This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Selzner, M. Articles by Clavien, P.-A. Search for Related Content PubMed PubMed Citation Articles by Selzner, M. Articles by Clavien, P.-A.

Induction of Apoptotic Cell Death and Prevention of Tumor Growth by Ceramide Analogues in Metastatic Human Colon Cancer¹

Departments of Surgery [M. S., H. A. R., D. S., P-A. C.] and Medicine [M. A. M.], Duke University Medical Center, Durham, North Carolina 27710; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina [A. B., Y. A. H.]; and Division of Visceral and Transplantation Surgery, University Hospital Zürich, Zürich, Switzerland [M. S., H. A. R., P-A. C.]

Dysfunction in the physiological pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogues in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a >50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogues and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic molecules, such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in maximum activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.

This article has been cited by other articles:

				Y. J. Jiang, Y. Uchida, B. Lu, P. Kim, C. Mao, M. Akiyama, P. M. Elias, W. M. Holleran, C. Grunfeld, and K. R. Feingold Ceramide Stimulates ABCA12 Expression via Peroxisome Proliferator-activated Receptor {delta} in Human Keratinocytes J. Biol. Chem., July 10, 2009; 284(28): 18942 - 18952. [Abstract] [Full Text] [PDF]

				S. Nemoto, M. Nakamura, Y. Osawa, S. Kono, Y. Itoh, Y. Okano, T. Murate, A. Hara, H. Ueda, Y. Nozawa, et al. Sphingosine Kinase Isoforms Regulate Oxaliplatin Sensitivity of Human Colon Cancer Cells through Ceramide Accumulation and Akt Activation J. Biol. Chem., April 17, 2009; 284(16): 10422 - 10432. [Abstract] [Full Text] [PDF]

				G. G. Guenther, E. R. Peralta, K. R. Rosales, S. Y. Wong, L. J. Siskind, and A. L. Edinger Ceramide starves cells to death by downregulating nutrient transporter proteins PNAS, November 11, 2008; 105(45): 17402 - 17407. [Abstract] [Full Text] [PDF]

				E. L. Smith and E. H. Schuchman The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases FASEB J, October 1, 2008; 22(10): 3419 - 3431. [Abstract] [Full Text] [PDF]

				N. Shtraizent, E. Eliyahu, J.-H. Park, X. He, R. Shalgi, and E. H. Schuchman Autoproteolytic Cleavage and Activation of Human Acid Ceramidase J. Biol. Chem., April 25, 2008; 283(17): 11253 - 11259. [Abstract] [Full Text] [PDF]

				H. M. A. Bakali, M. D. Herman, K. A. Johnson, A. A. Kelly, A. Wieslander, B. M. Hallberg, and P. Nordlund Crystal Structure of YegS, a Homologue to the Mammalian Diacylglycerol Kinases, Reveals a Novel Regulatory Metal Binding Site J. Biol. Chem., July 6, 2007; 282(27): 19644 - 19652. [Abstract] [Full Text] [PDF]

				L. E. van Vlerken, Z. Duan, M. V. Seiden, and M. M. Amiji Modulation of Intracellular Ceramide Using Polymeric Nanoparticles to Overcome Multidrug Resistance in Cancer Cancer Res., May 15, 2007; 67(10): 4843 - 4850. [Abstract] [Full Text] [PDF]

				L. Guan, K. Song, M. A. Pysz, K. J. Curry, A. A. Hizli, D. Danielpour, A. R. Black, and J. D. Black Protein Kinase C-mediated Down-regulation of Cyclin D1 Involves Activation of the Translational Repressor 4E-BP1 via a Phosphoinositide 3-Kinase/Akt-independent, Protein Phosphatase 2A-dependent Mechanism in Intestinal Epithelial Cells J. Biol. Chem., May 11, 2007; 282(19): 14213 - 14225. [Abstract] [Full Text] [PDF]

