ABSTRACT

Cervical cancer causes considerable mortality in women worldwide. Saikosaponin-A, a triterpenoid glycoside isolated from Bupleurum falcatum, has been proven to exert anti-cancer property. In this study, we evaluated the possibility of saikosaponin-A on cervical cancer in vitro and in vivo. The results showed that saikosaponin-A induced cell death and altered cellular morphology dose-dependently. Saikosaponin-A significantly induced apoptosis in HeLa cells, confirmed by Hoechst 33,342 staining and flow cytometry. Sequentially, saikosaponin-A triggered the mitochondrial-mediated apoptosis demonstrated by deficiency of MMP, induction of Bax/Bcl-2 ratio, leakage of cytochrome c to cytoplasm, and activation of caspase-3. Moreover, ER stress also participated in the apoptosis induced by saikosaponin-A in HeLa cells as indicated by the upregulation of GPR78, CHOP and caspase-12 expression. Furthermore, HeLa cells showed increased expressions of p-PI3K and p-AKT in response to saikosaponin-A treatment. Additionally, saikosaponin-A could inhibit HeLa tumor growth in nude mice and induce apoptosis, reflected by the induction of TUNEL and the expression of cytochrome c, caspase-3 and CHOP confirmed by immunohistochemistry. These findings at least to a certain extent suggested that saikosaponin-A triggered apoptosis through both mitochondrial pathway and ER stress pathway and inhibiting PI3K/Akt signaling, thereby contributing to against cervical cancer. This work provides a new understanding of saikosaponin-A on therapeutic application in treatment of cancer, which has the potential to be a promising candidate therapeutic agent for cervical cancer patients.

摘要

宫颈癌在世界范围内导致相当大的女性死亡率。Saikosaponin-A 是一种从柴胡中分离出来的三萜糖苷，已被证明具有抗癌特性。在这项研究中，我们评估了柴胡皂苷-A在体外和体内对宫颈癌的可能性. 结果表明，柴胡皂苷-A剂量依赖性地诱导细胞死亡和改变细胞形态。通过 Hoechst 33,342 染色和流式细胞术证实，Saikosaponin-A 显着诱导 HeLa 细胞凋亡。随后，柴胡皂苷-A 引发了线粒体介导的细胞凋亡，表现为 MMP 缺乏、Bax/Bcl-2 比率的诱导、细胞色素 c 渗入细胞质和 caspase-3 的激活。此外，内质网应激还参与了柴胡皂苷A诱导的HeLa细胞凋亡，如GPR78、CHOP和caspase-12表达上调所示。此外，HeLa 细胞响应于柴胡皂苷-A 处理显示出增加的 p-PI3K 和 p-AKT 表达。此外，柴胡皂苷A可抑制裸鼠HeLa肿瘤生长并诱导细胞凋亡，由 TUNEL 的诱导和免疫组织化学证实的细胞色素 c、caspase-3 和 CHOP 的表达所反映。这些发现至少在一定程度上表明，柴胡皂苷A通过线粒体途径和ER应激途径触发细胞凋亡，并抑制PI3K/Akt信号通路，从而有助于抗宫颈癌。这项工作为柴胡皂苷-A在癌症治疗中的治疗应用提供了新的认识，它有可能成为宫颈癌患者有希望的候选治疗药物。从而有助于预防宫颈癌。这项工作为柴胡皂苷-A在癌症治疗中的治疗应用提供了新的认识，它有可能成为宫颈癌患者有希望的候选治疗药物。从而有助于预防宫颈癌。这项工作为柴胡皂苷-A在癌症治疗中的治疗应用提供了新的认识，它有可能成为宫颈癌患者有希望的候选治疗药物。