Inserm, U, Université François Rabelais, Tours, France.
Br J Pharmacol. 2011 Jan;162(2):464-79. doi: 10.1111/j.1476-5381.2010.01044.x.
The 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (edelfosine) is an ether-linked phospholipid with promising anti-cancer properties but some side effects that preclude its full clinical therapeutic exploitation. We hypothesized that this lipid could interact with plasma membrane ion channels and modulate their function.
Using cell migration-proliferation assays, patch clamp, spectrofluorimetry and ¹²⁵I-Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA-MB-435s cells, mediated by the small conductance Ca²(+) -activated K(+) channel, SK3/K(Ca)2.3.
Edelfosine (1 µM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/K(Ca)2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit ¹²⁵I-Apamin binding to this SK(Ca) channel; rather, it reduced the calcium sensitivity of SK3/K(Ca)2.3 channel and dramatically decreased intracellular Ca²(+) concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SK(Ca) channel blockers. In contrast, K+ channel openers prevented edelfosine-induced anti-migratory effects. SK3 protein knockdown decreased cell migration and totally abolished the effect of edelfosine on MDA-MB-435s cell migration. In contrast, transient expression of SK3/K(Ca)2.3 protein in a SK3/K(Ca)2.3-deficient cell line increased cell migration and made these cells responsive to edelfosine.
Our data clearly establish edelfosine as an inhibitor of cancer cell migration by acting on SK3/K(Ca)2.3 channels and provide insights into the future development of a new class of migration-targeted, anti-cancer agents.
1-O-辛基-2-O-甲基-sn-甘油-3-磷酸胆碱（埃得福林）是一种醚连接的磷脂，具有有前途的抗癌特性，但一些副作用限制了其充分的临床治疗开发。我们假设这种脂质可以与质膜离子通道相互作用并调节其功能。
使用细胞迁移-增殖测定、膜片钳、荧光光谱法和 ¹²⁵I-Apamin 结合实验，我们研究了埃得福林对乳腺癌 MDA-MB-435s 细胞迁移的影响，这种迁移是由小电导钙激活钾通道 SK3/K(Ca)2.3 介导的。
埃得福林（1 µM）通过显著抑制 SK3/K(Ca)2.3 通道的活性，导致质膜去极化，我们之前已经证明该通道在癌细胞迁移中发挥重要作用。埃得福林不抑制 ¹²⁵I-Apamin 与该 SK(Ca)通道的结合；相反，它降低了 SK3/K(Ca)2.3 通道的钙敏感性，并显著降低了细胞内 Ca²(+)浓度，这可能是由于插入质膜中，正如蛋白酶 K 实验所表明的那样。埃得福林对细胞迁移的抑制程度与已知的 SK(Ca)通道阻滞剂相同。相比之下，K+通道开放剂可防止埃得福林引起的抗迁移作用。SK3 蛋白敲低降低了细胞迁移，完全消除了埃得福林对 MDA-MB-435s 细胞迁移的影响。相比之下，在 SK3/K(Ca)2.3 缺陷细胞系中瞬时表达 SK3/K(Ca)2.3 蛋白增加了细胞迁移，并使这些细胞对埃得福林敏感。
我们的数据清楚地表明，埃得福林通过作用于 SK3/K(Ca)2.3 通道，成为抑制癌细胞迁移的抑制剂，并为开发新的一类针对迁移的抗癌药物提供了新的思路。
