Induction of apoptosis by new ent-kaurene-type diterpenoids isolated from the New Zealand liverwort Jungermannia species.
Some diterpenoids show various biological activities, including anti-inflammatory, anti-HIV and anti-tumor activity. Previously, we have focused our research on the apoptosis-inducing properties of diterpenoids and found that some ent-kaurene-type diterpenoids induced apoptosis in human leukemia HL-60 cells. In this study, we have investigated the induction of apoptosis in HL-60 cells by the novel ent-kaurene-type diterpenoids, jungermannenones A (JA), B (JB), C (JC) and D (JD), isolated from the New Zealand liverwort Jungermannia species. Treatment of the cells with each compound for 12 h resulted in cytotoxicity (IC (50) values: A, 1.3; B, 5.3; C, 7.8; D, 2.7 microM) and caused DNA fragmentation and nuclear condensation, both biochemical markers of the induction of apoptosis. Treatment with the compounds resulted in activation of caspases, including caspase-3 and caspase-8. A broad-spectrum inhibitor of caspases, Z-Asp-CH (2)-DCB, attenuated the cytotoxicity induced by these compounds, suggesting that JA, JB, JC and JD induced apoptosis through a caspase-dependent pathway. JA and JD inhibited the activity of nuclear factor-kappaB, which is a transcriptional factor of anti-apoptotic factors. Thus, some of these new ent-kaurene-type diterpenoids may be promising candidates for anti-tumor agents.
Kondoh
Masuo
M
Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Machida, Tokyo, Japan.
Nagashima
Fumihiro
F
Suzuki
Ikue
I
Harada
Motoki
M
Fujii
Makiko
M
Asakawa
Yoshinori
Y
Watanabe
Yoshiteru
Y
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D045786:Diterpenes, Kaurane / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018922:HL-60 Cells; D035926:Hepatophyta; D006801:Humans
D000972:Antineoplastic Agents, Phytogenic; D045786:Diterpenes, Kaurane; D020169:Caspases