title: MART-10, a novel vitamin D analog, inhibits head and neck squamous carcinoma cells growth through cell cycle arrest at G0/G1 with upregulation of p21 and p27 and downregulation of telomerase.
abstract: For the head and neck squamous cell carcinoma (HNSCC), surgery in combination with radiation therapy is the current standard treatment. However, the complex anatomy and important functions over the head and neck region often make HNSCC patients with severe comorbidities. Even after aggressive treatment, the 5year survival for HNSCC patients is only around 61%. Thus, new therapeutic regimens against HNSCC are urgently needed. 1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3] is a potent anti-tumor agent in a variety of pre-clinical studies, but its clinical application is impeded by hypercalcemic side effect. A new class of less-calcemic 1α,25(OH)2D3 analog, MART-10 (19-nor-2α-(3-hydroxypropyl)- 1α,25-Dihydroxyvitamin D3), has been shown to be much more potent than 1α,25(OH)2D3 in inhibiting cancer cell growth in vitro and in vivo without inducing hypercalcemia. In this study, we compared the antiproliferative activity of MART-10 with 1α,25(OH)2D3 and the mechanism responsible for the inhibition in FaDu and SCC-25 squamous carcinoma cells. Our results demonstrate that MART-10 is more potent than 1α,25(OH)2D3 in suppressing FaDu and SCC-25 cell growth through greater cell cycle arrest at G0/G1, accompanied by a greater downregulation of ki-67 expression and upregulation of p21 and p27. We also showed that telomerase expression in SCC-25 was suppressed to a greater extent by MART-10 than by 1α,25(OH)2D3. Thus, given the previously-proven in vivo antitumor effect and safety of MART-10 and bleak background of HNSCC, based on our current result, we concluded that MART-10 has a potential as a chemo-preventive and - therapeutic agent to treat HNSCC.
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, 222, Mai-Chin Road, Keelung, Taiwan, ROC; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, ROC.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.forename: Jun-Te
authors.initials: JT
authors.lastname: Hsu
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Chen
authors.forename: Sheng-Fong
authors.initials: SF
authors.lastname: Kuo
authors.forename: Chi-Chin
authors.initials: CC
authors.lastname: Sun
authors.forename: Cheng-Cheng
authors.initials: CC
authors.lastname: Huang
authors.forename: Jong-Hwei S
authors.initials: JH
authors.lastname: Pang
authors.forename: John N
authors.initials: JN
authors.lastname: Flanagan
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.forename: Horng-Heng
authors.initials: HH
authors.lastname: Juang
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Yang
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D000077195:Squamous Cell Carcinoma of Head and Neck; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives*
chemical_list: C569618:19-nor-2-(3-hydroxypropyl)-1,25-dihydroxyvitamin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D014807:Vitamin D; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002762:Cholecalciferol; D019098:Telomerase
keywords: 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)(2)D(3); 1α,25(OH)(2)D; 1α,25-dihydroxyvitamin D; Cell cycle; E2F transcription factor 1; E2F-1; FBS; FITC; Head and neck cancer; MART-10; PI; Proliferation; RXR; SCC; VDR; VDRE; Vitamin D analog; fetal bovine serum; fluorescein isothiocyanate; propidium iodide; retinoid X receptor; vitamin D receptor; vitamin D response element