				M. Moussavi, K. Assi, A. Gomez-Munoz, and B. Salh Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells Carcinogenesis, August 1, 2006; 27(8): 1636 - 1644. [Abstract] [Full Text] [PDF]

				R. Fishelevich, A. Malanina, I. Luzina, S. Atamas, M. J. Smyth, S. A. Porcelli, and A. A. Gaspari Ceramide-Dependent Regulation of Human Epidermal Keratinocyte CD1d Expression during Terminal Differentiation J. Immunol., February 15, 2006; 176(4): 2590 - 2599. [Abstract] [Full Text] [PDF]

				D. E. Modrak, D. V. Gold, and D. M. Goldenberg Sphingolipid targets in cancer therapy. Mol. Cancer Ther., February 1, 2006; 5(2): 200 - 208. [Abstract] [Full Text] [PDF]

				M. S. Toledo, E. Suzuki, K. Handa, and S. Hakomori Effect of Ganglioside and Tetraspanins in Microdomains on Interaction of Integrins with Fibroblast Growth Factor Receptor J. Biol. Chem., April 22, 2005; 280(16): 16227 - 16234. [Abstract] [Full Text] [PDF]

				J. N.M. Ilsley, M. Nakanishi, C. Flynn, G. S. Belinsky, S. De Guise, J. N. Adib, R. T. Dobrowsky, J. V. Bonventre, and D. W. Rosenberg Cytoplasmic Phospholipase A2 Deletion Enhances Colon Tumorigenesis Cancer Res., April 1, 2005; 65(7): 2636 - 2643. [Abstract] [Full Text] [PDF]

				A. P. Struckhoff, R. Bittman, M. E. Burow, S. Clejan, S. Elliott, T. Hammond, Y. Tang, and B. S. Beckman Novel Ceramide Analogs as Potential Chemotherapeutic Agents in Breast Cancer J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 523 - 532. [Abstract] [Full Text] [PDF]

				F. Scarlatti, C. Bauvy, A. Ventruti, G. Sala, F. Cluzeaud, A. Vandewalle, R. Ghidoni, and P. Codogno Ceramide-mediated Macroautophagy Involves Inhibition of Protein Kinase B and Up-regulation of Beclin 1 J. Biol. Chem., April 30, 2004; 279(18): 18384 - 18391. [Abstract] [Full Text] [PDF]

				J. A. Shabbits, Y. Hu, and L. D. Mayer Tumor Chemosensitization Strategies Based on Apoptosis Manipulations Mol. Cancer Ther., August 1, 2003; 2(8): 805 - 813. [Full Text] [PDF]

				I. Silins, M. Nordstrand, J. Hogberg, and U. Stenius Sphingolipids suppress preneoplastic rat hepatocytes in vitro and in vivo Carcinogenesis, June 1, 2003; 24(6): 1077 - 1083. [Abstract] [Full Text] [PDF]

				K. J. Claycombe, D. Wu, M. Nikolova-Karakashian, H. Palmer, A. Beharka, K. E. Paulson, and S. N. Meydani Ceramide Mediates Age-associated Increase in Macrophage Cyclooxygenase-2 Expression J. Biol. Chem., August 16, 2002; 277(34): 30784 - 30791. [Abstract] [Full Text] [PDF]

				Y. A. Hannun and L. M. Obeid The Ceramide-centric Universe of Lipid-mediated Cell Regulation: Stress Encounters of the Lipid Kind J. Biol. Chem., July 12, 2002; 277(29): 25847 - 25850. [Full Text] [PDF]

				C. Mao, R. Xu, Z. M. Szulc, A. Bielawska, S. H. Galadari, and L. M. Obeid Cloning and Characterization of a Novel Human Alkaline Ceramidase. A MAMMALIAN ENZYME THAT HYDROLYZES PHYTOCERAMIDE J. Biol. Chem., July 6, 2001; 276(28): 26577 - 26588. [Abstract] [Full Text] [PDF]