Objective

Tumor cells experience hypoxia, acidosis, and hypoglycemia. Metabolic adaptation to glucose shortage is essential to maintain tumor cells’ survival because of their high glucose requirement. This study evaluated the hypothesis that acidosis might promote tumor survival during glucose shortage and if so, explored a novel drug targeting metabolic vulnerability to glucose shortage.

Methods

Cell survival and bioenergetics metabolism were assessed in lung cancer cell lines. Our in-house small-molecule compounds were screened to identify those that kill cancer cells under low-glucose conditions. Cytotoxicity against non-cancerous cells was also assessed. Tumor growth was evaluated in vivo using a mouse engraft model.

Results

Acidosis limited the cellular consumption of glucose and ATP, causing tumor cells to enter a metabolically dormant but energetically economic state, which promoted tumor cell survival during glucose deficiency. We identified ESI-09, a previously known exchange protein directly activated by cAMP (EAPC) inhibitor, as an anti-cancer compound that inhibited cancer cells under low-glucose conditions even when associated with acidosis. Bioenergetic studies showed that independent of EPAC inhibition, ESI-09 was a safer mitochondrial uncoupler than a classical uncoupler and created a futile cycle of mitochondrial respiration, leading to decreased ATP production, increased ATP dissipation, and fuel scavenging. Accordingly, ESI-09 exhibited more cytotoxic effects under low-glucose conditions than under normal glucose conditions. ESI-09 was also more effective than actively proliferating cells on quiescent glucose-restricted cells. Cisplatin showed opposite effects. ESI-09 inhibited tumor growth in lung cancer engraft mice.

Conclusions

This study highlights the acidosis-induced promotion of tumor survival during glucose shortage and demonstrates that ESI-09 is a novel potent anti-cancer mitochondrial uncoupler that targets a metabolic vulnerability to glucose shortage even when associated with acidosis. The higher cytotoxicity under lower-than-normal glucose conditions suggests that ESI-09 is safer than conventional chemotherapy, can target the metabolic vulnerability of tumor cells to low-glucose stress, and is applicable to many cancer cell types.

中文翻译：

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针对在低营养酸性微环境中存活的肿瘤细胞能量代谢的抗癌策略

客观的

肿瘤细胞经历缺氧、酸中毒和低血糖。对葡萄糖短缺的代谢适应对于维持肿瘤细胞的存活至关重要，因为它们需要高葡萄糖。该研究评估了酸中毒可能在葡萄糖短缺期间促进肿瘤存活的假设，如果是这样，则探索了一种针对葡萄糖短缺代谢脆弱性的新型药物。

方法

在肺癌细胞系中评估细胞存活和生物能量代谢。我们对我们内部的小分子化合物进行了筛选，以确定那些在低糖条件下可以杀死癌细胞的化合物。还评估了对非癌细胞的细胞毒性。使用小鼠移植模型在体内评估肿瘤生长。

结果

酸中毒限制了细胞对葡萄糖和 ATP 的消耗，导致肿瘤细胞进入代谢休眠但精力充沛的经济状态，从而促进了葡萄糖缺乏期间肿瘤细胞的存活。我们确定了 ESI-09，一种先前已知的由 cAMP (EAPC) 抑制剂直接激活的交换蛋白，作为一种抗癌化合物，即使在与酸中毒相关的情况下，它也能在低葡萄糖条件下抑制癌细胞。生物能学研究表明，与 EPAC 抑制无关，ESI-09 是比经典解偶联剂更安全的线粒体解偶联剂，并造成线粒体呼吸的无效循环，导致 ATP 产生减少、ATP 耗散增加和燃料清除。因此，ESI-09 在低葡萄糖条件下比在正常葡萄糖条件下表现出更多的细胞毒性作用。ESI-09 也比静止葡萄糖限制细胞上的活跃增殖细胞更有效。顺铂显示出相反的效果。ESI-09 抑制肺癌移植小鼠的肿瘤生长。

结论

这项研究强调了葡萄糖短缺期间酸中毒诱导的肿瘤存活率的提高，并证明 ESI-09 是一种新型有效的抗癌线粒体解偶联剂，即使与酸中毒有关，它也能针对葡萄糖短缺的代谢脆弱性。在低于正常葡萄糖条件下更高的细胞毒性表明 ESI-09 比常规化疗更安全，可以靶向肿瘤细胞对低葡萄糖应激的代谢脆弱性，并且适用于多种癌细胞类型。