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首页> 外文期刊>藥學雜誌 >Analysis of molecular mechanism of cancer cell differentiation and apoptosis induced by vitamin D3 analogs on the basis of molecular recognition of vitamin D receptor ligand binding domain
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Analysis of molecular mechanism of cancer cell differentiation and apoptosis induced by vitamin D3 analogs on the basis of molecular recognition of vitamin D receptor ligand binding domain

机译：基于维生素D受体配体结合域的分子识别分析维生素D3类似物诱导的癌细胞分化和凋亡的分子机制

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摘要

1 alpha,25-Dihydroxyvitamin D3 [1 alpha,25 (OH)2D3] has antiproliferative, differentiation and apoptosis-inducing effects on many malignant cells. These properties have raised the possibility of its use as a therapeutic agent in cancer. Our recent studies using stereoisomers of the A-ring of monohydroxylated 19-nor or 2-methyl substituted 1 alpha,25 (OH)2D3 have clearly demonstrated that the A-ring analogs that contain 1 alpha-hydroxy or 3 beta-hydroxy group are potent inducers of HL-60 cell differentiation. In contrast, the A-ring analogs that contain 1 beta-hydroxy or 3 alpha-hydroxy group are potent stimulators of HL-60 cell apoptosis. It was interesting to note that the analogs could induce differentiation or apoptosis of HL-60 cells on the basis of the stereochemistry of both hydroxy groups at positions 1 and 3 of the A-ring. To further elucidate the possible roles of both the hydroxy groups in regulating cell differentiation and apoptosis, we have synthesized all possible diastereomers of the A-ring of 1 alpha,25 (OH)2D3 and examined their molecular mechanism of differentiation and apoptosis-inducing actions of HL-60 cells in vitro. This study shows that differentiation and apoptosis of HL-60 cells are strictly controlled by the stereochemistry of both hydroxy groups at positions 1 and 3 of the A-ring of 1 alpha,25 (OH)2D3, and the proteins responsible for the regulation of cell cycle and mitochondrial membrane potential are the major targets of 1 alpha,25 (OH)2D3 analogs. These findings provide useful information not only for structure-function studies of 1 alpha,25 (OH)2D3 analogs but also for the development of therapeutic agents for the treatment of cancer.
机译：1 alpha，25-Dihydroxyvitamin D3 [1 alpha，25（OH）2D3]对许多恶性细胞具有抗增殖，分化和凋亡诱导作用。这些性质提高了其在癌症中用作治疗剂的可能性。我们最近使用单羟基化19-nor或2-甲基取代的1 alpha，25（OH）2D3的A环的立体异构体进行的最新研究清楚地表明，含有1个α-羟基或3个β-羟基的A环类似物是HL-60细胞分化的有效诱导剂。相反，含有1个β-羟基或3个α-羟基的A环类似物是HL-60细胞凋亡的有效刺激剂。有趣的是，根据A环1和3位置的两个羟基的立体化学，类似物可诱导HL-60细胞分化或凋亡。为了进一步阐明羟基在调节细胞分化和凋亡中的可能作用，我们合成了所有可能的1α，25（OH）2D3 A环非对映异构体，并研究了它们分化和诱导凋亡的分子机制HL-60细胞的体外培养。这项研究表明，HL-60细胞的分化和凋亡受到1 alpha，25（OH）2D3的A环1和3位置的两个羟基的立体化学严格控制，并且这些蛋白质负责调节细胞周期和线粒体膜电位是1 alpha，25（OH）2D3类似物的主要目标。这些发现不仅为1 alpha，25（OH）2D3类似物的结构功能研究提供有用的信息，而且为开发用于治疗癌症的治疗剂提供有用的信息。

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