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

• Published in: Journal of neuro-oncology Vol. 116; no. 2; pp. 221 - 230
• Main Authors: Wang, Di, Wong, Hei-Kiu, Feng, Yi-Bin, Zhang, Zhang-Jin
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-01-2014; Springer Nature B.V
• Subjects: Adenoma; Adenoma - drug therapy; Adenoma - pathology; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Apoptosis - drug effects; Cell Cycle - drug effects; Cell Line, Tumor; Disease Models, Animal; Glycyrrhetinic Acid - analogs & derivatives; Glycyrrhetinic Acid - pharmacology; Glycyrrhetinic Acid - therapeutic use; Humans; L-Lactate Dehydrogenase - metabolism; Laboratory Investigation; Medicine; Medicine & Public Health; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases - metabolism; Neurology; Oncology; Pituitary Neoplasms - drug therapy; Pituitary Neoplasms - pathology; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Time Factors; Transplantation, Heterologous - methods; 18beta-Glycyrrhetinic acid; Mitochondria; ROS/MAPKs; Apoptosis
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-013-1292-2

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.