JNCI Journal of the National Cancer Institute 2005 97(17):1272-1286; doi:10.1093/jnci/dji251
© 2005 Oxford University Press
Hypoxia-inducible Factor 1
and Antiangiogenic Activity of Farnesyltransferase Inhibitor SCH66336 in Human Aerodigestive Tract Cancer
Ji-Youn Han,
Seung Hyun Oh,
Floriana Morgillo,
Jeffrey N. Myers,
Edward Kim,
Waun Ki Hong,
Ho-Young Lee
Affiliation of authors: Department of Thoracic/Head and Neck Medical Oncology (J-YH, SHO, FM, EK, WKH, H-OL), Department of Head and Neck Surgery (JNM), The University of Texas M. D. Anderson Cancer Center, Houston, TX
Correspondence to: Ho-Young Lee, PhD, Unit 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: The farnesyltransferase inhibitor SCH66336, in combination with other receptor tyrosine kinase inhibitors, inhibits the growth of non–small-cell lung cancer (NSCLC) cells. We examined whether SCH66336 inhibits angiogenesis of aerodigestive tract cancer cells. Methods: Antiangiogenic activities of SCH66336 against NSCLC, head and neck squamous cell carcinoma (HNSCC), and endothelial cells were examined with cell proliferation, capillary tube formation, and chick aorta (under hypoxic, normoxic, insulin-like growth factor I (IGF)–stimulated, and unstimulated conditions); reverse transcription–polymerase chain reaction; and western blot analyses. The specific roles of the ubiquitin-mediated proteasome machinery, mitogen-activated protein kinase (MAPK) and Akt pathways, and heat shock protein 90 (Hsp90) in the SCH66336-mediated degradation of hypoxia-inducible factor 1
(HIF-1) were assessed with ubiquitin inhibitors and adenoviral vectors that express constitutively active MAP kinase kinase (MEK)1, constitutively active Akt, or Hsp90. Results: SCH66336 showed antiangiogenic activities and decreased the expression of vascular endothelial cell growth factor (VEGF) and HIF-1 in hypoxic, IGF-stimulated, and unstimulated aerodigestive tract cancer and endothelial cells. SCH66336 reduced the half-life of the HIF-1 protein, and ubiquitin inhibitors protected the hypoxia- or IGF-stimulated HIF-1 protein from SCH66336-mediated degradation. SCH66336 inhibited the interaction between HIF-1 and Hsp90. The overexpression of Hsp90, but not constitutive Akt or constitutive MEK, restored HIF-1 expression in IGF-stimulated or hypoxic cells but not in unstimulated cells. Conclusions: SCH66336 appears to inhibit angiogenic activities of NSCLC and HNSCC cells by decreasing hypoxia- or IGF-stimulated HIF-1 expression and to inhibit VEGF production by inhibiting the interaction between HIF-1 and Hsp90, resulting in the proteasomal degradation of HIF-1.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
|
|
 
W.-Y. Kim, Q. Jin, S.-H. Oh, E. S. Kim, Y. J. Yang, D. H. Lee, L. Feng, C. Behrens, L. Prudkin, Y. E. Miller, et al.
Elevated Epithelial Insulin-like Growth Factor Expression Is a Risk Factor for Lung Cancer Development
Cancer Res.,
September 15, 2009;
69(18):
7439 - 7448.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Mori, C. Moser, S. A. Lang, C. Hackl, E. Gottfried, M. Kreutz, H. J. Schlitt, E. K. Geissler, and O. Stoeltzing
Up-Regulation of Kruppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1{beta} Signaling and Hypoxia-Inducible Factor-1{alpha}
Mol. Cancer Res.,
August 1, 2009;
7(8):
1390 - 1398.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Sparano, S. Moulder, A. Kazi, D. Coppola, A. Negassa, L. Vahdat, T. Li, C. Pellegrino, S. Fineberg, P. Munster, et al.
Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer
Clin. Cancer Res.,
April 15, 2009;
15(8):
2942 - 2948.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.-Y. Kim, S. H. Oh, J.-K. Woo, W. K. Hong, and H.-Y. Lee
Targeting Heat Shock Protein 90 Overrides the Resistance of Lung Cancer Cells by Blocking Radiation-Induced Stabilization of Hypoxia-Inducible Factor-1{alpha}
Cancer Res.,
February 15, 2009;
69(4):
1624 - 1632.
[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]
|
|
|
|
|
|
|
K. Takata, K.-i. Morishige, T. Takahashi, K. Hashimoto, S. Tsutsumi, L. Yin, T. Ohta, J. Kawagoe, K. Takahashi, and H. Kurachi
Fasudil-induced hypoxia-inducible factor-1{alpha} degradation disrupts a hypoxia-driven vascular endothelial growth factor autocrine mechanism in endothelial cells
Mol. Cancer Ther.,
June 1, 2008;
7(6):
1551 - 1561.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. H. Oh, Q. Jin, E. S. Kim, F. R. Khuri, and H.-Y. Lee
Insulin-like Growth Factor-I Receptor Signaling Pathway Induces Resistance to the Apoptotic Activities of SCH66336 (Lonafarnib) through Akt/Mammalian Target of Rapamycin-Mediated Increases in Survivin Expression
Clin. Cancer Res.,
March 1, 2008;
14(5):
1581 - 1589.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Rapisarda and G. Melillo
HIF-1 Inhibitors: Novel Opportunities for Cancer Therapy
ASCO Educational Book,
January 1, 2008;
2008(1):
543 - 547.
[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]
|
|
|
|
|
|
|
M. W. Kieran, R. J. Packer, A. Onar, S. M. Blaney, P. Phillips, I. F. Pollack, J. R. Geyer, S. Gururangan, A. Banerjee, S. Goldman, et al.
Phase I and Pharmacokinetic Study of the Oral Farnesyltransferase Inhibitor Lonafarnib Administered Twice Daily to Pediatric Patients With Advanced Central Nervous System Tumors Using a Modified Continuous Reassessment Method: A Pediatric Brain Tumor Consortium Study
J. Clin. Oncol.,
July 20, 2007;
25(21):
3137 - 3143.
[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]
|
|
|
|
|
|
|
K S Kimbro and J W Simons
Hypoxia-inducible factor-1 in human breast and prostate cancer.
Endocr. Relat. Cancer,
September 1, 2006;
13(3):
739 - 749.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Melillo
Inhibiting Hypoxia-Inducible Factor 1 for Cancer Therapy
Mol. Cancer Res.,
September 1, 2006;
4(9):
601 - 605.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Sparano, S. Moulder, A. Kazi, L. Vahdat, T. Li, C. Pellegrino, P. Munster, M. Malafa, D. Lee, S. Hoschander, et al.
Targeted Inhibition of Farnesyltransferase in Locally Advanced Breast Cancer: A Phase I and II Trial of Tipifarnib Plus Dose-Dense Doxorubicin and Cyclophosphamide
J. Clin. Oncol.,
July 1, 2006;
24(19):
3013 - 3018.
[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]
|
|
|
