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.
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-G1 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-XL, 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.
Park
Bo-Young
BY
Natural Medicines Research Center, KRIBB, 52 Eoeun-dong, Yusong, Daejeon 305-806, South Korea.
Min
Byung-Sun
BS
Ahn
Kyung-Seop
KS
Kwon
Ok-Kyong
OK
Joung
Hyouk
H
Bae
Ki-Hwan
KH
Lee
Hyeong-Kyu
HK
Oh
Sei-Ryang
SR
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D032364:Daphne / Q000737:chemistry*; D004224:Diterpenes / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D035264:Flowers; D005786:Gene Expression Regulation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D007274:Injections, Intraperitoneal; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D004224:Diterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; C036412:genkwadaphnin; C029912:Yuanhuacin; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3