State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
Department of Pharmacy, China-Japan Friendship Hospital, Beijing 100050, People's Republic of China.
Sci Rep. 2017 Feb 10;7:42194. doi: 10.1038/srep42194.
Autophagy-induced cancer cell death has become a novel strategy for the development of cancer therapeutic drugs. Numerous studies have indicated that green tea polyphenols induce both autophagy and apoptosis in a variety of cancer cells. Here, we synthesized a series of green tea polyphenol analogues, among which JP8 was shown to potently activate autophagy. JP8 treatment had a stronger effect on apoptosis in B16-F10 melanoma cells than that in normal AML-12 hepatocytes. JP8 selectively resulted in reactive oxygen species (ROS) accumulation in B16-F10 cells, and this effect was associated with corresponding increases in key components of the ER stress-mediated apoptosis pathway. Pharmacological inhibition of ROS by N-acetyl-L-cysteine (NAC) attenuated JP8-induced autophagy and apoptosis, indicating an upstream role of ROS in JP8-induced autophagy. An in vivo study showed that JP8 had significant antitumor effects in a B16-F10 xenograft mouse model. Our results indicate that JP8 is a novel anticancer candidate with both autophagy and ROS induction activities.
自噬诱导的癌细胞死亡已成为开发癌症治疗药物的新策略。大量研究表明，绿茶多酚在多种癌细胞中诱导自噬和细胞凋亡。在这里，我们合成了一系列绿茶多酚类似物，其中 JP8 被证明能强烈激活自噬。JP8 处理对 B16-F10 黑素瘤细胞的凋亡作用强于正常 AML-12 肝细胞。JP8 选择性地导致 B16-F10 细胞中活性氧（ROS）的积累，这种作用与 ER 应激介导的凋亡途径的关键组成部分的相应增加有关。通过 N-乙酰-L-半胱氨酸（NAC）抑制 ROS 的药理学抑制作用减弱了 JP8 诱导的自噬和凋亡，表明 ROS 在 JP8 诱导的自噬中起上游作用。一项体内研究表明，JP8 在 B16-F10 异种移植小鼠模型中具有显著的抗肿瘤作用。我们的研究结果表明，JP8 是一种具有自噬和 ROS 诱导活性的新型抗癌候选物。
