Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer
Sodium chloride (NaCl) potentiates digoxin-induced anti-tumor activity in small cell lung cancer
复制标题
氯化钠 (NaCl) 增强地高辛诱导的小细胞肺癌抗肿瘤活性
DOI：
10.1080/15384047.2018.1504723
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发表时间：
2019-01-02
影响因子：
3.6
通讯作者：
Lin, Wenchu
中科院分区：
文献类型：
--
作者：
Deng, Ke;Shen, Jiawei;Lin, Wenchu
小细胞肺癌（small cell lung cancer，SCLC）是一种死亡率极高的神经内分泌恶性肿瘤。对于晚期SCLC患者，迫切需要有效的新疗法。通过筛选FDA批准的药物库，我们鉴定了一种强心苷（CG），即地高辛（细胞Na+/K+ ATP酶泵的抑制剂），其在抑制SCLC细胞生长方面非常有效。有趣的研究结果表明，NaCl补充显着增强地高辛的抗肿瘤活性在体外和体内模型的小细胞肺癌。随后的分析表明，地高辛/NaCl的这种新组合引起细胞内Na+和Ca 2+水平的上调，诱导SCLC细胞的更高静息膜电位。我们还发现，这种组合导致SCLC细胞的形态萎缩，以及高水平的细胞色素C释放。最后，我们的数据显示，NaCl补充能够诱导ATP 1A 1（Na+/K+ ATP酶亚基）的表达，其中直接有助于SCLC细胞对地高辛的敏感性增加。因此，这是第一次证明NaCl是一种有效的补充剂，需要地高辛对SCLC的上级抗癌作用。此外，我们的研究表明，地高辛治疗可能需要在未来的小细胞肺癌临床试验中与NaCl补充剂相结合，特别是在小细胞肺癌患者中经常存在低Na+的情况下。
Small cell lung cancer (SCLC) is a malignant neuroendocrine tumor with very high mortality. Effective new therapy for advanced SCLC patients is urgently needed. By screening a FDA-approved drug library, we identified a cardiac glycoside (CG), namely digoxin (an inhibitor of cellular Na+/K+ ATPase pump), which was highly effective in inhibiting SCLC cell growth. Intriguing findings showed that NaCl supplement markedly enhanced the anti-tumor activities of digoxin in both in vitro and in vivo models of SCLC. Subsequent analysis revealed that this novel combination of digoxin/NaCl caused an up-regulation of intracellular Na+ and Ca2+ levels with an induction of higher resting membrane potential of SCLC cells. We also found that this combination lead to morphological shrinking of SCLC cells, together with high levels of cytochrome C release. Lastly, our data revealed that NaCl supplement was able to induce the expression of ATP1A1 (a Na+/K+ ATPase subunit), in which contributes directly to the increased sensitivity of SCLC cells to digoxin. Thus, this is the first demonstration that NaCl is a potent supplement necessitating superior anti-cancer effects of digoxin for SCLC. Further, our study suggests that digoxin treatment could need to be combined with NaCl supplement in future clinical trial of SCLC, particularly where low Na+ is often present in SCLC patients.