A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer.
A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer.
复制标题
针对谷氨酰胺成瘾治疗人类肝癌的强大药物组合策略
DOI：
10.7554/elife.56749
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发表时间：
2020-10-05
期刊：
影响因子：
7.7
通讯作者：
Bernards R
中科院分区：
文献类型：
--
作者：
Jin H;Wang S;Zaal EA;Wang C;Wu H;Bosma A;Jochems F;Isima N;Jin G;Lieftink C;Beijersbergen R;Berkers CR;Qin W;Bernards R
癌细胞对谷氨酰胺的依赖性可能在治疗上被利用，作为治疗缺乏药物驱动基因的癌症的新策略。在这里，我们发现，人肝癌是依赖于细胞外谷氨酰胺。然而，使用谷氨酰胺酶抑制剂CB-839作为单一疗法靶向谷氨酰胺成瘾具有非常有限的抗癌作用，即使是针对大多数谷氨酰胺成瘾的人肝癌细胞。使用化学库，我们确定了V-9302，一种新的谷氨酰胺转运蛋白ASCT 2的抑制剂，作为敏感谷氨酰胺依赖性（GD）细胞CB-839治疗。机械上，CB-839和V-9302的组合耗尽谷胱甘肽并诱导活性氧（ROS），导致GD细胞凋亡。此外，该组合在体内HCC异种移植小鼠模型中也显示出肿瘤抑制。我们的研究结果表明，通过靶向谷氨酰胺酶和谷氨酰胺转运体ASCT 2双重抑制谷氨酰胺代谢代表了谷氨酰胺成瘾肝癌的潜在新治疗策略。
The dependency of cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells. Using a chemical library, we identified V-9302, a novel inhibitor of glutamine transporter ASCT2, as sensitizing glutamine dependent (GD) cells to CB-839 treatment. Mechanically, a combination of CB-839 and V-9302 depleted glutathione and induced reactive oxygen species (ROS), resulting in apoptosis of GD cells. Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.