Abstract
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.
Highlights
Cholangiocarcinoma (CCA), known as bile duct cancer, caused by Opisthorchis viverrini (Ov) infection through the consumption of the infected cyprinoid fish, has been recognized as a major public health problem in Northeast Thailand [1,2]
CAinina adose dose deKKU-100 and KKU-213 cells responded to the inhibitory effect depenpendent manner
We found a decrease in adenine in KKU-213 cells treated with coniferyl alcohol (CA), which might effect a lack of essential biomolecules such as nicotinamide
Summary
Cholangiocarcinoma (CCA), known as bile duct cancer, caused by Opisthorchis viverrini (Ov) infection through the consumption of the infected cyprinoid fish, has been recognized as a major public health problem in Northeast Thailand [1,2]. Surgery in combination with adjuvant chemotherapy and radiation therapy is required for increasing the survival rate of CCA patients. Many chemotherapeutic agents such as 5-fluorouracil, cisplatin and gemcitabine have been used to treat CCA patients [3,4]. Apoptosis resistance is an important hallmark of CCA, which leads to cell death and cell cycle checkpoints [6]. There is some evidence that CCA cells can escape apoptosis by increasing or decreasing the expression of anti-
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