| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Division of Molecular Pathology, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287
One of the key limiting factors in the treatment of advanced stage human epithelial malignancies is the lack of selective molecular targets for antineoplastic therapy. A substantial subset of human ovarian, endometrial, breast, colorectal, and prostatic cancers exhibit increased endogenous fatty acid biosynthesis and overexpress certain enzymes in the pathway. Cell lines derived from these tumors use endogenously synthesized fatty acids for cellular functions, whereas normal cells and tissues appear to utilize dietary lipids preferentially. We have previously shown that the difference in fatty acid biosynthesis between cancer and normal cells is an exploitable target for metabolic inhibitors in vitro. Here, we report observations in vivo using the i.p. model of the multiply drug-resistant OVCAR-3 human ovarian carcinoma in nude mice which demonstrate that: (a) fatty acid synthase overexpression in OVCAR-3 is comparable to levels in primary human tumors assessed by immunohistochemistry; (b) fatty acid synthetic activity of OVCAR-3 is comparably elevated in vitro and in vivo and is 4 to >20-fold higher than normal murine tissues; (c) treatment with the specific fatty acid synthase inhibitor, cerulenin, markedly reduces tumor cell fatty acid biosynthesis in vivo; (d) fatty acid synthase inhibition produces regression of established ascites tumor; and (e) treatment with cerulenin causes reduction in ascites incidence, delay in onset of ascites, and significantly increased survival (P < 0.04).
1 This work was supported by grants from the American Institute for Cancer Research and the W. W. Smith Charitable Trust. H. H. was supported by a grant from the Susan G. Komen Foundation. E. P. was supported by USPHS Grant T32 AI 07247 and by a grant from the Stetler Research Fund. The abstract was presented at the 1994 AACR Meeting on Novel Strategies Against Resistant Cancers.
2 To whom requests for reprints should be addressed, at Department of Pathology, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Ross 512, Baltimore, MD 21205.
Received 12/19/95. Accepted 1/31/96.
This article has been cited by other articles:
|
|
 |
|
  J. H. Suh, E.-Y. Gong, J. B. Kim, I.-K. Lee, H.-S. Choi, and K. Lee Sterol Regulatory Element-Binding Protein-1c Represses the Transactivation of Androgen Receptor and Androgen-Dependent Growth of Prostatic Cells Mol. Cancer Res., February 1, 2008; 6(2): 314 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. DeBerardinis, A. Mancuso, E. Daikhin, I. Nissim, M. Yudkoff, S. Wehrli, and C. B. Thompson Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis PNAS, December 4, 2007; 104(49): 19345 - 19350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Beckers, S. Organe, L. Timmermans, K. Scheys, A. Peeters, K. Brusselmans, G. Verhoeven, and J. V. Swinnen Chemical Inhibition of Acetyl-CoA Carboxylase Induces Growth Arrest and Cytotoxicity Selectively in Cancer Cells Cancer Res., September 1, 2007; 67(17): 8180 - 8187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Richardson and J. W. Smith Novel antagonists of the thioesterase domain of human fatty acid synthase Mol. Cancer Ther., July 1, 2007; 6(7): 2120 - 2126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhou, W. F. Han, L. E. Landree, J. N. Thupari, M. L. Pinn, T. Bililign, E. K. Kim, A. Vadlamudi, S. M. Medghalchi, R. El Meskini, et al. Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells Cancer Res., April 1, 2007; 67(7): 2964 - 2971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. DeBerardinis, J. J. Lum, and C. B. Thompson Phosphatidylinositol 3-Kinase-dependent Modulation of Carnitine Palmitoyltransferase 1A Expression Regulates Lipid Metabolism during Hematopoietic Cell Growth J. Biol. Chem., December 8, 2006; 281(49): 37372 - 37380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Browne, E. J. Hindmarsh, and J. W. Smith Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor FASEB J, October 1, 2006; 20(12): 2027 - 2035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. B. Kinlaw, J. L. Quinn, W. A. Wells, C. Roser-Jones, and J. T. Moncur Spot 14: A Marker of Aggressive Breast Cancer and a Potential Therapeutic Target Endocrinology, September 1, 2006; 147(9): 4048 - 4055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Lupu and J. A. Menendez Targeting Fatty Acid Synthase in Breast and Endometrial Cancer: An Alternative to Selective Estrogen Receptor Modulators? Endocrinology, September 1, 2006; 147(9): 4056 - 4066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Liu, Y. Shi, V. L. Giranda, and Y. Luo Inhibition of the phosphatidylinositol 3-kinase/Akt pathway sensitizes MDA-MB468 human breast cancer cells to cerulenin-induced apoptosis. Mol. Cancer