SHORT COMMUNICATION: Promotion of cholangiocarcinogenesis in the hamster liver by bile duct ligation after dimethylnitrosamine initiation

Thamavit, Witaya; Pairojkul, Chawalit; Tiwawech, Danai; Itoh, Makoto; Shirai, Tomoyuki; Ito, Nobuyuki

doi:10.1093/carcin/14.11.2415

Cited by 56 publications

(61 citation statements)

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“…These include subcutaneous xenograft model (Mareinfeld et al, 2003;Fava et al, 2005;Jimeno et al, 2005) or hepatobiliary CCA model (Johnson et al, 2001;Voskoglou-Nomokos et al, 2003;Bibby, 2004;Sausville and Burger, 2006) in hamsters or rats after treatment with carcinogens [N-nitrosobis (2-oxopropyl) amine, methylazoxymethyl acetate, dimethylnitrosamine, furan, thioacetamide] or infection with O. viverrini (OV) (Maronpot et al, 1991;Imray et al, 1992;Thamavit et al, 1993;Iki et al, 1998;Jan et al, 2007;Tesana et al, 2007), and genetic CCA models (Lai et al, 2005;Xu et al, 2006;Sirica et al, 2008). In our study, OV/DMN induced CCA in hamster model was used.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity, Toxicity, and Anticancer Activity of Zingiber Officinale Roscoe Against Cholangiocarcinoma

Plengsuriyakarn¹,

Viyanant²,

Eursitthichai³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Cholangiocarcinoma (CCA) is an uncommon adenocarcinoma which arises from the epithelial cells of the bile ducts. The aim of the study was to investigate the cytotoxicity, toxicity, and anticancer activity of a crude ethanolic extract of ginger (Zingiber officinale Roscoe) against CCA. Cytotoxic activity against a CCA cell line (CL-6) was assessed by calcein-AM and Hoechst 33342 assays and anti-oxidant activity was evaluated using the DPPH assay. Investigation of apoptotic activity was performed by DNA fragmentation assay and induction of genes that may be involved in the resistance of CCA to anticancer drugs (MDR1, MRP1, MRP2, and MRP3) was examined by real-time PCR. To investigate anti-CCA activity in vivo, a total of 80 OV and nitrosamine (OV/ DMN)-induced CCA hamsters were fed with the ginger extract at doses of 1000, 3000, and 5000 mg/kg body weight daily or every alternate day for 30 days. Control groups consisting of 10 hamsters for each group were fed with 5-fluorouracil (positive control) or distilled water (untreated control). Median IC 50 (concentration that inhibits cell growth by 50%) values for cytotoxicity and anti-oxidant activities of the crude ethanolic extract of ginger were 10.95, 53.15, and 27.86 μg/ml, respectively. More than ten DNA fragments were visualized and up to 7-9 fold up-regulation of MDR1 and MRP3 genes was observed following exposure to the ethanolic extract of ginger. Acute and subacute toxicity tests indicated absence of any significant toxicity at the maximum dose of 5,000 mg/kg body weight given by intragastric gavage. The survival time and survival rate of the CCA-bearing hamsters were significantly prolonged compared to the control group (median of 54 vs 17 weeks). Results from these in vitro and in vivo studies thus indicate promising anticancer activity of the crude ethanolic extract of ginger against CCA with the absence of any significant toxicity. Moreover, MDR1 and MRP3 may be involved in conferring resistance of CCA to the ginger extract.

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Section: Discussionmentioning

confidence: 99%

Cytotoxicity, Toxicity, and Anticancer Activity of Zingiber Officinale Roscoe Against Cholangiocarcinoma

Plengsuriyakarn¹,

Viyanant²,

Eursitthichai³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Although the incidence of ICC had been primarily associated with developing countries, ICC is now increasing in developed countries, especially in the United Kingdom and Japan (Kato et al, 1990;TaylorRobinson et al, 1997;McLean and Patel, 2006;West et al, 2006). Thailand has the highest incidence of ICC in the world, perhaps related to a tradition of eating raw fish, which may be contaminated with the liver fluke parasite, Opisthorchis viverrini, a cause of cholangiocarcinoma (Kurathong et al, 1985;Vatanasapt et al, 1990;Parkin et al, 1991;Thamavit et al, 1993;Sripa and Pairojkul, 2008). The prevalence of liver fluke infection in northeast Thailand is about 317.6 per 100,000 personyears (Sriamporn et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiling of Intrahepatic Cholangiocarcinoma

