Liu Ming, Zhang Weiyi, Wang Genzhu, Song Xiaoping, Zhao Xingzeng, Wang Xiangyun, Qi Xin, Li Jing
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
Institute of Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden, Mem. Sun Yat-sen), Nanjing, 210014, China.
Tumour Biol. 2016 May;37(5):6227-38. doi: 10.1007/s13277-015-4495-7. Epub 2015 Nov 28.
13-Oxyingenol dodecanoate (13OD) is an ingenol derivative prepared from Chinese traditional medicine Euphorbia kansui without any report about its bioactivity. The present study demonstrated for the first time that 13OD displayed potent cytotoxicity against chronic myeloid leukemia K562 cells in vitro. 13OD inhibited proliferation, induced G2/M phase arrest, and exhibited potent apoptotic activity in K562 cells. In K562 cells, 13OD disrupted the mitochondrial membrane potential and induced high level of ROS, which played an indispensable role in 13OD-induced apoptosis. Further investigations on the molecular mechanisms revealed that total Akt protein level was decreased in a caspase-dependent way after treatment with 13OD; in addition, ERK was activated by 13OD, and this activation played a protective role in 13OD stimulation. Altogether, these results revealed that the cytotoxic ingenol derivative 13OD induced apoptosis with novel mechanisms for the proapoptotic function in cancer cells, and suggested that 13OD may serve as a lead template for rational drug design and for future anticancer agent development.
13-氧代大戟醇十二烷酸酯（13OD）是一种从中国传统药物甘遂中制备的大戟醇衍生物，目前尚无关于其生物活性的报道。本研究首次证明13OD在体外对慢性髓性白血病K562细胞具有强大的细胞毒性。13OD抑制K562细胞增殖，诱导G2/M期阻滞，并表现出强大的凋亡活性。在K562细胞中，13OD破坏线粒体膜电位并诱导高水平的活性氧（ROS），这在13OD诱导的凋亡中起不可或缺的作用。对分子机制的进一步研究表明，用13OD处理后，总Akt蛋白水平以半胱天冬酶依赖性方式降低；此外，ERK被13OD激活，这种激活在13OD刺激中起保护作用。总之，这些结果表明，具有细胞毒性的大戟醇衍生物13OD通过新的机制诱导癌细胞凋亡，提示13OD可能作为合理药物设计和未来抗癌药物开发的先导模板。
