An ent-kaurene diterpene enhances apoptosis induced by tumor necrosis factor in human leukemia cells

Some antitumor agents, including tumor necrosis factor-alpha (TNF-alpha) and camptothecin (CPT), often cause resistance of tumor cells to antitumor agents through activation of the nuclear factor-kappaB (NF-kappaB) pathway that leads to up-regulation of anti-apoptotic proteins. Therefore, co-treatment of an inhibitor of the NF-kappaB pathway with antitumor agents is a useful strategy for chemotherapy. Here we report that ent-11alpha-hydroxy-16-kauren-15-one (KD) selectively inhibits NF-kappaB-dependent gene expression due to treatment with TNF-alpha. KD in combination with TNF-alpha 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-alpha. 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-alpha or CPT is elicited through selective inhibition of NF-kappaB-dependent anti-apoptotic proteins and thus may provide a basis for the development of useful approaches to the treatment of leukemia.