Labdane-type diterpenes as new cell cycle inhibitors and apoptosis inducers from Vitex trifolia L.

Abstract

Five labdane-type diterpenes, vitexilactone (1), (rel 5S,6R,8R,9R,10S)-6-acetoxy-9-hydroxy-13(14)-labden-16,15-olide (2), rotundifuran (3), vitetrifolin D (4), and vitetrifolin E (5), have been isolated from Vitex trifolia L., a Chinese folk medicine used to treat cancers, as new cell cycle inhibitors and apoptosis inducers through a bioassay-guided separation procedure and were identified by spectroscopic methods. Compounds 1–5 dramatically induced apoptosis both on tsFT210 and K562 cells at higher concentrations while at lower concentrations they inhibited the cell cycle progression of both tsFT210 and K562 cells at the G₀/G₁ phase. MIC values for 1–5 for inducing apoptosis and concentration regions for 1–5 for inhibiting cell cycle both on tsFT210 and K562 cells have also been determined. Furthermore, the inhibitory effects of 1–5 on the proliferation of tsFT210 and K562 cells have been evaluated by MTT assay to obtain IC₅₀ values to confirm that 1–5 are anticancer components of Vitex trifolia L., which exert their anti-proliferative effect on cancer cells through inducing apoptosis and inhibiting the cell cycle. The present results provide labdane-type diterpenes, 1–5, as a new class of cell cycle inhibitors and compounds 1, 2, 4, and 5 as new apoptosis inducers, which also explains, for the first time, the usage of Vitex trifolia L. by Chinese people to treat cancers.

Keywords:

• Vitex trifolia
• Diterpene
• Labdane-type diterpene
• Cell cycle inhibitor
• Apoptosis inducer
• Anticancer
• Verbenaceae

Acknowledgements

The authors are grateful to Dr H. Osada, head of the Antibiotics Laboratory, the Institute of Physical and Chemical Research (RIKEN), Japan, for his kind gift of the tsFT210 cell line. This work was supported by the Fund from the National Natural Science Foundation of China (C.-B. Cui, No. 39825126), and the Funds of the 973-project from the Ministry of Science and Technology (C.-B. Cui, No. 1998051113), China, and the Cheung Kong Scholar (C.-B. Cui) from the Cheung Kong Scholars Program, Ministry of Education of China. The plant materials were collected and identified by Professor Q.-S. Sun of Shenyang Pharmaceutical University, China.