{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T08:21:32Z","timestamp":1778746892476,"version":"3.51.4"},"reference-count":21,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2016,5,17]],"date-time":"2016-05-17T00:00:00Z","timestamp":1463443200000},"content-version":"vor","delay-in-days":4154,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["aao-hnsfjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Otolaryngol.--head neck surg."],"published-print":{"date-parts":[[2005,1]]},"abstract":"<jats:sec><jats:title>OBJECTIVES<\/jats:title><jats:p><jats:bold>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\u2010ceramides, alone and in combination with various chemotherapeutic agents, on cell survival, telomerase activity, and cell cycle arrest in HNSCC cell lines in vitro.<\/jats:bold><\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p><jats:bold>The concentration of pyridinium\u2010ceramides and chemotherapeutic agents that inhibited cell growth by 50% (IC<jats:sub>50<\/jats:sub>) 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.<\/jats:bold><\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p><jats:bold>Treatment of the human UM\u2010SCC\u201022A (SCC of the hypopharynx) cells, as well as various other HNSCC cell lines, with C<jats:sub>6<\/jats:sub>\u2010Pyr\u2010Cer resulted in the inhibition of cell survival with an IC<jats:sub>50<\/jats:sub> concentration of approximately 250 to 300\u00a0nM at 96 hours, whereas its IC<jats:sub>50<\/jats:sub> was greater than 1000\u00a0nM in noncancerous Wi\u201038 human lung fibroblasts, and adult human epidermal keratinocytes. Moreover, treatment with C<jats:sub>6<\/jats:sub>\u2010Pyr\u2010Cer also resulted in cell cycle arrest in G0\/G1, which correlated with a significant inhibition of telomerase activity in UM\u2010SCC\u201022A cells. Additional results demonstrated that the combination of C<jats:sub>6<\/jats:sub>\u2010Pyr\u2010Cer with gemcitabine (GMZ) or doxorubicin (DOX), which have the lowest IC<jats:sub>50<\/jats:sub> concentrations among various chemotherapeutic drugs in these cells, enhances the effects of these drugs in the inhibition of telomerase and cell growth.<\/jats:bold><\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p><jats:bold>These data suggest that the novel C<jats:sub>6<\/jats:sub>\u2010Pyr\u2010Cer with high solubility and bioavailability may lead to the development of new therapeutic strategies that target telomerase for the treatment of HNSCC.<\/jats:bold><\/jats:p><\/jats:sec>","DOI":"10.1016\/j.otohns.2004.08.015","type":"journal-article","created":{"date-parts":[[2005,1,4]],"date-time":"2005-01-04T07:16:53Z","timestamp":1104823013000},"page":"55-62","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Inhibition of growth and telomerase activity by novel cationic ceramide analogs with high solubility in human head and neck squamous cell carcinoma cells"],"prefix":"10.1002","volume":"132","author":[{"given":"Michael J.","family":"Rossi","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Charleston SC"},{"name":"College of Medicine Division of Head and Neck Oncologic Surgery Charleston SC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamala","family":"Sundararaj","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Charleston SC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serap","family":"Koybasi","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Charleston SC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monique S.","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Charleston SC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zdzislaw M.","family":"Szulc","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Charleston SC"},{"name":"Hollings Cancer Center Medical University of South Carolina Charleston SC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicja","family":"Bielawska","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Charleston SC"},{"name":"Hollings Cancer Center Medical University of South Carolina Charleston SC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terry A.","family":"Day","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Charleston SC"},{"name":"Hollings Cancer Center Medical University of South Carolina Charleston SC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina M.","family":"Obeid","sequence":"additional","affiliation":[{"name":"Hollings Cancer Center Medical University of South Carolina Charleston SC"},{"name":"Ralph H. Johnson Veterans Administration and the Department of Medicine Charleston SC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuf A.","family":"Hannun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Charleston SC"},{"name":"Hollings Cancer Center Medical University of South Carolina Charleston SC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Besim","family":"Ogretmen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Charleston SC"},{"name":"Hollings Cancer Center Medical University of South Carolina Charleston SC"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,5,17]]},"reference":[{"key":"e_1_2_5_2_1","first-page":"5911","article-title":"Hepatocyte growth factor\/scatter factor\u2010induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin\u20108 and vascular endothelial growth factor in head and neck squamous cell carcinoma","volume":"61","author":"Dong G","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_5_3_1","first-page":"1776","article-title":"Nasopharyngeal cancer and the Southeast Asian patient","volume":"63","author":"Her C","year":"2001","journal-title":"Am Fam Physician"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.53.1.5"},{"key":"e_1_2_5_5_1","volume-title":"SEER Cancer Statistics Review, 1975\u20132000","author":"Ries LAG","year":"2000"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2643164"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)82288-8"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.5.1347"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1054\/drup.2001.0225"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002800000140"},{"key":"e_1_2_5_11_1","first-page":"5600","article-title":"Telomerase activity in head and neck squamous cell carcinoma and adjacent tissues","volume":"56","author":"Mao L","year":"1996","journal-title":"Cancer Res"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M100314200"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110699200"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101350200"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.10274"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1989.7.7.829"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.2310\/7070.2001.20822"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra001375"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11864-003-0029-4"},{"key":"e_1_2_5_20_1","first-page":"1285","article-title":"Overexpression of cell cycle regulatory proteins correlates with advanced tumor stage in head and neck squamous cell carcinomas","volume":"22","author":"Nguyen DC","year":"2003","journal-title":"Int. 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