PDF(Pubmed)
Abstract：
Although up to 80% small cell lung cancer (SCLC) patients\' response is good for first-line chemotherapy regimen, most patients develop recurrence of the disease within weeks to months. Here, we report cytostatic effect of leflunomide (Leflu) and teriflunomide (Teri) on SCLC cell proliferation through inhibition of DRP1 phosphorylation at Ser616 and decreased mitochondrial fragmentation. When administered together, Teri and carboplatin (Carbo) act synergistically to significantly inhibit cell proliferation and DRP1 phosphorylation, reduce abundance of intermediates in pyrimidine de novo pathway, and increase apoptosis and DNA damage. Combination of Leflu&Carbo has anti-tumorigenic effect in vivo. Additionally, lurbinectedin (Lur) and Teri potently and synergistically inhibited spheroid growth and depleted uridine and DRP1 phosphorylation in mouse tumors. Our results suggest combinations of Carbo and Lur with Teri or Leflu are efficacious and underscore how the relationship between DRP1/DHODH and mitochondrial plasticity serves as a potential therapeutic target to validate these treatment strategies in SCLC clinical trials.
摘要：
尽管高达80%的小细胞肺癌（SCLC）患者对一线化疗方案的反应良好，大多数患者在数周至数月内出现疾病复发。这里,我们报道了来氟米特(Leflu)和特立氟胺(Teri)通过抑制Ser616的DRP1磷酸化和减少线粒体片段化对SCLC细胞增殖的细胞抑制作用.当一起施用时，Teri和卡铂（Carbo）协同作用，显著抑制细胞增殖和DRP1磷酸化，减少嘧啶从头途径中中间体的丰度，并增加细胞凋亡和DNA损伤。Leflu和Carbo的组合在体内具有抗肿瘤作用。此外,lurbinectedin（Lur）和Teri有效且协同地抑制了小鼠肿瘤中的球体生长，并减少了尿苷和DRP1磷酸化。我们的结果表明，Carbo和Lur与Teri或Leflu的组合是有效的，并强调了DRP1/DHODH与线粒体可塑性之间的关系如何作为在SCLC临床试验中验证这些治疗策略的潜在治疗目标。
