Inhibition of growth and telomerase activity by novel cationic ceramide analogs with high solubility in human head and neck squamous cell carcinoma cells
Restricted accessResearch articleFirst published online January, 2005
Inhibition of growth and telomerase activity by novel cationic ceramide analogs with high solubility in human head and neck squamous cell carcinoma cells
Head and neck squamous cell carcinoma (HNSCC) is notoriously resistant to chemotherapy. The sphingolipid ceramide and its analogs have been demonstrated to exert antitumor activity in many cell types; however, the effectiveness of these analogs has been limited by potency and solubility. This study focuses on the effects of novel highly soluble cationic pyridinium-ceramides, alone and in combination with various chemotherapeutic agents, on cell survival, telomerase activity, and cell cycle arrest in HNSCC cell lines in vitro.
METHODS:
The concentration of pyridinium-ceramides and chemotherapeutic agents that inhibited cell growth by 50% (IC50) was determined by MTT cell survival assays. The cell cycle profiles were determined by flow cytometry. Telomerase activity was determined by telomerase repeat amplification protocol (TRAP) assay.
RESULTS:
Treatment of the human UM-SCC-22A (SCC of the hypopharynx) cells, as well as various other HNSCC cell lines, with C6-Pyr-Cer resulted in the inhibition of cell survival with an IC50 concentration of approximately 250 to 300 nM at 96 hours, whereas its IC50 was greater than 1000 nM in noncancerous Wi-38 human lung fibroblasts, and adult human epidermal keratinocytes. Moreover, treatment with C6-Pyr-Cer also resulted in cell cycle arrest in G0/G1, which correlated with a significant inhibition of telomerase activity in UM-SCC-22A cells. Additional results demonstrated that the combination of C6-Pyr-Cer with gemcitabine (GMZ) or doxorubicin (DOX), which have the lowest IC50 concentrations among various chemotherapeutic drugs in these cells, enhances the effects of these drugs in the inhibition of telomerase and cell growth.
CONCLUSIONS
These data suggest that the novel C6-Pyr-Cer with high solubility and bioavailability may lead to the development of new therapeutic strategies that target telomerase for the treatment of HNSCC.
Get full access to this article
View all access options for this article.
References
1.
. DongGChenZLiZY, Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Res2001; 61: 5911–8.
2.
. HerC.Nasopharyngeal cancer and the Southeast Asian patient. Am Fam Physician2001;63:1776–82.
3.
. JemalAMurrayTSamuelsA, Cancer statistics, 2003. CA Cancer J Clin2003;53:5–26.
4.
. RiesLAGEisnerMPKosaryCL, et al (eds) SEER Cancer Statistics Review, 1975–2000, Bethesda, MD: National Cancer Institute, 2000.
5.
. HannunYABellRM.Functions of sphingolipids and sphingolipid breakdown products in cellular regulation. Science1989; 243:500–7.
. DbaiboGSPushkarevaMYJayadevS, Retinoblastoma gene product as a downstream target for a ceramide-dependent pathway of growth arrest. Proc Natl Acad Sci USA1995;92: 1347–51.
8.
. OgretmenBHannunYA.Updates on functions of ceramide in chemotherapy-induced cell death and in multidrug resistance. Drug Resistance Updates2001;4:368–77.
9.
. MehtaSBlackintonDOmarI, Combined cytotoxic action of paclitaxel and ceramide against the human Tu138 head and neck squamous carcinoma cell line. Cancer Chemother Pharmacol2000;46:85–92.
10.
. MaoLEl-NaggarAKFanYH, Telomerase activity in head and neck squamous cell carcinoma and adjacent tissues. Cancer Res1996;56:5600–4.
11.
. OgretmenBSchadyDUstaJ, Role of ceramide in mediating the inhibition of telomerase activity in A549 human lung adenocarcinoma cells. J Biol Chem2001;276: 24901–10.
12.
. OgretmenBPettusBJRossiMJ, Biochemical mechanisms of the generation of endogenous long chain ceramide in response to exogenous short chain ceramide in the A549 human lung adenocarcinoma cell line. Role for endogenous ceramide in mediating the action of exogenous ceramide. J Biol Chem2002; 277: 12960–9.
13.
. OgretmenBKravekaJMSchadyD, Molecular mechanisms of ceramide-mediated telomerase inhibition in the A549 human lung adenocarcinoma cell line. J Biol Chem2001;276:32506–14.
14.
. BradfordCRZhuSOgawaH, P53 mutation correlates with cisplatin sensitivity in head and neck squamous cell carcinoma lines. Head Neck2003;25:654–61.
15.
. CognettiFPinnaroPGiannarelliD, Prognostic factors for chemotherapy response and survival using combination chemotherapy as initial treatment of advanced head and neck squamous cell cancer. J Clin Oncol1989;7:829–37.
16.
. AllegrettoMSeikalyHMackeyJR.Intraoperative saline and gemcitabine irrigation improves tumor control in human squamous cell carcinoma-contaminated surgical wounds. J Otolaryngol2001;30:121–5.
17.
. ForastiereAKochWTrottiA, Head and neck cancer. N Engl J Med.2001; 345: 1890–900.
18.
. DayTADavisBKGillespieMB, Oral cancer treatment. Curr Treat Options Oncol2003;4:27–41.
19.
. NguyenDCParsaBCloseA, Overexpression of cell cycle regulatory proteins correlates with advanced tumor stage in head and neck squamous cell carcinomas. Int. J Oncol2003; 22: 1285–90.
20.
. AiroldiMCattelLCortesinaG, Gemcitabine and vinorelbine in recurrent head and neck cancer: pharmacokinetic and clinical results. Anticancer Res2003;23:2845–52.
21.
. OkunoSHMailliardJASumanVJ, Phase II study of methotrexate, vinblastine, DOX, and cisplatin in patients with squamous cell carcinoma of the upper respiratory or alimentary passages of the head and neck. Cancer2002;94:2224–31.
