Synergistic anticancer effect of combined use of Trichosanthes kirilowii with cisplatin and pemetrexed enhances apoptosis of H1299 non-small-cell lung cancer cells via modulation of ErbB3
Synergistic anticancer effect of combined use of Trichosanthes kirilowii with cisplatin and pemetrexed enhances apoptosis of H1299 non-small-cell lung cancer cells via modulation of ErbB3
复制标题
DOI：
10.1016/j.phymed.2019.153109
复制
发表时间：
2020-01-01
期刊：
影响因子：
7.9
通讯作者：
Ko, Seong-Gyu
中科院分区：
文献类型：
--
作者：
Ku, Jin Mo;Hong, Se Hyang;Ko, Seong-Gyu
背景：肺癌是世界范围内最常见的恶性肿瘤之一。为了治疗肺癌，开发和测试了各种抗癌药物，但由于耐药性而失败。在本研究中，我们测试了草药，如TK和CuD，作为抗癌药物，以减少副作用和resistance.Methods：细胞活力通过MIT测定。流式细胞仪检测细胞周期阻滞情况。通过annexin V-FITC/PI测定来测量葫芦素D诱导的细胞凋亡。我们进行了RTK试剂盒分析。通过蛋白质印迹分析测量p-ErbB 3、p-STAT 3、p-NF-κ B和半胱天冬酶的水平。免疫细胞化学法检测ErbB 3的核染色。结果：在原代培养的人非小细胞肺癌细胞中，TK与CDDP、PXD有协同作用。CDDP/PXD与TK或CuD联合应用可抑制H1299细胞的增殖。CDDP/PXD与TK或CuD联合应用可诱导H1299细胞发生亚G1期和G2/M期阻滞。CDDP/ PXD与TK或CuD联合应用可诱导H1299细胞凋亡，调节凋亡分子，引起细胞形态学改变，抑制集落形成。我们发现TK抑制p-ErbB 3表达和信号传导。CDDP/PXD和TK或CuD的组合抑制H1299细胞中的p-AKT、p-Erk和p-JNK信号传导并抑制Stat 3和NF-κ B转录活性。更重要的是，CDDP/PXD与TK或CuD的组合抑制H1299细胞中的p-ErbB 3及其下游分子。CDDP/PXD和TK或CuD的组合抑制ErbB 2/ErbB 3二聚化。结论：CDDP/PXD联合TK或CuD可通过抑制ErbB 3信号通路抑制H1299肺癌细胞的增殖并诱导其凋亡。TK或CuD可用作治疗肺癌的化合物。此外，靶向ErbB 3也可用于治疗肺癌。
Background: Lung cancer is one of the most common malignancies worldwide. To treat lung cancer, various anticancer drugs were developed and tested, but they failed because of drug resistance. In the present study, we tested herbal medicines, such as TK and CuD, as anticancer drugs to decrease side effects and resistance.Methods: Cell viability was measured by an MIT assay. Analysis of cell cycle arrest was performed by flow cytometry. Induction of apoptosis by cucurbitacin D was measured by an annexin V-FITC/PI assay. We performed RTK kit analysis. Levels of p-ErbB3, p-STAT3, p-NF-kappa B, and caspases were measured by western blot analysis. Nuclear staining of ErbB3 was measured by immunocytochemistry. Transcriptional activity of STAT3 and NF-kappa B was detected by STAT3 and NF-kappa B luciferase reporter gene assays.Results: We found a synergistic effect of TK with CDDP and PXD in primary culture of human NSCLC tumor cells. The combination of CDDP/PXD and TK or CuD inhibited the proliferation of H1299 cells. The combination of CDDP/PXD and TK or CuD induced sub-G1 and G2/M cell cycle arrest in H1299 cells. The combination of CDDP/ PXD and TK or CuD induced apoptosis, regulated apoptotic molecules, caused morphological changes and inhibited colony formation in H1299 cells. We found that TK suppresses p-ErbB3 expression and signaling. The combination of CDDP/PXD and TK or CuD inhibited p-AKT, p-Erk, and p-JNK signaling and suppressed Stat3 and NF-kappa B transcriptional activity in H1299 cells. More importantly, the combination of CDDP/PXD and TK or CuD inhibited p-ErbB3 and downstream molecules in H1299 cells. The combination of CDDP/PXD and TK or CuD inhibited ErbB2/ErbB3 dimerization. Our results clearly demonstrate that the synergistic effect of CDDP/PXD and TK or CuD inhibits cell growth and induces apoptosis by inhibiting ErbB3 signaling.Conclusion: The combination of CDDP/PXD and TK or CuD decreases cell proliferation and induces apoptosis by inhibiting ErbB3 signaling in H1299 lung cancer cells. TK or CuD could be useful as a compound to treat lung cancer. Additionally, targeting ErbB3 may also be useful for treating lung cancer.