Induction of Apoptosis by New ent-Kaurene-Type Diterpenoids Isolated from the New Zealand Liverwort Jungermannia Species

Abstract

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 (IC₅₀ values: A, 1.3; B, 5.3; C, 7.8; D, 2.7 μM) 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-CH₂-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-κB, 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.

Abbreviations

JA:jungermannenone A

JB:jungermannenone B

JC:jungermannenone C

JD:jungermannenone D

IAPs:inhibitory of apoptosis proteins

NF-κB:nuclear factor-κB

TNF-α:tumor necrosis factor-α

PARP:poly (ADP-ribose) polymerase

KD:ent-11α-hydroxy-16-kauren-15-one

Key words

Jungermannia species - diterpenoid - apoptosis - liverwort - caspase - NF-κB

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