Wang Di, Wong Hei-Kiu, Feng Yi-Bin, Zhang Zhang-Jin
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China.
J Neurooncol. 2014 Jan;116(2):221-30. doi: 10.1007/s11060-013-1292-2. Epub 2013 Oct 27.
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.
本研究的目的是评估从甘草中提取的天然化合物18β-甘草次酸（GA）对垂体腺瘤的抗肿瘤作用及其在培养细胞和异种移植肿瘤小鼠模型中的潜在机制。GA诱导大鼠垂体腺瘤来源的MMQ和GH3细胞发生细胞损伤，表现为细胞活力降低、乳酸脱氢酶释放增加、细胞内活性氧（ROS）和Ca(2+)浓度升高。GA还通过抑制线粒体膜电位和下调B细胞淋巴瘤2（Bcl-2）与Bax的比例，导致G0/G1期阻滞、凋亡率增加和线粒体膜通透性增加。GA激活钙/钙调蛋白依赖性蛋白激酶II（CaMKII）、c-Jun氨基末端激酶（JNK）和P38；但这些激活作用被ROS抑制剂N-乙酰-L-半胱氨酸预处理减弱。CaMKII抑制剂KN93预处理也消除了GA对JNK和P38的激活。GA显著抑制裸鼠移植垂体腺瘤的生长。这些结果表明，GA的抗垂体腺瘤作用与其通过激活线粒体介导的ROS/丝裂原活化蛋白激酶途径，特别是CaMKII的凋亡作用有关，CaMKII可能是ROS积累与JNK和P38激活之间的联系。本研究为进一步开发GA作为垂体腺瘤化疗药物提供了实验证据。
