A Novel Potent Anticancer Compound Optimized from a Natural Oridonin Scaffold Induces Apoptosis and Cell Cycle Arrest through the Mitochondrial Pathway

The cytotoxicity of the natural ent-kaurene diterpenoid, oridonin, has been extensively studied. However, the application of oridonin for cancer therapy was hampered primarily by its moderate potency. In this study, a series of oridonin A-ring modified analogues, and their derivatives bearing variou...

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Bibliographic Details
Published in:	Journal of medicinal chemistry 2017-02, Vol.60 (4), p.1449-1468
Main Authors:	Xu, Shengtao, Yao, Hong, Luo, Shanshan, Zhang, Yun-Kai, Yang, Dong-Hua, Li, Dahong, Wang, Guangyu, Hu, Mei, Qiu, Yangyi, Wu, Xiaoming, Yao, Hequan, Xie, Weijia, Chen, Zhe-Sheng, Xu, Jinyi
Format:	Article
Language:	eng
Subjects:	Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis - drug effects Breast - drug effects Breast - metabolism Breast - pathology Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Cycle Checkpoints - drug effects Cell Line, Tumor Cell Proliferation - drug effects Diterpenes, Kaurane - chemistry Diterpenes, Kaurane - pharmacology Diterpenes, Kaurane - therapeutic use Female Humans MCF-7 Cells Mice Mice, Nude Mitochondria - drug effects Mitochondria - metabolism Mitochondria - pathology Signal Transduction - drug effects
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Summary:	The cytotoxicity of the natural ent-kaurene diterpenoid, oridonin, has been extensively studied. However, the application of oridonin for cancer therapy was hampered primarily by its moderate potency. In this study, a series of oridonin A-ring modified analogues, and their derivatives bearing various substituents on 14-OH position, were designed, synthesized, and evaluated for anticancer efficacy. Some of the derivatives were significantly more potent than oridonin against both drug-sensitive and drug-resistant cancer cells. The most potent compound, 13p, was 200-fold more efficacious than oridonin in MCF-7 cancer cells. Furthermore, 13p induced apoptosis and cell cycle arrest at the G2/M phase. A decrease in mitochondrial membrane potential and an increase in Bax/Bcl-2 ratio, accompanied by activated caspase-3 cleavage, were observed in MCF-7 cells after treatment with 13p, suggesting that the mitochondrial pathway was involved in the 13p-mediated apoptosis. Moreover, 13p significantly inhibited tumor growth in mouse xenograft models and had no observable toxic effect.
ISSN:	0022-2623 1520-4804