紫杉烷类药物和 CDK4/6 抑制剂在携 KRAS 突变的肺癌细胞和小鼠中的协同抗肿瘤作用。
Synergistic Antitumor Effect of Taxanes and CDK4/6 Inhibitor in Lung Cancer Cells and Mice Harboring KRAS Mutations.
机构信息
Laboratory of Medical Oncology, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Department of Biomedicine & Health Sciences, Seoul, Republic of Korea.
出版信息
Anticancer Res. 2021 Oct;41(10):4807-4820. doi: 10.21873/anticanres.15296.
BACKGROUND/AIM: LY2835219 (LY), a novel CDK4/6 inhibitor, prevents cell proliferation through G1 arrest. Docetaxel (DTX) and paclitaxel (PTX) are cytotoxic drugs targeting tubulin-mediated apoptotic cell death via G2/M arrest. We evaluated the antitumor effects of DTX/PTX and LY individually and in combination in lung adenocarcinoma cells with or without KRAS mutations and xenograft mice harboring KRAS mutations.
MATERIALS AND METHODS
We investigated in vitro/in vivo changes in signaling molecules and analyzed cell proliferation, cycle, and apoptosis via flow cytometry and western blotting.
RESULTS
LY cytotoxicity was dose-dependent and varied with KRAS mutation status. DTX→LY showed synergistic cytotoxicity regardless of KRAS mutation. Furthermore, the synergistic effect of PTX→LY was significantly greater than that of PTX+LY. DTX→LY remarkably reduced the number of G0/G1 cells and increased the number of G2/M arrested cells, resulting in an increase in apoptosis and subG1 cells.
CONCLUSION
DTX→LY has synergistic antitumor effect in lung cancer cells and xenograft mice regardless of KRAS mutation.
背景/目的：LY2835219（LY）是一种新型的 CDK4/6 抑制剂，通过 G1 期阻滞来抑制细胞增殖。多西紫杉醇（DTX）和紫杉醇（PTX）是通过 G2/M 期阻滞靶向微管介导的细胞凋亡而发挥细胞毒性的药物。我们评估了 DTX/PTX 和 LY 单独使用以及联合使用对具有或不具有 KRAS 突变的肺腺癌细胞以及携带 KRAS 突变的异种移植小鼠的抗肿瘤作用。
材料和方法
我们通过流式细胞术和 Western blot 分析了体外/体内信号分子的变化，并分析了细胞增殖、周期和凋亡。
结果
LY 的细胞毒性呈剂量依赖性，并随 KRAS 突变状态而变化。无论 KRAS 突变状态如何，DTX→LY 均表现出协同的细胞毒性。此外，PTX→LY 的协同作用明显大于 PTX+LY。DTX→LY 显著减少了 G0/G1 期细胞的数量，并增加了 G2/M 期阻滞细胞的数量，导致细胞凋亡和亚 G1 期细胞增加。
结论
无论 KRAS 突变状态如何，DTX→LY 在肺癌细胞和异种移植小鼠中均具有协同的抗肿瘤作用。
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