Deng Qing-Ping, Wang Mao-Jie, Zeng Xing, Chen George Gong, Huang Run-Yue
The Second Affiliated Hospital, Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.
Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong.
Cell Physiol Biochem. 2017;41(4):1383-1392. doi: 10.1159/000467897. Epub 2017 Mar 16.
Currently, there is a global attempt to identify potential anti-cancer agents with low toxicity. Previous studies have found that glycyrrhizin exerts anti-cancer action with low toxicity through suppressing thromboxane A2 (TxA2) in lung cancer cell lines. However, these effects have not yet been determined in animal models of lung cancer.
Human lung adenocarcinoma xenografts were established in nude mice by the introduction of A549 cells with stable transfection of the TxA2 receptor (TPα). The animal model was confirmed by the hematoxylin and eosin (H&E) method. Tumor-bearing mice were then administered graded concentrations of glycyrrhizin, cisplatin or both. After the treatments, body weights of all animals were recorded, and immunohistochemistry staining of lung tissues and serum biochemistry detection of aspartate amino transferase (AST), alanine amino transferase (ALT), urea and creatinine were carried out.
Treatment with glycyrrhizin alone or the combination of cisplatin and glycyrrhizin profoundly reduced expression of thromboxane synthase (TxAS) as well as proliferating cell nuclear antigen (PCNA), recovered the body weight, and rescued damage of liver and kidney in tumor-bearing mice. Although it inhibited PCNA expression, cisplatin could not significantly suppress TxAS expression. Because of a positive feedback loop between TPα and TxAS, the effects of glycyrrhizin are possibly attributable to the suppression of the TxA2 pathway.
This study provides in vivo evidence to support glycyrrhizin as a potential candidate for developing new regimens to overcome tumor progression and the resistance and toxicity of cisplatin.
目前，全球都在努力寻找低毒性的潜在抗癌药物。先前的研究发现，甘草酸通过抑制肺癌细胞系中的血栓素A2（TxA2）发挥低毒性抗癌作用。然而，这些作用尚未在肺癌动物模型中得到证实。
通过导入稳定转染血栓素A2受体（TPα）的A549细胞，在裸鼠中建立人肺腺癌异种移植模型。采用苏木精-伊红（H&E）染色法对动物模型进行确认。然后给荷瘤小鼠给予不同浓度的甘草酸、顺铂或两者联合使用。治疗后，记录所有动物的体重，并对肺组织进行免疫组织化学染色，检测血清中天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、尿素和肌酐的生化指标。
单独使用甘草酸或顺铂与甘草酸联合治疗可显著降低血栓素合酶（TxAS）以及增殖细胞核抗原（PCNA）的表达，恢复荷瘤小鼠的体重，并减轻肝肾功能损伤。虽然顺铂能抑制PCNA表达，但不能显著抑制TxAS表达。由于TPα和TxAS之间存在正反馈回路，甘草酸的作用可能归因于对TxA2途径的抑制。
本研究提供了体内证据，支持甘草酸作为开发新方案以克服肿瘤进展、顺铂耐药性和毒性的潜在候选药物。
