1α,25-二羟基维生素D3类似物MART-10通过诱导G0/G1期细胞周期阻滞和凋亡抑制神经内分泌肿瘤细胞生长。

1α,25(OH)2D3 Analog, MART-10, Inhibits Neuroendocrine Tumor Cell Growth Through Induction of G0/G1 Cell-cycle Arrest and Apoptosis.

作者信息

Chiang Kun-Chun, Yeh Chun-Nan, Pang Jong-Hwei S, Hsu Jun-Te, Yeh Ta-Sen, Chen Li-Wei, Kuo Sheng-Fong, Hsieh Po-Jen, Pan Yi-Chun, Takano Masashi, Chen Tai C, Feng Tsui-Hsia, Kittaka Atsushi, Juang Horng-Heng

机构信息

General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, R.O.C. Zebrafish Center, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, R.O.C.

Department of General Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C.

出版信息

Anticancer Res. 2016 Jul;36(7):3307-13.

PMID:27354587

Abstract

BACKGROUND

Neuroendocrine tumors (NETs) are the second most common digestive malignancy. For advanced NETs, survival is not satisfactory. Vitamin D has emerged as a promising anticancer drug.

MATERIALS AND METHODS

Cell proliferation assay, western blot, flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays were applied.

RESULTS

We demonstrated that RIN-m cells, neuroendocrine tumor cells, expressed vitamin D receptor (VDR) and VDR expression increased with increasing exposure to 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] or MART-10, a 1α,25(OH)2D3 analog. MART-10 had anti-growth effect on RIN-m cells comparable to those of 1α,25(OH)2D3 The growth inhibition of both drugs was mediated by induction of cell-cycle arrest at G0/G1 phase and apoptosis. Western blot assay further revealed that this G0/G1 arrest was due to the up-regulation of p27 and down-regulation of cyclin dependent kinase 4 (CDK4), with MART-10 also reducing CDK6. Apoptosis induction was further supported by increased cleaved caspase-3 expression after treatment.

CONCLUSION

MART-10 appears to be a promising regimen for NET treatment.

摘要

背景

神经内分泌肿瘤（NETs）是第二常见的消化系统恶性肿瘤。对于晚期NETs，生存率并不理想。维生素D已成为一种有前景的抗癌药物。

材料与方法

应用细胞增殖测定、蛋白质印迹法、流式细胞术和末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）测定。

结果

我们证明，神经内分泌肿瘤细胞RIN-m细胞表达维生素D受体（VDR），且随着暴露于1α,25-二羟基维生素D3 [1α,25(OH)2D3] 或1α,25(OH)2D3类似物MART-10时间的增加，VDR表达增加。MART-10对RIN-m细胞具有与1α,25(OH)2D3相当的抗生长作用。两种药物的生长抑制作用均通过诱导细胞周期停滞在G0/G1期和凋亡来介导。蛋白质印迹分析进一步表明，这种G0/G1期停滞是由于p27上调和细胞周期蛋白依赖性激酶4（CDK4）下调所致，MART-10还降低了CDK6。治疗后裂解的半胱天冬酶-3表达增加进一步支持了凋亡诱导。