Ther., March 1, 2006; 5(3): 494 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Brusselmans, E. De Schrijver, G. Verhoeven, and J. V. Swinnen RNA Interference-Mediated Silencing of the Acetyl-CoA-Carboxylase-{alpha} Gene Induces Growth Inhibition and Apoptosis of Prostate Cancer Cells Cancer Res., August 1, 2005; 65(15): 6719 - 6725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Menendez, L. Vellon, and R. Lupu Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene Ann. Onc., August 1, 2005; 16(8): 1253 - 1267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Brusselmans, R. Vrolix, G. Verhoeven, and J. V. Swinnen Induction of Cancer Cell Apoptosis by Flavonoids Is Associated with Their Ability to Inhibit Fatty Acid Synthase Activity J. Biol. Chem., February 18, 2005; 280(7): 5636 - 5645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. M. Sinilnikova, S. M. Ginolhac, C. Magnard, M. Leone, O. Anczukow, D. Hughes, K. Moreau, D. Thompson, C. Coutanson, J. Hall, et al. Acetyl-CoA carboxylase {alpha} gene and breast cancer susceptibility Carcinogenesis, December 1, 2004; 25(12): 2417 - 2424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.-H. Zhou, M. Yao, T.-S. Lee, Y. Zhu, M. Martins-Green, and J. Y.-J. Shyy Vascular Endothelial Growth Factor Activation of Sterol Regulatory Element Binding Protein: A Potential Role in Angiogenesis Circ. Res., September 3, 2004; 95(5): 471 - 478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Kridel, F. Axelrod, N. Rozenkrantz, and J. W. Smith Orlistat Is a Novel Inhibitor of Fatty Acid Synthase with Antitumor Activity Cancer Res., March 15, 2004; 64(6): 2070 - 2075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. De Schrijver, K. Brusselmans, W. Heyns, G. Verhoeven, and J. V. Swinnen RNA Interference-mediated Silencing of the Fatty Acid Synthase Gene Attenuates Growth and Induces Morphological Changes and Apoptosis of LNCaP Prostate Cancer Cells Cancer Res., July 1, 2003; 63(13): 3799 - 3804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. D. Camassei, R. Cozza, A. Acquaviva, A. Jenkner, L. Rava, R. Gareri, A. Donfrancesco, C. Bosman, P. Vadala, T. Hadjistilianou, et al. Expression of the Lipogenic Enzyme Fatty Acid Synthase (FAS) in Retinoblastoma and Its Correlation with Tumor Aggressiveness Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2399 - 2403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Takahiro, K. Shinichi, and S. Toshimitsu Expression of Fatty Acid Synthase as a Prognostic Indicator in Soft Tissue Sarcomas Clin. Cancer Res., June 1, 2003; 9(6): 2204 - 2212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.-K. Kim, I. Miller, L. E. Landree, F. F. Borisy-Rudin, P. Brown, T. Tihan, C. A. Townsend, L. A. Witters, T. H. Moran, F. P. Kuhajda, et al. Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment Am J Physiol Endocrinol Metab, November 1, 2002; 283(5): E867 - E879. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-N. Li, M. Gorospe, F. J. Chrest, T. S. Kumaravel, M. K. Evans, W. F. Han, and E. S. Pizer Pharmacological Inhibition of Fatty Acid Synthase Activity Produces Both Cytostatic and Cytotoxic Effects Modulated by p53 Cancer Res., February 1, 2001; 61(4): 1493 - 1499. [Abstract] [Full Text]
|
|
|
|
|
|
E. W. Gabrielson, M. L. Pinn, J. R. Testa, and F. P. Kuhajda Increased Fatty Acid Synthase is a Therapeutic Target in Mesothelioma Clin. Cancer Res., January 1, 2001; 7(1): 153 - 157. [Abstract] [Full Text]
|
|
|
|
|
|
S. Hardy, Y. Langelier, and M. Prentki Oleate Activates Phosphatidylinositol 3-Kinase and Promotes Proliferation and Reduces Apoptosis of MDA-MB-231 Breast Cancer Cells, Whereas Palmitate Has Opposite Effects1 Cancer Res., November 1, 2000; 60(22): 6353 - 6358. [Abstract] [Full Text]
|
|
|
|
|
|
E. S. Pizer, J. Thupari, W. F. Han, M. L. Pinn, F. J. Chrest, G. L. Frehywot, C. A. Townsend, and F. P. Kuhajda Malonyl-Coenzyme-A Is a Potential Mediator of Cytotoxicity Induced by Fatty-Acid Synthase Inhibition in Human Breast Cancer Cells and Xenografts Cancer Res., January 1, 2000; 60(2): 213 - 218. [Abstract] [Full Text]
|
|
|
|
|
|
P. Visca, P. L. Alo, F. D. Nonno, C. Botti, G. Trombetta, F. Marandino, S. Filippi, U. D. Tondo, and R. P. Donnorso Immunohistochemical Expression of Fatty Acid Synthase, Apoptotic-regulating Genes, Proliferating Factors, and ras Protein Product in Colorectal Adenomas, Carcinomas, and Adjacent Nonneoplastic Mucosa Clin. Cancer Res., December 1, 1999; 5(12): 4111 - 4118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Moncur, J. P. Park, V. A. Memoli, T. K. Mohandas, and W. B. Kinlaw The "Spot 14" gene resides on the telomeric end of the 11q13 amplicon and is expressed in lipogenic breast cancers: Implications for control of tumor metabolism PNAS, June 9, 1998; 95(12): 6989 - 6994. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
