Mirzapoiazova Tamara, Tseng Liz, Mambetsariev Bolot, Li Haiqing, Lou Chih-Hong, Pozhitkov Alex, Ramisetty Sravani Keerthi, Nam Sangkil, Mambetsariev Isa, Armstrong Brian, Malhotra Jyoti, Arvanitis Leonidas, Nasser Mohd Wasim, Batra Surinder K, Rosen Steven T, Wheeler Deric L, Singhal Sharad S, Kulkarni Prakash, Salgia Ravi
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.
Department of Shared Resources, Light Microscopy Digital Imaging Core, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
iScience. 2024 May 27;27(6):110132. doi: 10.1016/j.isci.2024.110132. eCollection 2024 Jun 21.
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 Ser 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 pathway, and increase apoptosis and DNA damage. Combination of Leflu&Carbo has anti-tumorigenic effect . 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.
尽管高达80%的小细胞肺癌（SCLC）患者对一线化疗方案反应良好，但大多数患者在数周内至数月内疾病复发。在此，我们报告了来氟米特（Leflu）和特立氟胺（Teri）通过抑制丝氨酸处的动力相关蛋白1（DRP1）磷酸化和减少线粒体碎片化对SCLC细胞增殖的细胞抑制作用。当联合使用时，Teri与卡铂（Carbo）协同作用，显著抑制细胞增殖和DRP1磷酸化，减少嘧啶途径中间产物的丰度，并增加细胞凋亡和DNA损伤。Leflu与Carbo联合具有抗肿瘤作用。此外，鲁比卡丁（Lur）和Teri在小鼠肿瘤中有效且协同地抑制球体生长，并消耗尿苷和DRP1磷酸化。我们的结果表明，Carbo与Lur和Teri或Leflu联合是有效的，并强调了DRP1/二氢乳清酸脱氢酶（DHODH）与线粒体可塑性之间的关系如何作为一个潜在的治疗靶点，在SCLC临床试验中验证这些治疗策略。
