由于乳酸性酸中毒与癌症的相关性，已经开发了几种针对其产生和/或调节的治疗策略。在这个问题上，乳酸脱氢酶或单羧酸转运蛋白等关键蛋白的抑制方法已显示出有希望的结果，然而，代谢可塑性和肿瘤异质性限制了它们的功效。在这项研究中，我们利用一种名为 Lactrans-1 的小分子离子载体，探索了一种新策略的抗癌潜力，该策略的基础是干扰乳酸渗透性，与单羧酸转运蛋白活性无关。 Lactrans-1 源自 Click-tambjamines，可促进脂质体模型中乳酸的跨膜运输并降低癌细胞活力。结果显示，根据测试的细胞系，Lactrans-1 会引发细胞凋亡和坏死，与一线标准化疗药物顺铂联合显示出协同效应。该化合物向外转运乳酸阴离子的能力在 A549 和 HeLa 细胞中得到证实，这两种癌细胞系具有不同的乳酸生成率。此外，通过细胞活力逆转实验，可以建立乳酸转运量和所表现出的细胞毒性作用之间的相关性。乳酸阴离子的运动伴随着细胞内pH值的紊乱，包括溶酶体的碱化以及细胞质和线粒体的酸化。我们还观察到线粒体肿胀、ROS 产生增加以及氧化应激信号通路 p38-MAPK 和 JNK/SAPK 的激活。我们的研究结果证明，乳酸通透性的增强对于细胞 pH 稳态至关重要，并能有效引发癌细胞死亡，这表明 Lactrans-1 可能是一种有前景的抗癌疗法。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Due to the relevance of lactic acidosis in cancer, several therapeutic strategies have been developed targeting its production and/or regulation. In this matter, inhibition approaches of key proteins such as lactate dehydrogenase or monocarboxylate transporters have showed promising results, however, metabolic plasticity and tumor heterogeneity limits their efficacy. In this study, we explored the anticancer potential of a new strategy based on disturbing lactate permeability independently of monocarboxylate transporters activity using a small molecule ionophore named Lactrans-1. Derived from click-tambjamines, Lactrans-1 facilitates transmembrane lactate transportation in liposome models and reduces cancer cell viability. The results showed that Lactrans-1 triggered both apoptosis and necrosis depending on the cell line tested, displaying a synergistic effect in combination with first-line standard chemotherapeutic cisplatin. The ability of this compound to transport outward lactate anions was confirmed in A549 and HeLa cells, two cancer cell lines having distinct rates of lactate production. In addition, through cell viability reversion experiments it was possible to establish a correlation between the amount of lactate transported and the cytotoxic effect exhibited. The movement of lactate anions was accompanied with intracellular pH disturbances that included basification of lysosomes and acidification of the cytosol and mitochondria. We also observed mitochondrial swelling, increased ROS production and activation of oxidative stress signaling pathways p38-MAPK and JNK/SAPK. Our findings provide evidence that enhancement of lactate permeability is critical for cellular pH homeostasis and effective to trigger cancer cell death, suggesting that Lactrans-1 may be a promising anticancer therapy.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.