QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.101949v1 317/3/1188    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Senkal, C. E. Articles by Ogretmen, B. Search for Related Content PubMed PubMed Citation Articles by Senkal, C. E. Articles by Ogretmen, B.

CELLULAR AND MOLECULAR

Potent Antitumor Activity of a Novel Cationic Pyridinium-Ceramide Alone or in Combination with Gemcitabine against Human Head and Neck Squamous Cell Carcinomas in Vitro and in Vivo

Departments of Biochemistry and Molecular Biology (C.E.S., S.P., K.S., Z.S., J.B., A.B., B.C., L.M.O., Y.A.H., B.O.), Hollings Cancer Center (A.B., M.M., T.A.D., L.M.O., Y.A.H., B.O.), Otolaryngology and Head and Neck Surgery (M.J.R., S.K., T.A.D.), Biostatistics, Bioinformatics, and Epidemiology (D.S.), and Medicine and Ralph H. Johnson Veterans Administration Hospital (L.M.O.), Medical University of South Carolina (MUSC), Charleston, South Carolina

In this study, a cationic water-soluble ceramide analog L-threo-C₆-pyridinium-ceramide-bromide (L-t-C₆-Pyr-Cer), which exhibits high solubility and bioavailability, inhibited the growth of various human head and neck squamous cell carcinoma (HNSCC) cell lines at low IC₅₀ concentrations, independent of their p53 status. Consistent with its design to target negatively charged intracellular compartments, L-t-C₆-Pyr-Cer accumulated mainly in mitochondria-, and nuclei-enriched fractions upon treatment of human UM-SCC-22A cells [human squamous cell carcinoma (SCC) of the hypopharynx] at 1 to 6 h. In addition to its growth-inhibitory function as a single agent, the supra-additive interaction of L-t-C₆-Pyr-Cer with gemcitabine (GMZ), a chemotherapeutic agent used in HNSCC, was determined using isobologram studies. Then, the effects of this ceramide, alone or in combination with GMZ, on the growth of UM-SCC-22A xenografts in SCID mice was assessed following the determination of preclinical parameters, such as maximum tolerated dose, clearance from the blood, and bioaccumulation. Results demonstrated that treatment with L-t-C₆-Pyr-Cer in combination with GMZ significantly prevented the growth of HNSCC tumors in vivo. The therapeutic efficacy of L-t-C₆-Pyr-Cer/GMZ combination against HNSCC tumors was approximately 2.5-fold better than that of the combination of 5-fluorouracil/cis-platin. In addition, liquid chromatography/mass spectroscopy analysis showed that the levels of L-t-C₆-Pyr-Cer in HNSCC tumors weresignificantly higher than its levels in the liver and intestines; interestingly, the combination with GMZ increased the sustained accumulation of this ceramide by approximately 40%. Moreover, treatment with L-t-C₆-Pyr-Cer/GMZ combination resulted in a significant inhibition of telomerase activity and decrease in telomere length in vivo, which are among downstream targets of ceramide.

Address correspondence to: Dr. Besim Ogretmen, Medical University of South Carolina, Department of Biochemistry, 173 Ashley Avenue, Charleston, SC 29424. E-mail: ogretmen{at}musc.edu

This article has been cited by other articles:

				S. T. Pruett, A. Bushnev, K. Hagedorn, M. Adiga, C. A. Haynes, M. C. Sullards, D. C. Liotta, and A. H. Merrill Jr. Thematic Review Series: Sphingolipids. Biodiversity of sphingoid bases ("sphingosines") and related amino alcohols J. Lipid Res., August 1, 2008; 49(8): 1621 - 1639. [Abstract] [Full Text] [PDF]

				C. E. Senkal, S. Ponnusamy, M. J. Rossi, J. Bialewski, D. Sinha, J. C. Jiang, S. M. Jazwinski, Y. A. Hannun, and B. Ogretmen Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas Mol. Cancer Ther., February 1, 2007; 6(2): 712 - 722. [Abstract] [Full Text] [PDF]