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

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• 作者：Kun-Chun Chiang ; Chun-Nan Yeh ; Jun-Te Hsu ; Li-Wei Chen ; Sheng-Fong Kuo ; Chi-Chin Sun ; Cheng-Cheng Huang ; Jong-Hwei S. Pang ; John N. Flanagan ; Masashi Takano ; Atsushi Kittaka ; Horng-Heng Juang ; Shih-Wei Yang ; Tai C. Chen
• 关键词：1伪 ; 25(OH)2D ; 1伪 ; 25-dihydroxyvitamin D ; MART-10 ; 19-nor-2伪-(3-hydroxypropyl)-1伪 ; 25(OH)2D3 ; VDR ; vitamin D receptor ; VDRE ; vitamin D response element ; RXR ; retinoid X receptor ; PI ; propidium iodide ; E2F-1 ; E2F transcription factor 1 ; FBS ; fetal bovine serum ; FITC ; fluorescein isothiocyanate
• 刊名：The Journal of Steroid Biochemistry and Molecular Biology
• 出版年：November, 2013
• 年：2013
• 卷：138
• 期：Complete
• 页码：427-434
• 全文大小：1220 K

文摘

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 5 year survival for HNSCC patients is only around 61%. Thus, new therapeutic regimens against HNSCC are urgently needed. 1伪,25-Dihydroxyvitamin D₃ [1伪,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 1伪,25(OH)₂D₃ analog, MART-10 (19-nor-2伪-(3-hydroxypropyl)- 1伪,25-Dihydroxyvitamin D₃), has been shown to be much more potent than 1伪,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 1伪,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 1伪,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 1伪,25(OH)₂D_3. 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.