Purpose

Hyponatraemia is frequently observed in cancer patients and can be due to the syndrome of inappropriate anti-diuresis (SIAD), related to ectopic vasopressin secretion, particularly in small cell lung cancer (SCLC). Hyponatraemia is associated with a worse outcome in cancer patients. The vasopressin receptor antagonist tolvaptan effectively corrects hyponatraemia secondary to SIAD and there is in vitro evidence that it has also an antiproliferative effect in cancer cells. The purpose of this study was i) to analyse the effect of low sodium concentrations ([Na⁺]) in SCLC cells and ii) to determine whether tolvaptan counteracts tumor progression.

Methods

We evaluated cell proliferation, cell cycle, apoptosis, oxidative stress, invasivity in low [Na⁺] as well as after exposure to tolvaptan. We also analysed the intracellular signalling pathways involved.

Results

In reduced [Na⁺] cell proliferation was significantly increased compared to normal [Na⁺] and cells were mostly distributed in the G2/M phase. Apoptosis appeared reduced. In addition, the ability to cross matrigel-coated membranes markedly increased. As observed in other cancer cell models, the expression of the heme-oxigenase-1 gene was increased. Finally, we found that in cells cultured in low [Na⁺] the RhoA/ROCK1/2 pathway, which is involved in the regulation of actin cytoskeleton, was activated. On the other hand, we found that tolvaptan effectively inhibited cell proliferation, anchorage-independent growth, invasivity and promoted apoptosis. Accordingly, the RhoA/ROCK-1/2 pathway was inhibited.

Conclusions

These findings demonstrate for the first time that low [Na⁺] sodium favours tumor progression in SCLC cells, whereas tolvaptan effectively inhibits cell proliferation, survival and invasivity.

中文翻译：

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低钠和托伐普坦对人小细胞肺癌细胞有相反的作用

目的

在癌症患者中经常观察到低钠血症，这可能是由于与异位加压素分泌有关的抗利尿不适当综合征 (SIAD)，特别是在小细胞肺癌 (SCLC) 中。低钠血症与癌症患者的预后较差有关。加压素受体拮抗剂托伐普坦可有效纠正继发于 SIAD 的低钠血症，并且有体外证据表明它在癌细胞中也具有抗增殖作用。本研究的目的是 i) 分析低钠浓度 ([Na ⁺ ]) 在 SCLC 细胞中的影响，以及 ii) 确定托伐普坦是否能抵消肿瘤进展。

方法

^{我们评估了低 [Na +} ] 以及暴露于托伐普坦后的细胞增殖、细胞周期、细胞凋亡、氧化应激、侵袭性。我们还分析了所涉及的细胞内信号通路。

结果

^{与正常[Na + ]相比，[Na +} ]降低的细胞增殖显着增加，并且细胞主要分布在G2 / M期。细胞凋亡似乎减少了。此外，穿过基质胶涂层膜的能力显着提高。正如在其他癌细胞模型中观察到的，血红素氧化酶 1 基因的表达增加。最后，我们发现在低 [Na ⁺ ] 培养的细胞中，参与肌动蛋白细胞骨架调节的 RhoA/ROCK1/2 通路被激活。另一方面，我们发现托伐普坦有效抑制细胞增殖、非贴壁生长、侵袭性和促进细胞凋亡。因此，RhoA/ROCK-1/2 通路被抑制。

结论

这些发现首次证明低 [Na ⁺ ] 钠有利于 SCLC 细胞的肿瘤进展，而托伐普坦有效抑制细胞增殖、存活和侵袭。