2004; 96(20): 1536 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. David, J. Jett, H. LeBeau, G. Dy, J. Hughes, M. Friedman, and A. R. Brody Phospho-Akt Overexpression in Non-Small Cell Lung Cancer Confers Significant Stage-Independent Survival Disadvantage Clin. Cancer Res., October 15, 2004; 10(20): 6865 - 6871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. V. Scagliotti, G. Selvaggi, S. Novello, and F. R. Hirsch The Biology of Epidermal Growth Factor Receptor in Lung Cancer Clin. Cancer Res., June 15, 2004; 10(12): 4227S - 4232S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-Y. Sun, N. Hail Jr, and R. Lotan Apoptosis as a Novel Target for Cancer Chemoprevention J Natl Cancer Inst, May 5, 2004; 96(9): 662 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Turek-Etienne, M. Lei, J. S. Terracciano, E. F. Langsdorf, R. W. Bryant, R. F. Hart, and A. C. Horan Use of Red-Shifted Dyes in a Fluorescence Polarization AKT Kinase Assay for Detection of Biological Activity in Natural Product Extracts J Biomol Screen, February 1, 2004; 9(1): 52 - 61. [Abstract] [PDF]
|
|
|
|
|
|
H.-Y. Lee, Y.-A. Suh, J. W. Kosmeder, J. M. Pezzuto, W. K. Hong, and J. M. Kurie Deguelin-Induced Inhibition of Cyclooxygenase-2 Expression in Human Bronchial Epithelial Cells Clin. Cancer Res., February 1, 2004; 10(3): 1074 - 1079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. West, I. R. Linnoila, S. A. Belinsky, C. C. Harris, and P. A. Dennis Tobacco Carcinogen-Induced Cellular Transformation Increases Activation of the Phosphatidylinositol 3'-Kinase/Akt Pathway in Vitro and in Vivo Cancer Res., January 15, 2004; 64(2): 446 - 451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Swede, Y. Dong, M. Reid, J. Marshall, and C. Ip Cell Cycle Arrest Biomarkers in Human Lung Cancer Cells After Treatment with Selenium in Culture Cancer Epidemiol. Biomarkers Prev., November 1, 2003; 12(11): 1248 - 1252. [Abstract] [Full Text]
|
|
|
|
|
|
A. L. Sabichi, M.-F. Demierre, E. T. Hawk, C. E. Lerman, and S. M. Lippman Frontiers in Cancer Prevention Research Cancer Res., September 15, 2003; 63(18): 5649 - 5655. [Full Text] [PDF]
|
|
|
|
 |
|
 V. C. Jordan Targeting antihormone resistance in breast cancer: a simple solution Ann. Onc., July 1, 2003; 14(7): 969 - 970. [Full Text] [PDF]
|
|