Morin fosters apoptosis in experimental hepatocellular carcinogenesis model.

Abstract

Here we investigated the in vivo effect of morin (500ppm in diet) in fostering apoptosis in diethylnitrosamine (DEN) (200mg/kg bodyweight) mediated experimental hepatocellular carcinogenesis model. We analyzed the expression of cytosolic protein Akt and their important apoptotic downstream targets like caspase-9, Bcl-2, Bax, GSK-3betain vivo, by immunoblot analysis. In silico docking studies indicated that morin could serve as a better inhibitor than the classical PI3K inhibitor LY294002. The results obtained from in vivo studies confirm this. We also demonstrate here that morin's interaction with a defined set of amino acids of PI3K p110gamma catalytic subunit resulted in the down-regulation of p-Akt(Ser473), p-Akt(Thr308) and total Akt causing the attenuation of its downstream targets in DEN-induced hepatocellular carcinoma. Further, morin caused the up-regulation of tumor suppressor PTEN, an important negative regulator of Akt, thus initiating apoptosis. Supplementation of morin to experimental animals modulated Bcl-2/Bax ratio causing the release of cyt C and up-regulation of caspase-3 and -9. Morin was also found to prevent the Akt-mediated suppression of GSK-3beta possibly causing cell cycle arrest at the G1/S phase. These observations were supported by the DNA fragmentation and transmission electron microscopy results, which showed the occurrence of apoptosis. In conclusion, our findings demonstrate that morin begets apoptosis in DEN-induced hepatocellular carcinoma.

• Authors: Venkatabalasubramanian Sivaramakrishnan, Sivasitambaram Niranjali Devaraj
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 183 Issue 2 Pg. 284-92 (Jan 27 2010) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 19931519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2009 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Antioxidants
• Flavonoids
• Phosphoinositide-3 Kinase Inhibitors
• bcl-2-Associated X Protein
• Diethylnitrosamine
• morin
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• PTEN Phosphohydrolase
• Pten protein, mouse
• Caspase 3
• Caspase 9

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Antioxidants (chemistry, pharmacology)
• Apoptosis
• Binding Sites
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Computer Simulation
• Diethylnitrosamine (toxicity)
• Flavonoids (chemistry, pharmacology)
• G1 Phase
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Liver Neoplasms, Experimental (chemically induced, metabolism)
• PTEN Phosphohydrolase (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (metabolism)
• S Phase
• bcl-2-Associated X Protein (metabolism)