抗癌植物新药-柯里拉京抑制卵巢癌生长转移的分子机制研究

Corilagin is a kind of tannin compounds derived from an anticancer herb Phyllanthus urinaria L., which has antitumor activity. The pharmacological studies indicated that Corilagin can significantly inhibit the growth of tumor cells with low toxicity, especially for ovarian cancer. So Corilagin has a great value of an new anti-ovarian cancer drug. Our previous studies have shown that Corilagin can inhibit the secretion of TGF-β, reduce the stabilizing effects of TGF-β on Snail, and inhibit the phosphorylation of Akt and ERK, while TGF-β is an important regulatory factor of EMT inducers such as Snail. Therefore, we speculate that Corilagin may inhibit the invasion and metastasis of ovarian cancer cells via mediating TGF-β pathway. Our data also indicate that anti-ovarian cancer clinical drugs Paclitaxel and Corilagin have sensitization effect in pharmacological efficacy, so that they have the possibility of combination therapy. Therefore, this study intends to investigate the molecular mechanism of inhibiting invasion and metastasis of ovarian cancer by Corilagin with focus on signaling pathways of TGF-β/EMT, and to further explore the possibility of combination therapy with Corilagin and paclitaxel. The study is expected to reveal the anti-ovarian cancer molecular mechanism of Corilagin, and to provide evidence for the development of this new anti-cancer herbal drug.

柯里拉京是本课题组从福建省闽南民间抗癌草药叶下珠中获得的具有抗癌活性的鞣质。研究显示，它可显著抑制多种肿瘤细胞的生长，尤以抗卵巢癌效果为著，且毒性低，极具抗卵巢癌新药开发价值，但其作用机制不明。我们前期研究表明，柯里拉京可下调Akt和ERK的磷酸化，抑制卵巢癌细胞TGF-β的分泌，并能明显减弱TGF-β对Snail的稳定作用，而TGF-β是调控Snail等转录因子并导致上皮间充质转化(EMT)的重要因子。据此，我们推测柯里拉京可能主要通过抑制TGF-β通路从而抑制卵巢癌侵袭转移。此外，我们前期研究还发现，治疗卵巢癌的一线药物紫杉醇和柯里拉京有增敏增效作用，具联合用药的可能。据此，本研究拟围绕TGF-β/EMT信号通路，探讨柯里拉京抗卵巢癌侵袭转移的分子机制，进一步寻求其与紫杉醇联合用药的可能性。本研究有望揭示柯里拉京抗卵巢癌的关键分子机制，为其作为植物抗癌新药开发提供重要依据。

柯里拉京是本课题组从福建省闽南民间抗癌草药叶下珠中获得的具有抗癌活性的鞣质。研究显示，它可显著抑制多种肿瘤细胞的生长，尤以抗卵巢癌效果为著，且毒性低，极具抗卵巢癌新药开发价值，但其作用机制不明。我们前期研究表明，柯里拉京可下调Akt 和ERK 的磷酸化，抑制卵巢癌细胞TGF-β的分泌，并能明显减弱TGF-β对Snail 的稳定作用，而TGF-β是调控Snail 等转录因子并导致上皮间充质转化(EMT)的重要因子。据此，我们推测柯里拉京可能主要通过抑制TGF-β通路从而抑制卵巢癌侵袭转移。此外，我们前期研究还发现，治疗卵巢癌的一线药物紫杉醇和柯里拉京有增敏增效作用，具联合用药的可能。.据此，本项目通过细胞的增值和侵袭转移的药理药效学研究发现，柯里拉京能够通过Caspase-9/Caspase-3信号通路，cyclin B1/cdc2信号通路介导的G2/M期周期阻滞抑制癌细胞生长，通过TGF-β/AKT/ERK/Smad，Snail，PLK1，RB1, …，癌细胞的侵袭转移，以及相关的其它不同信号转导通路，如PI3K/Akt，以及糖酵解途径；另外，通过柯里拉京与紫杉醇联合抗癌用药的药理药效学效果，比较Corilagin与Paclitaxel单独和联合抗癌用药的差异，发现柯里拉京与紫杉醇单独和联合作用的分子机制，能够下调Snail和p-ERK的表达，进而产生协同作用。.总之，本研究进一步系统研究柯里拉京抗癌生长和侵袭转移的药理药效学，重点围绕TGF-β/EMT信号通路，探讨柯里拉京抗癌的分子机制及其关键分子靶点，并以此为基础，进一步探讨柯里拉京与紫杉醇联合用药前后的抗癌作用效果，揭示柯里拉京抗癌的关键分子机制，为其作为植物抗癌新药开发提供重要依据。