18beta-glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway.

Abstract

The purpose of the present study was to evaluate the anti-tumor effects of 18beta-glycyrrhetinic acid (GA), a natural compound extracted from liquorice, against pituitary adenoma and its underlying mechanisms in cultured cells and mouse model of xenografted tumor. GA induced cellular damage in rat pituitary adenoma-derived MMQ and GH3 cells, manifested as reduced cell viability, increased lactate dehydrogenase release, elevated intracellular reactive oxygen species (ROS) and Ca(2+) concentration. GA also caused G0/G1 phase arrest, increased apoptosis rate and increased mitochondrial membrane permeabilization by suppressing the mitochondrial membrane potential and down-regulating a ratio of B cell lymphoma 2 (Bcl-2) and Bax. GA activated calcium/calmodulin-dependent protein kinase II (CaMKII), c-Jun N-terminal kinase (JNK) and P38; but these activating effects were attenuated by pretreatment with N-acetyl-L-cysteine, a ROS inhibitor. Pretreatment with KN93, a CaMKII inhibitor, also abolished the GA activation of JNK and P38. GA remarkably inhibited growth of pituitary adenoma grafted on nude mice. These results suggest that the anti-pituitary adenoma effect of GA is associated with its apoptotic actions by activating mitochondria-mediated ROS/mitogen-activated protein kinase pathways in particular CaMKII that may serve a linkage between ROS accumulation and the activation of JNK and P38. This study provides experimental evidence in the support of further developing GA as a chemotherapeutic agent for pituitary adenoma.

• Authors: Di Wang, Hei-Kiu Wong, Yi-Bin Feng, Zhang-Jin Zhang
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 116 Issue 2 Pg. 221-30 (Jan 2014) ISSN: 1573-7373 [Electronic] United States
• PMID: 24162829 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Reactive Oxygen Species
• 18alpha-glycyrrhetinic acid
• L-Lactate Dehydrogenase
• Mitogen-Activated Protein Kinase Kinases
• Glycyrrhetinic Acid

Topics

• Adenoma (drug therapy, pathology)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Disease Models, Animal
• Glycyrrhetinic Acid (analogs & derivatives, pharmacology, therapeutic use)
• Humans
• L-Lactate Dehydrogenase (metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Pituitary Neoplasms (drug therapy, pathology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Transplantation, Heterologous (methods)