Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
Kikuchi Medical-Respiratory Clinic, Sapporo, Japan.
Cell Cycle. 2023 Sep;22(17):1854-1864. doi: 10.1080/15384101.2023.2243761. Epub 2023 Aug 17.
Mitotic slippage, which enables cancer cells to bypass cell death by transitioning from mitosis to the G1 phase without undergoing normal cytokinesis, is one likely mechanism of paclitaxel (PTX) resistance. DNA double-strand breaks (DSBs) in the G1 phase are mainly repaired through non-homologous end joining (NHEJ). Therefore, inhibiting NHEJ could augment the PTX-induced cytotoxicity by impeding the repair of PTX-induced DSBs during the G1 phase following mitotic slippage. We aimed to evaluate the effects of NHEJ inhibition on mitotic slippage after PTX treatment in non-small cell lung cancer (NSCLC). H1299, A549, H1975, and H520 NSCLC cell lines were employed. In addition, A-196 and JQ1 were used as NHEJ inhibitors. H1299 cells were PTX-resistant and exhibited an increased frequency of mitotic slippage upon PTX treatment. NHEJ inhibitors significantly augmented the PTX-induced cytotoxicity, DSBs, and apoptosis in H1299 cells. The newly generated PTX-resistant cells were even more prone to mitotic slippage following PTX treatment and susceptible to the combined therapy. Docetaxel further demonstrated synergistic effects with the NHEJ inhibitor in PTX-resistant cells. NHEJ inhibition may overcome intrinsic or acquired PTX resistance resulting from mitotic slippage by synergistically increasing the cytotoxic effects of antimitotic drugs in NSCLC.
有丝分裂滑溜，使癌细胞能够通过从有丝分裂到 G1 期的过渡而避免细胞死亡，而无需经历正常的胞质分裂，这是紫杉醇（PTX）耐药的一种可能机制。G1 期的 DNA 双链断裂（DSB）主要通过非同源末端连接（NHEJ）修复。因此，抑制 NHEJ 可以通过阻碍有丝分裂滑溜后 G1 期 PTX 诱导的 DSB 的修复来增强 PTX 诱导的细胞毒性。我们旨在评估 NHEJ 抑制对非小细胞肺癌（NSCLC）中 PTX 治疗后有丝分裂滑溜的影响。使用了 H1299、A549、H1975 和 H520 NSCLC 细胞系。此外，A-196 和 JQ1 被用作 NHEJ 抑制剂。H1299 细胞对 PTX 具有耐药性，并且在 PTX 处理后有丝分裂滑溜的频率增加。NHEJ 抑制剂显著增强了 H1299 细胞中 PTX 诱导的细胞毒性、DSB 和细胞凋亡。新生成的 PTX 耐药细胞在 PTX 处理后更容易发生有丝分裂滑溜，并易受联合治疗的影响。多西他赛进一步证明了在 PTX 耐药细胞中与 NHEJ 抑制剂的协同作用。NHEJ 抑制可能通过协同增加抗有丝分裂药物在 NSCLC 中的细胞毒性作用来克服有丝分裂滑溜引起的内在或获得性 PTX 耐药。
