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

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