Targeting polyamine metabolism is a proven anticancer strategy. Cancers often escape the polyamine biosynthesis inhibitors by increased polyamine import. Therefore, there is much interest in identifying polyamine transport inhibitors (PTIs) to be used in combination therapies. In a search for new PTIs, we serendipitously discovered a LAT-1 efflux agonist, which induces intracellular depletion of methionine, leucine, spermidine, and spermine, but not putrescine. Because S-adenosylmethioninamine is made from methionine, a loss of intracellular methionine leads to an inability to biosynthesize spermidine, and spermine. Importantly, we found that this methionine-depletion approach to polyamine depletion could not be rescued by exogenous polyamines, thereby obviating the need for a PTI. Using 3H-leucine (the gold standard for LAT-1 transport studies) and JPH-203 (a specific LAT-1 inhibitor), we showed that the efflux agonist did not inhibit the uptake of extracellular leucine but instead facilitated the efflux of intracellular leucine pools.

中文翻译：

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在寻找多胺转运抑制剂期间偶然发现了亮氨酸和蛋氨酸消耗剂。

靶向多胺代谢是一种行之有效的抗癌策略。癌症通常通过增加多胺的进口而逃脱多胺生物合成抑制剂。因此，在鉴定将用于联合疗法中的多胺转运抑制剂（PTI）方面引起了很多兴趣。在寻找新的PTI时，我们偶然发现了LAT-1外排激动剂，它诱导了蛋氨酸，亮氨酸，亚精胺和亚精胺的细胞内消耗，但没有腐胺。因为S-腺苷蛋氨酸胺是由蛋氨酸制成的，所以细胞内蛋氨酸的损失导致无法生物合成亚精胺和精胺。重要的是，我们发现外源多胺无法挽救这种蛋氨酸消耗多胺消耗的方法，从而消除了对PTI的需求。