Brusatol enhances the chemotherapy efficacy of Cisplatin and Gemcitabine in KKU-100 cholangiocarcinoma cells through ROS-mediated apoptosis

        Cholangiocarcinoma (CCA), a cancer of the bile duct, is a major health problem in the Mekong basin region, including northeastern Thailand. It is difficult to diagnose, so most patients are found at an advanced stage when surgery is no longer possible. The standard chemotherapy, cisplatin combined with gemcitabine, often loses its effect because the cancer cells become drug resistant, and the cancer can also spread to other organs. This study asked whether brusatol, a natural compound from the plant Brucea javanica, could help these standard drugs work better in human CCA cells (KKU-100).

        We found that brusatol reduced the viability of CCA cells in a dose- and time-dependent manner. When it was combined with cisplatin or gemcitabine, the drugs killed more cancer cells than when used alone. The combinations raised the level of reactive oxygen species (ROS) inside the cells, and an antioxidant (N-acetylcysteine) reduced the killing effect, showing that ROS are important for this action. The combinations also caused loss of mitochondrial membrane potential and increased the activity of caspase-3, -8 and -9, indicating that both the intrinsic (mitochondrial) and extrinsic (death-receptor) apoptosis pathways were activated. The effect depended on the drug partner: brusatol with cisplatin was about additive to slightly synergistic (combination index 0.97), whereas brusatol with gemcitabine was antagonistic by this measure (combination index 1.42).

        In addition, the combinations strongly reduced the ability of surviving cells to form colonies and suppressed cell migration and invasion, which are key steps in cancer spread. Together, these results suggest that brusatol is a promising anticancer agent or adjunct to current chemotherapy for CCA. Further studies in animal models are needed before clinical use.