益肾骨康方通过Keap1/Nrf2调控氧化应激反应抑制乳腺癌骨转移的机制研究

Latest studies have found that Keap1/Nrf2 signaling pathway-mediated oxidative stress plays a role in tumorigenesis and metastasis. Our previous studies have confirmed that Yishengukang decoction with the actions of reinforcing the healthy qi, resolving toxins, and dissolving stasis is of great effect on osseous metastasis and osseous metastasis pain of malignant tumor. After further exploration of mechanism, we found that Yishengukang decoction can markedly upregulatethe Keap1 expression in bone metastasis tissue and downregulate the intranuclear expression of Nrf2, suggesting regulation of Keap1/Nrf2-mediated oxidative stress response as its potential signaling pathway to inhibit tumorigenesis and bone metastasis. In current study, we will establish the model using in vitro co-culture system and in vivo tumor deposit. The protein and mRNA expression in the Keap1/Nrf2 signaling pathway and biological effect indicators will be detected by Cell Counting Kit-8 (CCK-8), Western blot (WB), quantitative reverse transcription polymerase chain reaction (qRT-PCR), flow cytometry, micro-computer tomography (MicroCT), etc to uncover the mechanism of Yishengukang decoction on treating bone metastasis from breast cancer and explore new ideas of studying the mechanism of bone metastasis in traditional Chinese medicine.

最新研究发现，Keap1/Nrf2信号通路介导的氧化应激反应在肿瘤的形成及转移中发挥作用，课题组前期研究证实扶正解毒化瘀中药“益肾骨康方”在治疗肿瘤骨转移及骨转移疼痛方面有显著疗效，进一步机制研究发现，益肾骨康方可显著上调骨转移造模组织内的Keap1表达及下调Nrf2核内表达，提示了其可能的作用途径为调控Keap1/Nrf2通路介导的氧化应激反应以抗肿瘤及其骨转移。本研究通过体外共培养体系及体内肿瘤种植建模，采用CCK-8、WB、qRT-PCR、流式细胞术、MicroCT等，检测该通路蛋白、mRNA表达及生物学效应指标，以求揭示该方治疗乳腺癌骨转移的作用机理，并探索中医药治疗骨转移机制研究的新思路。

本项目通过研究益肾骨康方（后更名为益肾祛痛颗粒）通过Keap1/Nrf2信号通路抑制乳腺癌骨转移的机制，为阐释其作用机制及转化奠定基础。Keap1/Nrf2信号通路介导的氧化应激反应在肿瘤的形成及转移中发挥作用，课题组前期研究证实扶正解毒化瘀中药“益肾骨康方”在治疗肿瘤骨转移及骨转移疼痛方面有显著疗效，进一步机制研究发现，益肾骨康方可显著上调骨转移造模组织内的Keap1表达及下调Nrf2核内表达，提示了其可能的作用途径为调控Keap1/Nrf2通路介导的氧化应激反应以抗肿瘤及其骨转移。本研究通过体外及体内肿瘤种植建模，采用CCK-8、WB、qRT-PCR、MicroCT等，检测该通路蛋白、mRNA表达及生物学效应指标，验证了益肾骨康方通过调控Keap1/Nrf2 介导的氧化应激反应从而抑制乳腺癌骨转移，并验证了抑制Nrf2可能是通过下调骨桥蛋白的表达，从而抑制小鼠乳腺癌骨转移的作用机制。本项目结题时，共发表中文核心期刊2 篇；2022年本项目作为内容之一一起申报的成果，获得北京市科委科技进步二等奖（基于扶正解毒理论抗肿瘤中药新药研发转化与临床应用），项目负责人为第5位。研究药物更名为“益肾祛痛颗粒”并与药厂签约转化，转化经费为2000万元。培养硕士研究生1 名；晋升副主任医师1名；参加国际会议1 次。