ascorbic-acid and Bile-Duct-Neoplasms

Cholangiocarcinoma (CC) is a devastating malignancy with late diagnosis and poor response to conventional chemotherapy. Recent studies have revealed anti-cancer effect of vitamin C (l-ascorbic acid, ascorbate) in several types of cancer. However, the effect of l-ascorbic acid (AA) in CC remains elusive. Herein, we demonstrated that AA induced cytotoxicity in CC cells by generating intracellular reactive oxygen species (ROS), and subsequently DNA damage, ATP depletion, mTOR pathway inhibition. Moreover, AA worked synergistically with chemotherapeutic agent cisplatin to impair CC cells growth both in vitro and in vivo. Intriguingly, sodium-dependent vitamin C transporter 2 (SVCT-2) expression was inversely correlated with IC50 values of AA. Knockdown of SVCT-2 dramatically alleviated DNA damage, ATP depletion, and inhibition of mTOR pathway induced by AA. Furthermore, SVCT-2 knockdown endowed CC cells with the resistance to AA treatment. Finally, the inhibitory effects of AA were further confirmed in patient-derived CC xenograft models. Thus, our results unravel therapeutic potential of AA alone or in combination with cisplatin for CC. SVCT2 expression level may serve as a positive outcome predictor for AA treatment in CC.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Bile Duct Neoplasms; Cell Death; Cell Line, Tumor; Cholangiocarcinoma; Cisplatin; DNA Damage; Dose-Response Relationship, Drug; Energy Metabolism; Humans; Inhibitory Concentration 50; Male; Mice, Nude; Reactive Oxygen Species; RNA Interference; Signal Transduction; Sodium-Coupled Vitamin C Transporters; Time Factors; TOR Serine-Threonine Kinases; Transfection; Tumor Burden; Xenograft Model Antitumor Assays

Vegetable and fruit consumption may have a protective effect against several types of cancers. However, the effect on biliary cancers is unclear. We investigated the association of vegetable/fruit consumption with the risks of gallbladder cancer (GBC), intrahepatic bile duct cancer (IHBDC) and extrahepatic bile duct cancer (EHBDC) in a population-based prospective cohort study in Japan. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazard model, and the exposure level was categorized into quartiles, with the lowest group used as the reference. A total of 80,371 people aged 45 to 74 years were enrolled between 1995 and 1999, and followed up for 1,158,632 person-years until 2012, during which 133 GBC, 99 IHBDC, and 161 EHBDC cases were identified. Increased consumption of total vegetable and fruit was significantly associated with a decreased risk of EHBDC (HR = 0.49; 95% CI: 0.29-0.81 for the highest group; p trend = 0.005). From the analysis of relevant nutrients, significantly decreased risk of EHBDC was associated with folate and insoluble fiber (HR = 0.48, 0.53; 95% CI: 0.28-0.85, 0.31-0.88 for the highest group; p trend = 0.010, 0.023; respectively), and a significant trend of decreased EHBDC risk associated with vitamin C was observed (p trend = 0.029). No decreased risk of GBC and IHBDC was found. Our findings suggest that increased vegetable/fruit consumption may decrease a risk of EHBDC, and folate, vitamin C, and insoluble fiber might be key contributors to the observed protective effect.

Topics: Adult; Alcohol Drinking; Ascorbic Acid; Bile Duct Neoplasms; Carcinoma; Cholelithiasis; Comorbidity; Diabetes Mellitus; Diet; Dietary Fiber; Female; Folic Acid; Follow-Up Studies; Fruit; Gallbladder Neoplasms; Hepatitis, Viral, Human; Humans; Japan; Life Style; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Smoking; Surveys and Questionnaires; Vegetables

Gallbladder and biliary tract cancer is a serious clinical problem. In-spite of wide range of new diagnostic and therapeutic methods, the significant improvement of treatment results, has not been noticed so far. The research about prevention methods, seems to be important, among the ways of improvement of the diagnosis and therapy outcomes of these diseases. It is related for example to study about one of the cause of biliary tract carcinogenesis--the imbalance between production of reactive oxygen species (ROS) and their inactivation by the antioxidative barrier. One of the components of this organism protection complex are antioxidative vitamins. The aim of this study was to measure the concentration of antioxidative vitamins (A, C, E, and beta-carotene) in serum, in patients with cancer of gallbladder and and biliary tract, in comparison to the results of healthy volunteers. The study groups comprised of 56 patients, both sexes with acute and chronic cholecystitis and with above-mentioned neoplasmas. The results shoved, that concentration of antioxidative vitamins in serum of patients with gallbladder and biliary tract cancer, was significantly decreased. The outcomes of this research, seem to confirm the participation of antioxidative barrier in inhibition of carcinogenesis of in those important parts of digestive system.

Topics: Adult; Aged; Aged, 80 and over; Antioxidants; Ascorbic Acid; Bile Duct Neoplasms; Carotenoids; Case-Control Studies; Female; Gallbladder Neoplasms; Humans; Male; Middle Aged; Reference Values; Vitamin A; Vitamin E; Vitamins

Topics: Adenoma, Bile Duct; Ascorbic Acid; Azo Compounds; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Chemical Phenomena; Chemistry; Coloring Agents; Diet; Liver; Liver Neoplasms; Pharmacology; Rats; Research; Sulfhydryl Compounds; Trichloroacetic Acid