Abstract
Cholangiocarcinoma (CCA) is a fatal cancer with poor prognosis and less than 10% of CCA patients can be offered surgical cure. Conventional chemotherapy results in unfavorable outcomes. At present, plant-derived compounds are gaining interest as potential cancer therapeutics, particularly for treatment-refractory cancers. In this study, antitumor activity of tiliacorinine, the major alkaloid isolated from a tropical plant, on CCA was first demonstrated. Antiproliferative effects of tiliacorinine on human CCA cell lines were investigated using SRB assays. Acridine orange/ethidium bromide staining, flow cytometric analysis and DNA laddering assays were used for apoptotic determination. Apoptosis-related proteins were verified by Western blotting and antitumor activity of tiliacorinine in vivo was demonstrated in CCA xenografted mice. Tiliacorinine significantly inhibited proliferation of human CCA cell lines with IC50 4.5-7 μM by inducing apoptosis through caspase activation, up- regulation of BAX, and down-regulation of BclxL and XIAP. Tiliacorinine considerably reduced tumor growth in CCA xenografted mice. These results demonstrated antitumor effects of tiliacorinine on human CCA in vitro and in vivo. Tiliacorinine may be an effective agent for CCA treatment.
Highlights
Cholangiocarcinoma (CCA), a malignant cancer arising from bile duct epithelium, is a rare liver cancer but a serious public health problem in the northeast of Thailand as it has the highest incidence and mortality rate in the world (Sripa and Pairojkul, 2008)
Antibodies were obtained from companies as indicated: Bcl-2-associated X protein (BAX), B-cell leukemia protein xL (BclxL), X-linked inhibitor of apoptosis protein (XIAP), and poly-adenosine diphosphate ribose polymerase (PARP) from Santa Cruz Biotechnology (Santa Cruz, CA); anti-caspase-3 and-9, goat anti-rabbit IgG- and goat anti-mouse IgG-conjugated to horseradish peroxidase (HRP) from Cell Signaling Technology (Beverly, MA), and β-actin antibody from
As KKU-M214 and KKU-100 were less sensitive to tiliacorinine, they were selected as representative of CCA cells for the subsequent studies
Summary
Cholangiocarcinoma (CCA), a malignant cancer arising from bile duct epithelium, is a rare liver cancer but a serious public health problem in the northeast of Thailand as it has the highest incidence and mortality rate in the world (Sripa and Pairojkul, 2008). To reduce the mortality rate of CCA, new effective treatment strategies are needed. Plant-derived compounds are gaining interest as potential cancer therapeutics (Shukla, 2007; Aras et al, 2014), for treatment-refractory cancers such as CCA (Naus et al, 2007). 1A), the bisbenzylisoquinoline alkaloid isolated from a tropical medicinal plant, Tiliacora triandra (Colebr.) Diels, was investigated for antitumor activity in CCA cell lines in vitro and in vivo. The molecular mechanism by which tiliacorinine induces apoptosis of CCA was determined. Our findings suggested tiliacorinine to be a new promising compound for effective treatment against human CCA
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