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Background Opisthorchis viverrini (Ov) infection-induced cholangiocarcinoma (CCA) is a major public health problem in northeastern Thailand. Praziquantel was shown to prevent CCA development in an Ov-infected hamster model; however, the molecular mechanism remains unknown. Materials and methods In this study, we used a hamster model with Ov and N-nitrosodimethylamine-induced CCA to study the mechanisms of praziquantel action. The liver tissues from the hamsters with and without praziquantel treatment were analyzed using 1H nuclear magnetic resonance spectroscopy. Results A total of 14 metabolites were found to be significantly different between the two groups. Furthermore, the combination of acetate, inosine and sarcosine was shown to exert an anti-inflammatory effect through interleukin-6 inhibition in a macrophage cell line, suggesting a mechanism by which praziquantel may prevent inflammation caused by Ov, cholangiocyte transformation and further CCA develpoment. Conclusion These findings might avail the development of a preventive strategy for CCA in high-risk populations.

Background/aim This study examined the in vitro effects of the bile duct cancer drug PRIMA-1MET on cholangiocarcinoma (CCA) cell growth to determine its potential usefulness in CCA therapy. Materials and methods The effect of this drug on the expression of senescent markers (p16INK4A and p21) and the phosphorylation of p53 was investigated, as was the association between senescent markers and the patients' clinicopathological data. Results PRIMA-1MET inhibited CCA cell growth with the half maximal-inhibitory concentration (IC50) values of 21.9-40.8 μM. PRIMA-1MET induced phospho-p53, p16INK4A and p21 triggering cellular senescence and apoptosis. High expressions of p16INK4A and p21 were associated with a high survival rate of patients with CCA. Conclusion PRIMA-1MET may potentially be an alternative anticancer agent that might lead to a better prognosis in patients with CCA.

CD44 is a transmembrane glycoprotein, the phosphorylation of which can directly trigger intracellular signaling, particularly Akt protein, for supporting cell growth, motility and invasion. This study examined the role of CD44 on the progression of Cholangiocarcinoma (CCA) using metabolic profiling to investigate the molecular mechanisms involved in the Akt signaling pathway. Our results show that the silencing of CD44 decreases Akt and mTOR phosphorylation resulting in p21 and Bax accumulation and Bcl-2 suppression that reduces cell proliferation. Moreover, an inhibition of cell migration and invasion regulated by CD44. Similarly, the silencing of CD44 showed an alteration in the epithelial-mesenchymal transition (EMT), e.g. an upregulation of E-cadherin and a downregulation of vimentin, and the reduction of the matrix metalloproteinase (MMP)-9 signal. Interestingly, a depletion of CD44 leads to metabolic pathway changes resulting in redox status modification and Trolox (anti-oxidant) led to the recovery of the cancer cell functions. Based on our findings, the regulation of CCA progression and metastasis via the redox status-related Akt signaling pathway depends on the alteration of metabolic profiling synchronized by CD44.

The protein 14-3-3ζ contributes important regulatory functions in several cellular processes via binding to phosphorylated serine/threonine residues, which promotes cell cycle progression, cell proliferation and anti-apoptosis in multiple types of cancer. The aim of the present study was to investigate the functions of 14-3-3ζ in cholangiocarcinoma (CCA) progression and elucidate the molecular mechanism of 14-3-3ζ expression-mediated protein kinase B (Akt) phosphorylation and chemosensitivity in CCA cells. In the present study, 14-3-3ζ expression was investigated in clinical specimens using immunohistochemistry and compared with the clinicopathological features of patients with CCA. The association between 14-3-3ζ and phosphorylated Akt (pAkt) was determined among the tissues of the same patients using bivariate correlation analysis. The effects of 14-3-3ζ suppression on CCA cell function and gemcitabine sensitivity were investigated using small interfering RNA (siRNA). It was identified that 14-3-3ζ expression was positively correlated with pAkt (P=0.013) and that increased expression of 14-3-3ζ and pAkt were significantly associated with poor overall survival rate and metastasis (P=0.025 and 0.006, respectively). Downregulation of 14-3-3ζ using siRNA in CCA cell lines decreased cell proliferation, resulting in the inhibition of pAkt activity and increasing the protein level of the cell cycle inhibitor p27. The suppression of 14-3-3ζ enhanced the inhibitory effect of gemcitabine on CCA cell proliferation by inducing apoptotic cell death. Taken together, the results of the present study indicated that 14-3-3ζ is a potential target for CCA and may serve as a novel therapeutic approach to enhance chemosensitivity in the treatment of CCA.

Cholangiocarcinoma (CCA) is a major cause of mortality in Northeast Thailand with about 14,000 deaths each year. There is an urgent necessity for novel drug discovery to increase effective treatment possibilities. A recent study reported that lignin derived from Scoparia dulcis can cause CCA cell inhibition. However, there is no evidence on the inhibitory effect of coniferyl alcohol (CA), which is recognized as a major monolignol-monomer forming a very complex structure of lignin. Therefore, we aimed to investigate the effect of CA on CCA cell apoptosis. We demonstrated that a half-inhibitory concentration of CA on KKU-100 cells at 48 h and 72 h was 361.87 ± 30.58 and 268.27 ± 18.61 μg/mL, respectively, and on KKU-213 cells 184.37 ± 11.15 and 151.03 ± 24.99 μg/mL, respectively. Furthermore, CA induced CCA cell apoptosis as demonstrated by annexin V/PI staining in correspondence with an increase in the BAX/Bcl-2 ratio. A metabonomic study indicated that CA significantly decreased the intracellular concentrations of glutathione and succinate in KKU-213 cells and increased dihydrogen acetone phosphate levels in KKU-100 cells treated with 200 µg/mL of CA compared to the control group. In conclusion, CA induced cellular metabolic changes which are involved in the antioxidant defense mechanism, glycerophospholipid metabolism and the tricarboxylic acid cycle. CA may serve as a potent anticancer agent for CCA treatment by inducing CCA cellular apoptosis.