Weidemann Heidrun, Sarsour Alaa Daoud, Brodie Chaya
Department Internal Medicine, St. Georg Hospital, Eisenach, Germany.
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Front Physiol. 2025 Oct 3;16:1685871. doi: 10.3389/fphys.2025.1685871. eCollection 2025.
Since their first discovery as potential anti-cancer drugs there is increasing evidence that cardiotonic steroids e.g., Ouabain have anti-tumor properties by interacting with their natural receptor the Na-K-ATPase (NKA) and by inducing diverse intracellular signaling pathways. It is well established that the NKA represents a signal transducer that is partly independent from its pump activity. In the early 90ies endogenous Ouabain (EO) was discovered in the serum of different species, including human beings. It was demonstrated that Ouabain is synthesized and released from the adrenal gland. The concept of endogenous Ouabain as a "stress hormone" playing important roles in the regulation of hypertension, volume homeostasis, cardiac function and, last but not least, cancer was established. We developed the hypothesis that long-lasting stress with adrenal exhaustion i.e., very low endogenous Ouabain levels may predispose to tumorigenesis. On the contrary, some authors recently have questioned the tumor-protective role of Ouabain and claimed that endogenous Ouabain promotes tumor escape mechanisms. In order to clarify these and other opposing or contradictious data we will summarize in this review PubMed data from the last 50 years about "Ouabain and cancer". We will demonstrate that overwhelming evidence speaks in favor of an anti-tumor effect of Ouabain. Exogenous Ouabain has been shown to be identical to endogenous Ouabain, hence we conclude that a potential harmful role of endogenous Ouabain is minor compared to the huge potential benefit of Ouabain in defeating and suppressing the development of cancer.
自从强心甾体类药物（如哇巴因）首次被发现具有潜在的抗癌作用以来，越来越多的证据表明，它们通过与其天然受体钠钾-ATP酶（NKA）相互作用并诱导多种细胞内信号通路，从而具有抗肿瘤特性。众所周知，NKA是一种信号转导分子，其部分功能与其泵活性无关。20世纪90年代初，在包括人类在内的不同物种的血清中发现了内源性哇巴因（EO）。研究表明，哇巴因是由肾上腺合成并释放的。内源性哇巴因作为一种“应激激素”，在高血压、容量稳态、心脏功能以及最后但同样重要的癌症调节中发挥重要作用的概念由此确立。我们提出了一个假说，即长期应激导致肾上腺功能衰竭，即内源性哇巴因水平极低，可能易引发肿瘤发生。相反，最近一些作者对哇巴因的肿瘤保护作用提出了质疑，并声称内源性哇巴因促进肿瘤逃逸机制。为了澄清这些以及其他相互矛盾的数据，我们将在本综述中总结过去50年PubMed数据库中关于“哇巴因与癌症”的数据。我们将证明，压倒性的证据支持哇巴因具有抗肿瘤作用。外源性哇巴因已被证明与内源性哇巴因相同，因此我们得出结论，与哇巴因在对抗和抑制癌症发展方面的巨大潜在益处相比，内源性哇巴因的潜在有害作用较小。
