19-nor-1α,25-dihydroxyvitamin D2 (Paricalcitol) inhibits the proliferation of human pancreatic cancer cells in vitro and in vivo
19-nor-1α,25-dihydroxyvitamin D2 (Paricalcitol) inhibits the proliferation of human pancreatic cancer cells in vitro and in vivo
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DOI：
10.4161/cbt.7.3.5418
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发表时间：
2008-03-01
影响因子：
3.6
通讯作者：
Koumenis, Constantinos
中科院分区：
文献类型：
--
作者：
Schwartz, Gary G.;Eads, Dawn;Koumenis, Constantinos
1，25-二羟基维生素D-3（1，25（OH）D-2（3）;骨化三醇）是维生素D的激素形式，在体外和体内对肿瘤细胞发挥生长抑制、促凋亡和抗转移作用，但其临床应用受到其钙调作用的限制。先前的研究表明，钙离子较少的骨化三醇类似物19-去甲-1，25-（OH）2D 2（帕立骨化醇）对前列腺肿瘤细胞系的抗增殖作用与1，25（OH）D-2的抗增殖作用无法区分（3）。因此，我们研究了帕立骨化醇在体外和体内对胰腺肿瘤细胞系生长的抗增殖作用。1，25（OH）2D 3和帕立骨化醇均以剂量依赖性方式抑制BxPC-3、Hs 700 T和AsPC-1细胞系的生长。这种抗增殖活性与细胞周期抑制剂p21（Waf 1/CIP 1）和p27（Kip 1）的上调相关。第四种胰腺细胞系Hs 766 T对帕立骨化醇和骨化三醇均无反应。Hs 766 T细胞也未能上调p21/ Waf-1/Cip 1或p27/ KiP在这些药物的治疗响应。帕立骨化醇每周给药三次，在不引起高钙血症的剂量下抑制裸鼠AsPC-1胰腺肿瘤细胞异种移植物的生长。肿瘤抑制伴随着p21和p27表达的体内上调。鉴于胰腺癌患者的治疗选择很少，有必要进一步探索帕立骨化醇（一种FDA批准的药物）。
1,25-dihydroxyvitamin D-3, ( 1,25( OH) D-2(3); calcitriol), the hormonal form of vitamin D, exerts growth-inhibitory, pro-apoptotic and anti-metastatic effects on tumor cells in vitro and in vivo but its clinical use is limited by its calcemic effects. Previous studies have shown that the antiproliferative effects of the less calcemic calcitriol analog 19-nor-1,25-(OH) 2D2 ( paricalcitol) on prostate tumor cell lines are indistinguishable from those of 1,25( OH) D-2(3). We therefore investigated the anti-proliferative effects of paricalcitol on the growth of pancreatic tumor cell lines in vitro and in vivo. Both 1,25( OH) 2D3 and paricalcitol inhibited the growth of BxPC-3, Hs700T and AsPC-1 lines in a dose-dependent manner. This antiproliferative activity correlated with upregulation of the cell cycle inhibitors p21 ( Waf1/ CIP1) and p27( Kip1). A fourth pancreatic cell line, Hs766T, was unresponsive to both paricalcitol and calcitriol. Hs766T cells also failed to upregulate p21/ Waf-1/ Cip1 or p27/ KiP in response to treatments with these agents. Paricalcitol, given three times per week, inhibited the growth of AsPC-1 pancreatic tumor cell xenografts in nude mice at a dose that did not cause hypercalcaemia. Tumor inhibition was accompanied by in vivo upregulation of p21 and p27 expression. Given the few therapeutic options for patients with pancreatic cancer, further exploration of paricalcitol, an FDA-approved medication, is warranted.