Cucurbitacin B induces mitochondrial-mediated apoptosis pathway in cholangiocarcinoma cells via suppressing focal adhesion kinase signaling.

Abstract

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.

• Authors: Sirinapha Klungsaeng, Veerapol Kukongviriyapan, Auemduan Prawan, Sarinya Kongpetch, Laddawan Senggunprai
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 392 Issue 3 Pg. 271-278 (03 2019) ISSN: 1432-1912 [Electronic] Germany
• PMID: 30470919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• RNA, Small Interfering
• Triterpenes
• cucurbitacin B
• Focal Adhesion Kinase 1
• PTK2 protein, human

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Bile Duct Neoplasms (drug therapy, metabolism)
• Cell Line
• Cell Survival (drug effects)
• Cholangiocarcinoma (drug therapy, metabolism)
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Humans
• Mitochondria (metabolism)
• RNA, Small Interfering (genetics)
• Rats
• Signal Transduction (drug effects)
• Triterpenes (pharmacology)