Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Mar;392(3):271-278. doi: 10.1007/s00210-018-1584-3. Epub 2018 Nov 23.
Low efficacy and high resistance rate associated with existing chemotherapeutic drugs enforce a requirement for novel therapeutic strategies for extremely aggressive cholangiocarcinoma (CCA). In the present study, the apoptosis-inducing activity of cucurbitacin B, a compound derived from plants of Cucurbitaceae family, against KKU-100 CCA cells and the underlying mechanism mediating its effect were investigated. The results showed that cucurbitacin B significantly decreased CCA cells viability by induction of apoptosis. Increased apoptotic cell death following cucurbitacin B treatment was correlated with caspase-9 and caspase-3 activations, Bax upregulation, increased cytochrome c, apoptosis-inducing factor release, and decreased Bcl-2 and Bcl-XL levels, suggesting activation of the mitochondrial-mediated apoptosis pathway. Further molecular analyses revealed that cucurbitacin B inhibited focal adhesion kinase (FAK), which is an important regulator of the apoptosis process, and its downstream pathway, PI3K/Akt. Knockdown of FAK expression by small interfering RNA appeared to induce CCA cell apoptosis which was accompanied with elevated level of cytochrome c and cleaved caspase-9, and decreased level of Bcl-2, phospho-PI3K, and phospho-Akt. Taken together, cucurbitacin B induces an intrinsic mitochondrial apoptosis pathway in CCA cells partly through suppression of FAK-mediated oncogenic signaling. This compound should be considered as a candidate agent for CCA treatment.
低疗效和高耐药率与现有的化疗药物相关，这使得我们迫切需要新的治疗策略来治疗侵袭性极强的胆管癌（CCA）。在本研究中，我们研究了来源于葫芦科植物的葫芦素 B 对 KKU-100 CCA 细胞的诱导凋亡活性及其作用机制。结果表明，葫芦素 B 通过诱导细胞凋亡显著降低 CCA 细胞活力。葫芦素 B 处理后凋亡细胞死亡增加与 caspase-9 和 caspase-3 的激活、Bax 的上调、细胞色素 c 的增加、凋亡诱导因子的释放以及 Bcl-2 和 Bcl-XL 水平的降低有关，提示激活了线粒体介导的凋亡途径。进一步的分子分析表明，葫芦素 B 抑制了黏着斑激酶（FAK），FAK 是凋亡过程的重要调节因子及其下游通路 PI3K/Akt。小干扰 RNA 敲低 FAK 表达似乎诱导了 CCA 细胞凋亡，伴随着细胞色素 c 和裂解 caspase-9 的水平升高，Bcl-2、磷酸化 PI3K 和磷酸化 Akt 的水平降低。总之，葫芦素 B 通过抑制 FAK 介导的致癌信号通路，在 CCA 细胞中诱导内在的线粒体凋亡途径。该化合物可被视为 CCA 治疗的候选药物。
