An ent-Kaurene Diterpene Enhances Apoptosis Induced by Tumor Necrosis Factor in Human Leukemia Cells

Abstract

Some antitumor agents, including tumor necrosis factor-α (TNF-α) and camptothecin (CPT), often cause resistance of tumor cells to antitumor agents through activation of the nuclear factor-κB (NF-κB) pathway that leads to up-regulation of anti-apoptotic proteins. Therefore, co-treatment of an inhibitor of the NF-κB pathway with antitumor agents is a useful strategy for chemotherapy. Here we report that ent-11α-hydroxy-16-kauren-15-one (KD) selectively inhibits NF-κB-dependent gene expression due to treatment with TNF-α. KD in combination with TNF-α caused a dramatic increase in apoptosis in human leukemia cells accompanied by activation of caspases. A broad-spectrum inhibitor of caspases decreased the apoptosis induced by treatment with KD and TNF-α. KD in combination with CPT also caused an increase in apoptosis. These results suggest that the apoptotic potency of co-treatment of KD with TNF-α or CPT is elicited through selective inhibition of NF-κB-dependent anti-apoptotic proteins and thus may provide a basis for the development of useful approaches to the treatment of leukemia.

Abbreviations

NF-κB:nuclear factor-κB

KD:ent-11α-hydroxy-16-kauren-15-one

PARP:poly (ADP-ribose) polymerase

TNF-α:tumor necrosis factor-α

CPT:camptothecin

IAPs:inhibitor of apoptosis proteins

Kaurene diterpenes - NF-κB - TNF-α - CPT - Apoptosis - caspase

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