文章：

磷酸二酯酶抑制以增强非小细胞肺癌对培美曲塞的敏感性：一把双刃剑策略

Phosphodiesterase Inhibition to Sensitize Non-Small-Cell Lung Cancer to Pemetrexed: A Double-Edged Strategy

原文发布日期：6 July 2024

DOI: 10.3390/cancers16132475

类型: Article

开放获取: 是

英文摘要：

Phosphosidesterases (PDEs) are key regulators of cyclic nucleotide signaling, controlling many hallmarks of cancer and playing a role in resistance to chemotherapy in non-small-cell lung cancer (NSCLC). We evaluated the anti-tumor activity of the anti-folate agent pemetrexed (PMX), alone or combined with biochemical inhibitors of PDE5, 8, 9, or 10, against squamous and non-squamous NCSLC cells. Genomic alterations to PDE genes (PDEmut) or PDE biochemical inhibition (PDEi) can sensitize NSCLC to PMX in vitro (observed in 50% NSCLC evaluated). The synergistic activity of PDEi with PMX required microdosing of the anti-folate drug. As single agents, none of the PDEis evaluated have anti-tumor activity. PDE biochemical inhibitors, targeting either cAMP or cGMP signaling (or both), resulted in significant cross-modulation of downstream pathways. The use of PDEi may present a new strategy to overcome PMX resistance of PDEwtNSCLC tumors but comes with important caveats, including the use of subtherapeutic PMX doses.

摘要翻译： 

磷酸二酯酶（PDEs）是环核苷酸信号传导的关键调节因子，控制着癌症的多种特征，并在非小细胞肺癌（NSCLC）的化疗耐药中发挥作用。我们评估了抗叶酸药物培美曲塞（PMX）单独使用或与PDE5、8、9或10的生化抑制剂联合使用，对鳞状和非鳞状非小细胞肺癌细胞的抗肿瘤活性。PDE基因的基因组改变（PDEmut）或PDE生化抑制（PDEi）可在体外使非小细胞肺癌对培美曲塞敏感（在所评估的50%非小细胞肺癌中观察到）。PDEi与培美曲塞的协同活性需要抗叶酸药物的微剂量使用。作为单一药物，所评估的PDEi均无抗肿瘤活性。靶向cAMP或cGMP信号传导（或两者）的PDE生化抑制剂，导致下游通路的显著交叉调节。使用PDEi可能为克服PDE野生型非小细胞肺癌肿瘤的培美曲塞耐药提供新策略，但存在重要注意事项，包括使用亚治疗剂量的培美曲塞。

原文链接：

Phosphodiesterase Inhibition to Sensitize Non-Small-Cell Lung Cancer to Pemetrexed: A Double-Edged Strategy