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 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.
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Shengtao
S
Xu
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Hong
H
Yao
Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai 201203, P. R. China.
Shanshan
S
Luo
College of Pharmacy and Health Sciences, St. John's University , 8000 Utopia Parkway, Queens, New York 11439, United States.
Yun-Kai
YK
Zhang
College of Pharmacy and Health Sciences, St. John's University , 8000 Utopia Parkway, Queens, New York 11439, United States.
Dong-Hua
DH
Yang
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.|Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University , 103 Wen Hua Road, Shenyang 110016, China.
Dahong
D
Li
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Guangyu
G
Wang
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Mei
M
Hu
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Yangyi
Y
Qiu
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Xiaoming
X
Wu
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Hequan
0000-0003-4865-820X
H
Yao
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Weijia
W
Xie
College of Pharmacy and Health Sciences, St. John's University , 8000 Utopia Parkway, Queens, New York 11439, United States.
Zhe-Sheng
ZS
Chen
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Jinyi
0000-0002-1961-0402
J
Xu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D045786:Diterpenes, Kaurane; C011959:oridonin