Subrungruanga¹,

Thawornkunob²,

Chawalitchewinkoon-Petmitrc³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Intrahepatic cholangiocarcinoma (ICC) is ranked as one of the top five causes of cancer-related deaths. ICC in Thai patients is associated with infection with the liver fluke, Opisthorchis viverrini, but the molecular basis for development remains unclear. The present study employed a microarray approach to compare gene expression profiles of ICCs and normal liver tissues from the same patients residing in Northeast Thailand, a region with a high prevalence of liver fluke infection. In ICC samples, 2,821 and 1,361 genes were found to be significantly up-and down-regulated respectively (unpaired t-test, p<0.05; fold-change ≥2.0). For validation of the microarray results, 7 up-regulated genes (FXYD3, GPRC5A, CEACAM5, MUC13, EPCAM, TMC5, and EHF) and 3 downregulated genes (CPS1, TAT, and ITIH1) were selected for confirmation using quantitative RT-PCR, resulting in 100% agreement. The metallothionine heavy metal pathway contains the highest percentage of genes with statistically significant changes in expression. This study provides exon-level expression profiles in ICC that should be fruitful in identifying novel genetic markers for classifying and possibly early diagnosis of this highly fatal type of cholangiocarcinoma.

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“…There is evidence of the relationship, probably through the interaction with the nuclear receptor FXR (farnesoid X receptor) or the membrane-bound receptor TGR5, between bile acids and the proliferation and survival of biliary epithelial cells (4). Moreover, several studies in animals support the relationship between cholestasis and cholangiocarcinoma progression (5,6). On the other hand, FXR, whose expression is decreased in cholangiocarcinoma (7), is involved in liver cells chemoprotection against genotoxic compounds (8).…”

Section: Introductionmentioning

confidence: 99%

Cocarcinogenic Effects of Intrahepatic Bile Acid Accumulation in Cholangiocarcinoma Development

Lozano

Sanchez-Vicente

Monte

et al. 2014

Molecular Cancer Research

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Bile acid accumulation in liver with cholangiolar neoplastic lesions may occur before cholestasis is clinically detected. Whether this favors intrahepatic cholangiocarcinoma development has been investigated in this study. The E. coli RecA gene promoter was cloned upstream from Luc2 to detect in vitro direct genotoxic ability by activation of SOS genes. This assay demonstrated that bile acids were not able to induce DNA damage. The genotoxic effect of the DNA-damaging agent cisplatin was neither enhanced nor hindered by the hepatotoxic and hepatoprotective glycochenodeoxycholic and glycoursodeoxycholic acids, respectively. In contrast, thioacetamide metabolites, but not thioacetamide itself, induced DNA damage. Thus, thioacetamide was used to induce liver cancer in rats, which resulted in visible tumors after 30 weeks. The effect of bile acid accumulation on initial carcinogenesis phase (8 weeks) was investigated in bile duct ligated (BDL) animals. Serum bile acid measurement and determination of liver-specific healthy and tumor markers revealed that early thioacetamide treatment induced hypercholanemia together with upregulation of the tumor marker Neu in bile ducts, which were enhanced by BDL. Bile acid accumulation was associated with increased expression of interleukin (IL)-6 and downregulation of farnesoid X receptor (FXR). Bile duct proliferation and apoptosis activation, with inverse pattern (BDL > thioacetamide þ BDL >> thioacetamide vs. thioacetamide > thioacetamide þ BDL > BDL), were observed. In conclusion, intrahepatic accumulation of bile acids does not induce carcinogenesis directly but facilitates a cocarcinogenic effect due to stimulation of bile duct proliferation, enhanced inflammation, and reduction in FXR-dependent chemoprotection.

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SHORT COMMUNICATION: Promotion of cholangiocarcinogenesis in the hamster liver by bile duct ligation after dimethylnitrosamine initiation

Cited by 56 publications

References 0 publications

Cytotoxicity, Toxicity, and Anticancer Activity of Zingiber Officinale Roscoe Against Cholangiocarcinoma

Cytotoxicity, Toxicity, and Anticancer Activity of Zingiber Officinale Roscoe Against Cholangiocarcinoma

Gene Expression Profiling of Intrahepatic Cholangiocarcinoma

Cocarcinogenic Effects of Intrahepatic Bile Acid Accumulation in Cholangiocarcinoma Development

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