女贞苷通过阻滞G1/S期抑制非小细胞肺癌奥西替尼耐药细胞增殖

Ligustroflavone mediates the resistance of non-small cell lung cancer to osimertinib by arresting G1/S phase

天然产物是抗肿瘤先导化合物开发的重要来源,但其在非小细胞肺癌(non-small cell lung cancer,NSCLC)奥西替尼耐药中的药理学作用及其调控机制有待进一步阐明。本研究以天然产物女贞苷为研究对象,通过细胞增殖实验和细胞周期检测分析女贞苷在非小细胞肺癌奥西替尼耐药细胞中的药效;使用公共数据库及生物信息学手段筛选女贞苷在非小细胞肺癌奥西替尼耐药细胞中的潜在作用靶点;并用分子对接结合微量热泳动实验鉴定女贞苷与靶点分子的作用关系;Western blot检测女贞苷对靶点分子及其下游通路的影响。结果发现,女贞苷能够抑制非小细胞肺癌奥西替尼耐药细胞的活力,其可阻滞耐药细胞G1/S期进程;进一步分析发现,细胞周期调控分子细胞周期依赖性激酶6(cyclin-dependent kinase 6,CDK6)是女贞苷在非小细胞肺癌奥西替尼耐药细胞中的潜在靶点;女贞苷能够抑制CDK6-Rb轴的激活。综上,天然产物女贞苷具有抵抗非小细胞肺癌奥西替尼耐药性的作用,其可通过调控细胞周期相关分子抑制耐药细胞增殖。本研究为天然产物治疗非小细胞肺癌靶向耐药提供了理论基础,也为临床联合用药开发提供了新的思路。

Natural products are an important source for the development of antitumor lead compounds,but the pharmacological effects and regulatory mechanisms of natural products in osimertinib resistance in non-small cell lung cancer(NSCLC)are not well understood.The natural product ligustroflavone was used as the research object to analyze its efficacy in osimertinib-resistant NSCLC cells by cell proliferation assay and cell cycle detection.The potential targets of ligustroflavone in osimertinib-resistant NSCLC cells were screened by public databases and bioinformatics,molecular docking and microscale thermophoresis were used to identify the interaction between privet and target molecules.Western blot was used to detect the effect of privet on the target molecules and their downstream pathways.Ligustroflavone reduced the proliferation of osimertinib-resistant NSCLC cells,and could arrest the cell cycle.Cyclin-dependent kinase 6(CDK6)was the potential target of ligustroflavone in osimertinibresistant NSCLC cells.Ligustroflavone inhibited the activation of CDK6-Rb axis.Together,ligustroflavone could regulate osimertinib resistance in NSCLC cells by binding cell cyclin-related molecules.This study provides a theoretical basis for the targeted drug resistance of NSCLC with natural products,and also provides a new idea for the development of clinical drug combination.