Department of Histology, Faculty of Medicine, Medical University of Gdańsk, 1a Debinki, Gdańsk, 80-211, Poland.
Department of Histology, Faculty of Medicine, Medical University of Gdańsk, 1a Debinki, Gdańsk, 80-211, Poland.
Eur J Pharmacol. 2020 Aug 15;881:173170. doi: 10.1016/j.ejphar.2020.173170. Epub 2020 May 20.
Vitamin D compounds are versatile molecules widely considered as promising agents in cancer prevention and treatment, including melanoma. Previously we investigated series of double point modified vitamin D analogs as well as non-calcemic 20S-hydroxyvitamin D and 21-hydroxypregnacalciferol as to their anti-melanoma activity. Surprisingly, short side-chain vitamin D analogs were found to be biologically active compounds. Thus, here we tested novel derivatives of pregnacalciferol with an additional hydroxyl at the end of the truncated side chain, PRI-1203 and PRI-1204, as to their potency against human melanoma A375 and RPMI7951 cell lines. Tested compounds are geometric isomers, with 19-methylene positioned in PRI-1203 like in a calcitriol molecule, but reversed in the PRI-1204 analog to the (5E,7E) geometry (5,6-trans). We noticed a decrease in cells viability exerted by PRI-1203. The antiproliferative effect of PRI-1204 was very low, emphasizing the importance of the natural 19-methylene geometry in the PRI-1203. PRI-1203 was also effective in inhibition of A375 melanoma cells migration. PRI-1203, but not PRI-1204, increased the percentage of A375 and RPMI7951 melanoma cells in the G0/G1 phase of cell cycle, possibly in a p21 and p27 independent manner. Both, analogs have very low effect on the level of CYP24A1 mRNA, in comparison to active form of vitamin D - 1.25(OH)2D3. In addition, both tested compounds failed to elicit VDR translocation to the nucleus. Thus, it could be postulated that side chain shortening strongly affects binding of analogs to VDR and activation of genomic responses, however do not impair their antiproliferative activities.
维生素 D 化合物是用途广泛的分子，被广泛认为是预防和治疗癌症的有前途的药物，包括黑色素瘤。我们之前研究了一系列双点修饰的维生素 D 类似物以及非钙调的 20S-羟基维生素 D 和 21-羟孕甾烷钙作为其抗黑色素瘤活性。令人惊讶的是，短侧链维生素 D 类似物被发现是具有生物活性的化合物。因此，我们在这里测试了具有末端截断侧链上额外羟基的新型孕甾烷钙类似物 PRI-1203 和 PRI-1204，以研究它们对人黑色素瘤 A375 和 RPMI7951 细胞系的效力。测试化合物是几何异构体，PRI-1203 中的 19-亚甲基位于类似于骨化三醇分子的位置，但在 PRI-1204 类似物中反转至（5E，7E）几何形状（5,6-反式）。我们注意到 PRI-1203 降低了细胞活力。PRI-1204 的抗增殖作用非常低，强调了 PRI-1203 中天然 19-亚甲基几何形状的重要性。PRI-1203 还能有效抑制 A375 黑色素瘤细胞迁移。PRI-1203，但不是 PRI-1204，增加了 A375 和 RPMI7951 黑色素瘤细胞在细胞周期 G0/G1 期的百分比，可能以 p21 和 p27 不依赖的方式。与活性形式的维生素 D-1,25(OH)2D3 相比，这两种类似物对 CYP24A1 mRNA 的水平都有非常低的影响。此外，这两种测试化合物都未能引起 VDR 向核内易位。因此，可以假设侧链缩短强烈影响类似物与 VDR 的结合和基因组反应的激活，但不会损害它们的抗增殖活性。
