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-kappa B (NF-kappa B) pathway that leads to up-regulation of anti-apoptotic proteins. Therefore, co-treatment of an inhibitor of the NF-kappa B pathway with antitumor agents is a useful strategy for chemotherapy. Here we report that ent-11 alpha-hydroxy-16-kauren-15-one (KD) selectively inhibits NF-kappa B-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-kappa B-dependent anti-apoptotic proteins and thus may provide a basis for the development of useful approaches to the treatment of leukemia.
Suzuki
Ikue
I
Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo, Japan.
Kondoh
Masuo
M
Harada
Motoki
M
Koizumi
Naoya
N
Fujii
Makiko
M
Nagashima
Fumihiro
F
Asakawa
Yoshinori
Y
Watanabe
Yoshiteru
Y
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D005786:Gene Expression Regulation; D018922:HL-60 Cells / Q000187:drug effects; D035926:Hepatophyta; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D045786:Diterpenes, Kaurane; D016328:NF-kappa B; D010936:Plant Extracts; D014409:Tumor Necrosis Factor-alpha