APE1作为氧化苦参碱抗肿瘤作用的新靶点的研究

Oxymatrine(OMT) is a kind of alkaloid components extracted from the roots of sophora species, Sophora flavescens Aiton used as a traditional Chinese medicine. Oxymatrine is gaining more and more attention in regarding to its potential anti-tumor activity. However, the mechanisms remain elusive. Apurinic/apyrimidinic endonuclease 1(APE1) is the key enzyme for DNA base excision repair as well as plays important roles in redox-mediated transcription activation. APE1 is upregulated in many tumors and the inhibition of APE1 confers tumor cells the sensitivity to ionization and chemotherapy. So APE1 is regarded as a novel anti-tumor target. Our preliminary data showed that OMT suppressed the proliferation of the non-small cell lung cancer cell lines A549 and downregulated the level of APE1 protein that was concomitant with increased DNA base damages. Knockdown of APE1 sensitized A549 cells to OMT. These data indicate that APE1 may be a target of oxymatrine. This finding was reported from our lab for the first time. Even until now there is no report on this finding. So in this study we plan to demonstrate whether OMT targets APE1 by directly inhibiting DNA repair function and/or redox function of APE1. This study will further unveil the molecular mechanism of anti-tumor activity of oxymatrine and provide invaluable information for further improving its anti-tumor activity.

氧化苦参碱是从传统中药苦参中提取到的一种有效成分，在抗肿瘤方面具有良好的药理活性和应用前景, 日益引起了人们的重视。但具体机制尚待深入研究。脱嘌呤/脱嘧啶核酸内切酶-1(APE1)是DNA碱基切除修复途径关键限速酶，同时也具有氧化还原依赖的转录辅助活性。APE1在多种肿瘤细胞中表达上调，肿瘤 APE1被认为是一个新的抗肿瘤的靶点。我们初步研究发现：氧化苦参碱抑制A549增殖，下调APE1 蛋白，引起DNA碱基损伤增多，敲低APE1后细胞对氧化苦参碱变得敏感了，提示APE1可能是氧化苦参碱的作用靶点，这一发现属于本课题组首次发现，尚未见其他报道。因此本研究将证实APE1是否是氧化苦参碱的直接作用靶点，并分别解析 APE1 的 DNA 修复功能和氧化还原功能在氧化苦参碱介导的抗肿瘤中的具体作用，进一步阐明氧化苦参碱抗肿瘤的分子机制，为优化其抗肿瘤活性提供理论依据，具有重大的临床意义。

氧化苦参碱是从传统中药苦参中提取到的一种有效成分，在抗肿瘤方面具有良好的药理活性和应用前景,日益引起了人们的重视。但具体机制尚待深入研究。脱嘌呤/脱嘧啶核酸内切酶-1(APE1)是DNA碱基切除修复途径关键限速酶，同时也具有氧化还原依赖的转录辅助活性。APE1在多种肿瘤细胞中表达上调，肿瘤APE1被认为是一个新的抗肿瘤的靶点。我们初步研究发现：氧化苦参碱抑制A549增殖，下调APE1蛋白，引起DNA碱基损伤增多，敲低APE1后细胞对氧化苦参碱变得敏感了，提示APE1可能是氧化苦参碱的作用靶点，这一发现属于本课题组首次发现，尚未见其他报道。因此本研究将证实APE1是否是氧化苦参碱的直接作用靶点，并分别解析APE1的DNA修复功能和氧化还原功能在氧化苦参碱介导的抗肿瘤中的具体作用，进一步阐明氧化苦参碱抗肿瘤的分子机制，为优化其抗肿瘤活性提供理论依据，具有重大的临床意义。