Cucurbitacin B induces mitochondrial-mediated apoptosis pathway in cholangiocarcinoma cells. - GreenMedInfo Summary
Cucurbitacin B induces mitochondrial-mediated apoptosis pathway in cholangiocarcinoma cells via suppressing focal adhesion kinase signaling.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Mar ;392(3):271-278. Epub 2018 Nov 23. PMID: 30470919
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.