scholarly journals Cyclic adenosine monophosphate-mediated protection against bile acid-induced apoptosis in cultured rat hepatocytes

Hepatology ◽  
1998 ◽  
Vol 27 (5) ◽  
pp. 1324-1331 ◽  
Author(s):  
Cynthia R.L. Webster ◽  
M. Sawkat Anwer
Keyword(s):  
Bile Acid ◽  
Cyclic Adenosine Monophosphate ◽  
Rat Hepatocytes ◽  
Adenosine Monophosphate ◽  
Cultured Rat Hepatocytes ◽  
Induced Apoptosis

cAMP inhibits bile acid-induced apoptosis by blocking caspase activation and cytochromecrelease

2002 ◽  
Vol 283 (3) ◽  
pp. G727-G738 ◽  
Author(s):  
Cynthia R. L. Webster ◽  
Paul Usechak ◽  
M. Sawkat Anwer
Keyword(s):  
Bile Acid ◽  
Cytochrome C ◽  
Rat Hepatocytes ◽  
Dependent Manner ◽  
Cytochrome C Release ◽  
Akt Phosphorylation ◽  
Apoptotic Effect ◽  
Cultured Rat Hepatocytes ◽  
Phosphoinositide 3 Kinase ◽  
Induced Apoptosis

We have previously shown that cAMP protects against bile acid-induced apoptosis in cultured rat hepatocytes in a phosphoinositide 3-kinase (PI3K)-dependent manner. In the present studies, we investigated the mechanisms involved in this anti-apoptotic effect. Hepatocyte apoptosis induced by glycodeoxycholate (GCDC) was associated with mitochondrial depolarization, activation of caspases, the release of cytochrome c from the mitochondria, and translocation of BAX from the cytosol to the mitochondria. cAMP inhibited GCDC-induced apoptosis, caspase 3 and caspase 9 activation, and cytochrome c release in a PI3K-dependent manner. cAMP activated PI3K in p85 immunoprecipitates and resulted in PI3K-dependent activation of the survival kinase Akt. Chemical inhibition of Akt phosphorylation with SB-203580 partially blocked the protective effect of cAMP. cAMP resulted in wortmannin-independent phosphorylation of BAD and was associated with translocation of BAD from the mitochondria to the cytosol. These results suggest that GCDC-induced apoptosis in cultured rat hepatocytes proceeds through a caspase-dependent intracellular stress pathway and that the survival effect of cAMP is mediated in part by PI3K-dependent Akt activation at the level of the mitochondria.

scholarly journals Bile acid secretion by cultured rat hepatocytes. Regulation by cholesterol availability.

1983 ◽  
Vol 258 (6) ◽  
pp. 3661-3667 ◽  
Author(s):  
R A Davis ◽  
P M Hyde ◽  
J C Kuan ◽  
M Malone-McNeal ◽  
J Archambault-Schexnayder
Keyword(s):  
Bile Acid ◽  
Acid Secretion ◽  
Rat Hepatocytes ◽  
Cultured Rat Hepatocytes ◽  
Bile Acid Secretion

Theophylline synergizes with chlorambucil in inducing apoptosis of B- chronic lymphocytic leukemia cells

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 2172-2182 ◽  
Author(s):  
F Mentz ◽  
MD Mossalayi ◽  
F Ouaaz ◽  
S Baudet ◽  
F Issaly ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Apoptotic Cell ◽  
Protein A ◽  
Phosphodiesterase Inhibitor ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Lymphocytic Leukemia ◽  
Interleukin 4 ◽  
Induced Apoptosis

We tested the effects of theophylline, a phosphodiesterase inhibitor inducing intracellular accumulation of cyclic adenosine monophosphate (cAMP), on malignant B cells from 15 patients with B-chronic lymphocytic leukemia (B-CLL). We observed a large increase in apoptotic cell numbers (mean, 90% v 20% in medium alone) in the presence of theophylline (100 micrograms/mL) or chlorambucil (10 mumol/L) after 72 hours of incubation. Maximal apoptosis (90%) was reached after 36 hours when the two drugs were used together at fourfold lower concentrations, indicating a synergistic effect; no effect was observed with normal B cells, suggesting that the combination might have therapeutic interest. Chlorambucil induced intracellular Ca+2 influx, pointing to the involvement of two signaling pathways that might explain its synergy with theophylline through their effects on oncogenes. The expression of bcl-2 protein, a proto-oncogene inhibiting apoptosis, decreased after incubation with the drugs, while c-myc, recently described as having a potent role in apoptosis, was overexpressed. For p53 we observed an overexpression in the presence of chlorambucil or both theophylline- chlorambucil and a decrease after theophylline incubation. Chlorambucil- and theophylline-induced apoptosis was partially inhibited by interleukin-4 (IL-4), which also abrogated the effects on oncogene expression. These results provide insight into the mechanisms underlying B-CLL apoptosis and suggest that the theophylline- chlorambucil combination may be of therapeutic value in this setting.

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