Received for publication January 30, 2006.
Revised February 23, 2006.
Accepted for publication February 28, 2006.

Potent Anti-Tumor 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

Abstract

In this study, a cationic water-soluble ceramide analogue L-threo-C₆-Pyridinium-Ceramide-bromide (L-t-C₆-Pyr-Cer), which exhibits high solubility and bio-availability, 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 UM-SCC-22A cells (human SCC of the hypopharynx) at 1-6 hr. 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 pre-clinical parameters, such as maximum tolerated dose (MTD), clearance from the blood, and bio-accumulation. 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 about 2.5-fold better than that of the combination of 5-fluorouracil (5-FU)/cisplatin (CP). In addition, LC/MS analysis showed that the levels of L-t-C₆-Pyr-Cer in HNSCC tumors were significantly higher than its levels in the liver and intestines, and interestingly, the combination with GMZ increased the sustained accumulation of this ceramide by about 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 down-stream targets of ceramide.

Key words: ceramide, chemotherapy, head and neck cancer, lipids, sphingolipids, telomerase

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