Cytotoxic and Apoptosis‐Inducing Activities,and Anti‐Tumor‐Promoting Effects of Cyanogenated and Oxygenated Triterpenes |
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| Authors: | Takashi Kikuchi Kenta Ishii Eri Ogihara Jie Zhang Motohiko Ukiya Harukuni Tokuda Takashi Iida Reiko Tanaka Toshihiro Akihisa |
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| Affiliation: | 1. College of Science and Technology, Nihon University, 1‐8‐14 Kanda Surugadai, Chiyoda‐ku, Tokyo 101‐8308, Japan;2. Osaka University of Pharmaceutical Sciences, 4‐20‐1 Nasahara, Takatsuki, Osaka 569‐1094, Japan;3. Graduate School of Medical Science, Kanazawa University, 13‐1 Takara‐machi, Kanazawa 920‐8640, Japan;4. College of Humanities and Sciences, Nihon University, 3‐25‐40 Sakurajousui, Setagaya‐ku, Tokyo 156‐8550, Japan;5. Akihisa Medical Clinic, 1086‐3 Kamo, Sanda‐shi, Hyogo 669‐1311, Japan, (fax: +81‐79‐567‐1980) |
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| Abstract: | Two of each semisynthetic lanostane‐ and cycloartane‐type triterpenes with a cyano‐enone functionality, i.e., 13 and 18 , and 23 and 28 , respectively, sixteen of their synthetic intermediates, 9 – 12, 14 – 17, 19 – 22 , and 24 – 27 , along with seven semisynthetic oxygenated triterpene acetates, 29 – 35 , and eight natural hydroxy triterpenes, 1 – 8 , were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK‐BR‐3) cancer cell lines. One natural triterpene, 8 , and ten semisynthetic triterpenes, 9, 13, 15, 18, 23, 25, 28, 29, 32 , and 33 , exhibited potent cytotoxicities against one or more cell lines with IC50 values in the range of 1.4–9.9 μM . Two lanostane‐type triterpenes with a cyano‐enone functionality, 3‐oxolanosta‐1,8,24‐triene‐2‐carbonitrile ( 13 ) and 3‐oxolanosta‐1,8‐diene‐2‐carbonitrile ( 18 ), induced apoptosis in HL60 cells, as observed by membrane phospholipid exposure in flow cytometry. Western blot analysis showed that 13 and 18 significantly reduced procaspases‐3, ‐8, and ‐9, and increased cleaved caspases‐3, ‐8, and ‐9. These findings indicated that compounds 13 and 18 induced apoptosis in HL60 cells via both the mitochondrial and the death receptor‐mediated pathways. In addition, upon evaluation of the inhibitory effects on Epstein? Barr virus early antigen (EBV‐EA) activation induced with 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in Raji cells, seven natural triterpenes, 1 – 6 and 8 , and ten semisynthetic triterpenes, 9, 10, 14, 15, 19, 20, 24, 25, 29 , and 30 , exhibited inhibitory effects which were higher than that of β‐carotene, a vitamin A precursor studied widely in cancer‐chemoprevention animal models. |
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| Keywords: | Cyano‐enone‐functionalized triterpenes Triterpenes Cytotoxic activity Apoptosis Caspase‐dependent apoptosis Epstein Barr virus early antigen |
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