γ-Aminobutyric Acid Inhibits Cholangiocarcinoma Growth by Cyclic AMP–Dependent Regulation of the Protein Kinase A/Extracellular Signal-Regulated Kinase 1/2 Pathway

Fava, Giammarco; Marucci, Luca; Glaser, Shannon; Francis, Heather; Morrow, Sharon De; Benedetti, Antonio; Alvaro, Domenico; Venter, Julie; Meininger, Cynthia J.; Patel, Tushar; Taffetani, Silvia; Marzioni, Marco; Summers, Ryun; Reichenbach, Ramona; Alpini, Gianfranco

doi:10.1158/0008-5472.can-05-1470

Cited by 85 publications

(112 citation statements)

References 45 publications

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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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“…Among neuroendocrine factors that either inhibit proliferation or induce apoptosis secretin, gastrin, γ-aminobutyric acid, endothelin-1 and the endocannabinoid anandamide have been described 103,104,[106][107][108][109][110][111] . Although the activation of histamine H 3 and H 4 receptors (HRH 3 and HRH 4 ) inhibits CCA growth, histamine itself is considered proliferative as it sustains CCA growth by forming an autocrine loop 112,113 .…”

Section: Nature Reviews | Gastroenterology and Hepatologymentioning

confidence: 99%

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Bañales

Cardinale

Carpino

et al. 2016

Nat Rev Gastroenterol Hepatol

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1,139

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“…After 24 h of incubation, cholangiocyte proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) proliferation assay. 6,40 This is the same approach that we have used for evaluating the stimulatory effects of nerve growth factor (NGF, present in the supernatant of primary cultures of BDL cholangiocytes) on the proliferation of normal cholangiocytes. 41 …”

Section: Intracellular Signaling Mechanismsmentioning

confidence: 99%

“…1,2 Cholangiocytes display neuroendocrine phenotypes during cholestatic liver diseases and secrete neural factors and respond to neuropeptides with alterations in proliferation. 1,[3][4][5][6][7][8] Interruption of parasympathetic and sympathetic innervation decreases cholangiocyte cAMP levels and proliferation, and induces biliary apoptosis in BDL rats. 4,7 Administration of cAMP-agonists reverses the decrease in cholangiocyte proliferation and the increase in cholangiocyte apoptosis induced by parasympathetic and sympathetic denervation.…”

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confidence: 99%

Knockout of α-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice

Glaser

Ueno

DeMorrow

et al. 2007

Laboratory Investigation

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The role of sensory innervation in the regulation of liver physiology and the pathogenesis of cholestatic liver disease are undefined. Biliary proliferation has been shown to be coordinately controlled by parasympathetic and sympathetic innervation of the liver. The aim of our study was to address the role of the sensory neuropeptide calcitonin gene-related peptide (a-CGRP) in the regulation of cholangiocyte proliferation during cholestasis induced by extrahepatic bile duct obstruction (BDL). Our study utilized a knockout (KO) mouse model, which lacks the sensory neuropeptide a-CGRP. Wildtype (WT) and a-CGRP KO mice were subjected to sham surgery or BDL for 3 and 7 days. In addition, immediately after BDL, WT and KO mice were administered the CGRP receptor antagonist (CGRP 8-37 ) for 3 and 7 days by osmotic minipumps. Liver sections and isolated cholangiocytes were evaluated for proliferation markers. Isolated WT BDL (3 days) cholangiocytes were stimulated with a-and b-CGRP and evaluated for proliferation and cAMP-mediated signaling. Lack of a-CGRP inhibits cholangiocyte proliferation induced by BDL at both 3 and 7 days. BDL-induced cholangiocyte proliferation in WT mice was associated with increases of circulating a-CGRP levels. In vitro, a-and b-CGRP stimulated proliferation in purified BDL cholangiocytes, induced elevation of cAMP levels, and stimulated the activation of cAMPdependent protein kinase A and cAMP response element binding protein DNA binding. In conclusion, sensory innervation of the liver and biliary expression of a-CGRP play an important role in the regulation of cholangiocyte proliferation during cholestasis.

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γ-Aminobutyric Acid Inhibits Cholangiocarcinoma Growth by Cyclic AMP–Dependent Regulation of the Protein Kinase A/Extracellular Signal-Regulated Kinase 1/2 Pathway

Cited by 85 publications

References 45 publications

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

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

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Knockout of α-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice

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