Daphnane diterpene esters isolated from flower buds of Daphne genkwa induce apoptosis in human myelocytic HL-60 cells and suppress tumor growth in Lewis lung carcinoma (LLC)-inoculated mouse model

• Published in: Journal of ethnopharmacology 2007-05, Vol.111 (3), p.496-503
• Main Authors: Park, Bo-Young, Min, Byung-Sun, Ahn, Kyung-Seop, Kwon, Ok-Kyong, Joung, Hyouk, Bae, Ki-Hwan, Lee, Hyeong-Kyu, Oh, Sei-Ryang
• Format: Article
• Language: English
• Subjects: Animals; antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; bioassays; Biological and medical sciences; buds; carcinoma; Carcinoma, Lewis Lung - drug therapy; Caspase 3 - drug effects; Caspase 3 - metabolism; Caspase-3; Cell Growth Processes - drug effects; Cell Line, Tumor; chemical constituents of plants; Daphne; Daphne - chemistry; Daphne genkwa; Diterpenes - administration & dosage; Diterpenes - isolation & purification; Diterpenes - pharmacology; diterpenoids; Dose-Response Relationship, Drug; Flow Cytometry; Flowers; gebjwadaphnin; Gene Expression Regulation - drug effects; General pharmacology; Genkwadaphnin; HL-60 Cells; human cell lines; Humans; Immunoblotting; Injections, Intraperitoneal; lung neoplasms; Lung Neoplasms - drug therapy; Medical sciences; medicinal plants; medicinal properties; Mice; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; plant extracts; Poly(ADP-ribose) Polymerases - drug effects; Poly(ADP-ribose) Polymerases - metabolism; Proto-Oncogene Proteins c-bcl-2 - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Tumor Burden - drug effects; Yuanhuacine
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2006.12.023

In this study, two daphnane diterpene esters isolated from the flower buds of Daphne genkwa, genkwadaphnin ( 1) and yuanhuacine ( 2), were assessed with regard to their apoptotic activity in human promyelocytic HL-60 cells. Both 1 and 2 were demonstrated to activate the apoptotic process, including DNA fragmentation, chromatin condensation, and sub-G 1 hypodiploidy. In our immunoblotting analysis, treatment with compounds 1 and 2 resulted in the cleavage of procaspase-3 and poly(ADP-ribose)polymerase (PARP) into active forms, and the expression of Bcl-2 proteins was shifted toward apoptosis; the expression of the pro-apoptotic protein, Bax, was increased, and the expression of Bcl-2 and Bcl-X L, both anti-apoptotic proteins, were suppressed in a dose-dependent manner. The administration (ip) of the compounds to Lewis lung carcinoma (LLC)-inoculated mice evidenced a significant inhibition of tumor growth (volume), with reductions of 47.9% and 63.1% ( 1), and 24.2% and 45.8% ( 2) at concentrations of 0.1 mg/kg and 0.5 mg/kg, as compared with the control mice. These results indicate that compounds 1 and 2 are potent apoptotic constituents of Daphne genkwa, and might be potent as anti-tumoric agents.