Back to Search
Start Over
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.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2006 Jun; Vol. 317 (3), pp. 1188-99. Date of Electronic Publication: 2006 Mar 01. - Publication Year :
- 2006
-
Abstract
- 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 were significantly 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.
- Subjects :
- Animals
Antineoplastic Combined Chemotherapy Protocols adverse effects
Antineoplastic Combined Chemotherapy Protocols pharmacokinetics
Cations
Cell Line, Tumor
Ceramides administration & dosage
Ceramides adverse effects
Ceramides pharmacokinetics
Ceramides therapeutic use
Deoxycytidine administration & dosage
Deoxycytidine adverse effects
Deoxycytidine analogs & derivatives
Deoxycytidine pharmacokinetics
Deoxycytidine therapeutic use
Dose-Response Relationship, Drug
Head and Neck Neoplasms pathology
Humans
Inactivation, Metabolic
Maximum Tolerated Dose
Mice
Mice, Inbred BALB C
Mice, SCID
Neoplasms, Squamous Cell pathology
Pyridinium Compounds administration & dosage
Pyridinium Compounds adverse effects
Pyridinium Compounds pharmacokinetics
Pyridinium Compounds therapeutic use
Tissue Distribution
Xenograft Model Antitumor Assays
Gemcitabine
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Cell Proliferation drug effects
Head and Neck Neoplasms drug therapy
Neoplasms, Squamous Cell drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3565
- Volume :
- 317
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 16510697
- Full Text :
- https://doi.org/10.1124/jpet.106.101949