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上个世纪出生的读者，应该还记得一种叫宝塔糖的药品，其主要成分即蛔蒿素，又称山道年、散道宁，是从菊科植物蛔蒿（山道年蒿）头状花序提取的倍半萜酮内酯，也可人工合成，具有麻痹蛔虫的作用，过去被中国、苏联、美国、英国等国药典列为驱蛔药。近年来，由于倍半萜酮内酯被发现具有强大的抗癌作用而备受关注。 2019年5月18日，美国《医学科学监测》在线发表复旦大学上海医学院、复旦大学附属肿瘤医院的研究报告，评估了天然倍半萜酮内酯蛔蒿素对人类乳腺癌细胞的抗癌作用。 该研究所用人类乳腺癌细胞（SK-BR-3）来自1970年美国纽约纪念医院斯隆凯特林癌症中心（MSKCC）从一例43岁白人女性分离培养的HER2过表达耐药乳腺癌细胞后代。本研究利用细胞计数试剂盒8对细胞活动进行测定，利用能够与DNA强力结合的荧光染料4',6-二脒基-2-苯基吲哚（DAPI）和膜联蛋白V碘化丙啶染色对细胞凋亡进行检测，利用流式细胞技术对于细胞分裂周期进行分析，利用蛋白质免疫印迹法对蛋白质表达进行估算。 结果，蛔蒿素随着浓度增加，对乳腺癌SK-BR-3细胞发挥显著的抗增殖作用，50%抑制浓度为16微摩尔。DAPI染色表明，蛔蒿素引起SK-BR-3细胞DNA断裂，提示细胞凋亡。膜联蛋白V碘化丙啶染色表明，蛔蒿素浓度达32微摩尔时，凋亡细胞比例增至34.32%。蛔蒿素可引起调节细胞凋亡的BCL-2相关X蛋白BAX、胱天蛋白酶3、胱天蛋白酶9的表达增加，BCL-2的表达减少。蛔蒿素还阻止SK-BR-3细胞由DNA复制蛋白质合成后期G2进入有丝分裂期M，并抑制细胞有丝分裂周期蛋白A和B1的表达。最后，蛔蒿素还可阻断乳腺癌细胞的有丝分裂信号转导通路RAF→MEK→ERK。 因此，该体外细胞研究结果表明，天然倍半萜酮内酯蛔蒿素通过诱导线粒体所致细胞凋亡、胱天蛋白酶活化、细胞有丝分裂周期停滞、阻断细胞有丝分裂信号转导通路，对于耐药乳腺癌细胞可以发挥抗癌作用，对于耐药乳腺癌具有治疗潜力，有望成为抗癌药物。 Med Sci Monit. 2019 May 18;25:3676-3682. Naturally Occurring Sesquiterpene Lactone-Santonin, Exerts Anticancer Effects in Multi-Drug Resistant Breast Cancer Cells by Inducing Mitochondrial Mediated Apoptosis, Caspase Activation, Cell Cycle Arrest, and by Targeting Ras/Raf/MEK/ERK Signaling Pathway. Wu Z, Wang C, Huang M, Tao Z, Yan W, Du Y. Shanghai Medical College, Fudan University, Shanghai, China; Fudan University Shanghai Cancer Center, Shanghai, China. BACKGROUND: Sesquiterpene lactones have gained tremendous attention owing to their potent anticancer properties. The main focus of this study was to evaluate the anticancer effects of a naturally occurring sesquiterpene lactone, santonin, against human breast cancer SK-BR-3 cells. MATERIAL AND METHODS: Cell counting kit 8 assay was used for the determination of cell viability. Apoptosis was detected by DAPI (4',6-diamidino-2-phenylindole) and annexin V/propidium iodide (PI) staining. Flow cytometry was used for cell cycle analysis and western blotting was used for the estimation of protein expression. RESULTS: Results showed that santonin exerts significant anti-proliferative effects on the SK-BR-3 breast cancer cells in a concentration dependent manner. Santonin showed an IC50 of 16 uM against SK-BR-3 cells. DAPI staining showed that santonin caused DNA fragmentation in the SK-BR-3 cells, which is indicative of apoptosis. Annexin V/PI staining showed that apoptotic cell percentage increased up to 34.32% at 32 uM concentration of santonin. Santonin also caused an increase in the expression of Bax, caspase-3, and caspase-9, and a decrease in the expression of Bcl-2. Santonin also caused the arrest of the SK-BR-3 cells at the G2/M phase of the cell cycle and suppressed the expression of cyclin A and B1. Finally, santonin could also block the Raf/MEK/ERK pathway in breast cancer cells. CONCLUSIONS: The findings of this study suggest the potential for the naturally occurring sesquiterpene lactone santonin in breast cancer treatment and also suggest that it could be developed as a promising anticancer agent. PMID: 31101800 DOI: 10.12659/MSM.915246
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