G-四链体逆转卵巢癌耐药的分子机制和临床应用潜能的研究

针对临床肿瘤治疗中肿瘤耐药的问题，我们提出了利用G-四链体逆转肿瘤耐药的设想，并在前期实验中证实了可行性。为了奠定G-四链体作为新型抗肿瘤药物的理论基础，我们将继续在分子、细胞和动物水平上进一步解析核酸抗肿瘤药物——G-四链体AS1411在逆转卵巢癌耐药的分子机制。我们将考察核仁素在卵巢癌细胞、耐紫杉醇卵巢癌细胞和AS1411作用后的耐药卵巢癌细胞中的表达特性（表达、定位、磷酸化）以及核仁素与AS1411的相互作用在逆转卵巢癌耐药的生物学功能，研究AS1411与参与组装微管的相关蛋白之间的调控关系对逆转卵巢癌耐药的作用，进而阐明AS1411逆转卵巢癌耐药的机制；通过比较其它逆转肿瘤耐药方法（小分子逆转剂、siRNA干扰）和裸鼠荷瘤实验，总结AS1411逆转肿瘤耐药的技术优点和不足，为研究核酸抗肿瘤药物的分子机理和进一步评估其它新型G-四链体抗肿瘤药物的临床治疗价值提供实验基础和理论依据。

Chemoresistance of cancers has been an urgent problem in clinical cancer treatment. We proposed a strategy to reverse the chemoresistance of cancers using G-quadruplexes and obtained promising results in preliminary experiments. In this proposal, we will further investigate the molecular mechanisms of G-quadruplex AS1411 to reverse the chemoresistance of ovarian cancer cells at molecular, cellular and animal levels. We will examine the expression properties (quantity, cellular localization, phosphorelation) of nucleolin and biological functions of the nucleolin-AS1411 interactions in the chemoresistance reversal, and will explore the interactions between AS1411 and proteins participating in the microtubulin assembly as well as the effects on the chemoresistance reversal mechanism. By comparing with other reversal strategies (small organic reversing reagents and siRNA) and mouse model, we will evaluate the advantages and shortages of AS1411 as a novel anti-cancer drug in cancer treatment. This study will provide a solid theoretical foundation and experimental basis for exploring the anti-cancer treatment and for developing novel G-quadruplex anti-cancer drugs for clinical applications.