基于PKC/NF-κB-PXR信号通路及P-gp功能干预的灵芝逆转肿瘤多药耐药活性成分及作用机制研究

肿瘤多药耐药(MDR)是癌症患者化疗失败的主要原因之一，其中P-糖蛋白（P-gp）介导的药物外排是导致肿瘤MDR的经典机制。因此通过抑制P-gp外排功能而逆转肿瘤MDR是目前医药研究领域的一大热点。灵芝为赤芝和紫芝的子实体，常应用于癌症的辅助治疗。本课题组前期初步研究显示赤芝中三萜酸酯类成分具有显著的抑制P-gp活性，并发现PKC/NF-κB-PXR信号通路对P-gp表达具有重要的调控作用。基于此，本项目计划通过体外活性追踪，运用多种现代药学技术与方法，高效分离、鉴定及筛选赤芝和紫芝中逆转肿瘤MDR的三萜酸酯类成分，以期获得结构新颖的活性成分；评价其对耐药细胞株MCF-7/ADR、A549/ADM中P-gp外排功能以及PKC/NF-κB-PXR信号通路相关蛋白表达的影响，进而阐明灵芝逆转P-gp介导肿瘤MDR的物质基础及作用机制，为研发高效低毒的新型肿瘤MDR逆转剂奠定科学基础。

Multidrug resistance (MDR) is one of the important reasons for chemotherapy failure in cancer patients, involving multiple mechanisms. Among them, the classical MDR mechanism mediated by over-expression of P-glycoprotein (P-gp) is closely related to the formation of MDR, which can excrete intracellular chemotherapeutic drugs and significantly reduce the therapeutic effect. Therefore, reversing cancer MDR by inhibiting the function of P-glycoprotein is a hot spot in the field of medical research. Lingzhi, including both Ganoderma lucidum and Ganoderma sinense as recorded in Chinese Pharmacopoeia of 2015, which are commonly used in the adjuvant treatment of cancer. In the previous research, we investigated a 95% EtOH extract of the aerial parts of Ganoderma lucidum, and identified 32 lanostane-type triterpene derivatives. In in vitro bioassays, some lanostane-type triterpene acid esters (1, 5, 22, and 26) had significant inhibitory effects on P-gp. We also found that PKC/NF-κB-PXR signaling pathway might play crucial roles in modulation of P-gp gene expression. As part of our continuing search for functional substances from Ganoderma lucidum and Ganoderma sinense, we are plan to further enrich, separate and identify these lanostane-type triterpene acid esters with guidance of bioactivities screening, and investigate the effect of bioactive compounds on reversing MDR in P-gp-overexpressing cancer cells (MCF-7/ADR and A549/ADM) and elucidated the underlying mechanisms based on PKC/NF-κB-PXR signaling pathway and P-gp functional intervention. In summary, we hope to provide scientific evidence for the development of higher efficacy and low toxicity MDR modulators from Lingzhi.