DT-13 synergistically enhanced vinorelbine-mediated mitotic arrest through inhibition of FOXM1-BICD2 axis in non-small-cell lung cancer cells.
DT-13 synergistically enhanced vinorelbine-mediated mitotic arrest through inhibition of FOXM1-BICD2 axis in non-small-cell lung cancer cells.
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DT-13 通过抑制非小细胞肺癌细胞中的 FOXM1-BICD2 轴协同增强长春瑞滨介导的有丝分裂阻滞
DOI：
10.1038/cddis.2017.218
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发表时间：
2017-05-25
影响因子：
9
通讯作者：
Lin S
中科院分区：
文献类型：
--
作者：
Li H;Sun L;Li H;Lv X;Semukunzi H;Li R;Yu J;Yuan S;Lin S
非小细胞肺癌（NSCLC）是最常见的恶性疾病，也是癌症相关死亡的主要原因。联合治疗仍是非小细胞肺癌临床治疗的主要策略。长春瑞滨（NVB）是一种半合成的长春花生物碱，用于晚期和转移性非小细胞肺癌，通过破坏微管的形成，诱导有丝分裂停止和细胞死亡。然而，NVB的副作用严重影响了其临床治疗效果。因此，开发新的药物与NVB协同作用，减少不良反应具有重要意义。在我们的研究中，我们发现矮百合块茎的皂苷单体13 DT-13具有抗血管生成和抗转移的作用，并与NVB协同抑制NSCLC细胞的增殖。通过组合指数值证实了DT-13与NVB的协同作用。此外，DT-13和NVB协同作用，抑制长期的菌落形成。此外，DT-13/NVB共同处理可诱导有丝分裂停止和随后的细胞凋亡。在机制上，我们发现联合处理显著降低了转录因子叉头盒M1 （FOXM1）的核表达和运动适配器BICD2 （BICD2）的水平。重要的是，癌基因FOXM1被确定为BICD2的关键调控因子，而BICD2在nvb诱导的有丝分裂纺锤体缺陷中起着关键作用。此外，FOXM1和BICD2的过表达显著逆转了DT-13/NVB共处理诱导的有丝分裂阻滞，针对这两个基因的sirna大大增加了组合效应。此外，体内研究显示，DT-13联合NVB可显著抑制裸鼠异种移植瘤模型的肿瘤生长，下调肿瘤组织中FOXM1和BICD2的表达，与体外研究一致。总之，DT-13可能为NSCLC治疗中NVB的化疗增敏提供了一种新的策略。
Non-small-cell lung cancer (NSCLC) is the most commonly diagnosed malignant disease with the leading cause of cancer-related death. Combination treatment remains the major strategy in the clinical therapy of NSCLC. Vinorelbine (NVB), a semi-synthetic vinca alkaloid, is used for advanced and metastatic NSCLC by destabilizing microtubule formation to induce mitotic arrest and cell death. However, the side effect of NVB heavily affected its effectiveness in clinical therapy. Hence, it is of great significance to develop new agents to synergize with NVB and decrease the adverse effect. In our study, we found that the saponin monomer 13 of the dwarf lilyturf tuber, DT-13, exhibiting anti-angiogenesis and anti-metastasis effect, synergized with NVB to inhibit cell proliferation in NSCLC cells. The synergistic interaction of DT-13 and NVB was confirmed by combination Index values. Also, DT-13 and NVB act in concert to inhibit the long-term colony formation. Furthermore, DT-13/NVB co-treatment cooperated to induce mitotic arrest and subsequent apoptosis. Mechanistically, we found that nuclear expression of transcription factors forkhead box M1 (FOXM1) and levels of motor adaptor bicaudal D2 (BICD2) were dramatically reduced by combination treatment. Importantly, oncogene FOXM1 was identified as the crucial regulator of BICD2, which played critical roles in NVB-induced mitotic spindle defects. Moreover, overexpression of FOXM1 and BICD2 significantly reversed mitotic arrest induced by DT-13/NVB co-treatment, and siRNAs against both genes greatly increased the combinational effects. In addition, in vivo study revealed that DT-13 combined with NVB significantly suppressed tumor growth in nude mice xenograft model, and downregulated the expression of FOXM1 and BICD2 in tumor tissues, which was consistent with in vitro study. In conclusion, DT-13 might provide a novel strategy for the chemosensitization of NVB in NSCLC therapy.
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