Antitumor effects of two less-calcemic vitamin D analogs (paricalcitol and QW-1624F2-2) in squamous cell carcinoma cells
Antitumor effects of two less-calcemic vitamin D analogs (paricalcitol and QW-1624F2-2) in squamous cell carcinoma cells
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DOI：
10.1159/000098813
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发表时间：
2006-01-01
期刊：
影响因子：
3.5
通讯作者：
Foster, Barbara A.
中科院分区：
文献类型：
--
作者：
Alagbala, Adebusola A.;Johnson, Candace S.;Foster, Barbara A.
维生素D-3的活性代谢物（1 α，25-二羟基维生素D-3，骨化三醇）在体内和体外对多种肿瘤具有有效的抗肿瘤活性。对骨化三醇诱导高钙血症的担忧和对更有效药物的渴望促使了低钙维生素D类似物的开发。这些研究表明，两种维生素D类似物19-no -1 α，25-二羟基维生素d2 （paricalcitol）和1 α -羟甲基-16-烯-24,24-二氟-25-羟基-26,27-二羟基维生素D-3（QW- 1624f (2)-2， QW）在骨化三醇反应性鳞状细胞癌（SCC）细胞系中具有抗癌作用。Paricalcitol （GI(50) = 0.7 nM）和QW （GI(50) = 0.001 nM）抑制SCC细胞生长；然而，QW更有效。Paricalcitol （10 nM）和QW （10 nM）诱导G(0)/G(1)细胞周期阻滞，对DNA合成的抑制率为95%。维生素D类似物可调节细胞周期调节因子，包括降低p21(Waf1/Cip1) （p21）和周期蛋白依赖性激酶2 （cdk2）的mRNA和蛋白水平，增加p27(Kip1) （p27）蛋白的表达。维生素D类似物诱导凋亡、caspase-3切割和促凋亡MEKK-1表达增加。促进细胞生长和存活的Akt、MEK和ERK1/2的磷酸化被维生素D类似物抑制。白藜芦醇和白藜芦醇的抗癌作用与骨化三醇相当。这些低钙维生素D类似物在体外与骨化三醇一样有效，有望用于预防和治疗癌症和其他疾病。版权所有(c) 2006 S. Karger AG，巴塞尔
The active metabolite of vitamin D-3 (1 alpha,25-dihydroxyvitamin D-3, calcitriol) has potent antitumor activities in vitro and in vivo in multiple cancers. Concerns about induction of hypercalcemia by calcitriol and the desire for more potent agents have prompted development of less-calcemic vitamin D analogs. These studies demonstrate that two vitamin D analogs, 19-nor- 1 alpha,25-dihydroxyvitamin D 2 ( paricalcitol) and 1 alpha-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D-3(QW-1624F(2)-2, QW), have anticancer effects in the calcitriol-responsive squamous cell carcinoma (SCC) cell line. Paricalcitol (GI(50) = 0.7 nM) and QW (GI(50) = 0.001 nM) inhibited SCC cell growth; however, QW was more potent. Paricalcitol (10 nM) and QW (10 nM) induced G(0)/G(1) cell cycle arrest and inhibited DNA synthesis by similar to 95%. The vitamin D analogs modulated cell cycle regulators, including decreasing mRNA and protein levels of p21(Waf1/Cip1) (p21) and cyclin-dependent kinase 2 (cdk2), and increasing p27(Kip1) (p27) protein expression. Vitamin D analogs induced apoptosis, caspase-3 cleavage and increased expression of pro-apoptotic MEKK-1. Phosphorylation of Akt, MEK and ERK1/2 that promote cell growth and survival were inhibited by vitamin D analogs. The anticancer effects of paricalcitol and QW are comparable to the effect of calcitriol. These less-calcemic vitamin D analogs are as effective as calcitriol in vitro and are promising for prevention and treatment of cancer and other diseases. Copyright (c) 2006 S. Karger AG, Basel