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

Key words

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

References

• 1 Johnstone R W, Ruefli A A, Lowe S W. Apoptosis: a link between cancer genetics and chemotherapy.  Cell. 2002;  108 153-64
• 2 Baldwin Jr A S. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB.  J Clin Invest. 2001;  107 241-6
• 3 Thevenod F, Friedmann J M, Katsen A D, Hauser I A. Up-regulation of multidrug resistance P-glycoprotein via nuclear factor-κB activation protects kidney proximal tubule cells from cadmium- and reactive oxygen species-induced apoptosis.  J Biol Chem. 2000;  275 1887-96
• 4 Tang W, Eisenbrand G. Chinese Drugs of Plant Origin: Chemistry, Pharmacology, and Use in Traditional and Modern Medicine. Springer-Verlag Berlin, Heidelberg; 1992: pp 817-47
• 5 Hwang B Y, Lee J H, Koo T H, Kim H S, Hong Y S, Ro J S. et al . Kaurane diterpenes from Isodon japonicus inhibit nitric oxide and prostaglandin E2 production and NF-κB activation in LPS-stimulated macrophage RAW264.7 cells.  Planta Medica. 2001;  67 406-10
• 6 Hou A, Li M L, Jiang B, Lin Z W, Ji S Y, Zhou Y P. et al . New 7,20 : 14,20-diepoxy-ent-kauranoids from Isodon xerophilus .  J Nat Prod. 2000;  63 599-601
• 7 Jiang B, Lu Z Q, Hou A J, Zhao Q S, Sun H D. ent-Kaurane diterpenoids from Isodon lungshengensis .  J Nat Prod. 1999;  62 941-5
• 8 Lee J H, Koo T H, Hwang B Y, Lee J J. Kaurane diterpene, kamebakaurin, inhibits NF-κB by directly targeting the DNA-binding activity of p50 and blocks the expression of antiapoptotic NF-κB target genes.  J Biol Chem. 2002;  277 18 411-20
• 9 Nagashima F, Kondoh M, Kawase M, Simizu S, Osada H, Fujii M. et al . Apoptosis-inducing properties of ent-kaurene-type diterpenoids from the liverwort Jungermannia truncata .  Planta Medica. 2003;  69 377-9
• 10 Nagashima F, Kondoh M, Uematsu T, Nishiyama A, Saito S, Sato M. et al . Cytotoxic and apoptosis-inducing ent-kaurane-type diterpenoids from the Japanese liverwort Jungermannia truncata Nees.  Chem Pharm Bull. 2002;  50 808-13
• 11 Dolle R E, Hoyer D, Prasad C V, Schmidt S J, Helaszek C T, Miller R E. et al . P1 aspartate-based peptide α-((2,6-dichlorobenzoyl)oxy)methyl ketones as potent time-dependent inhibitors of interleukin-1β-converting enzyme.  J Med Chem. 1994;  37 563-4
• 12 Castrillo A, Heras B, Hortelano S, Rondriguez B, Villar A, Bosca L. Inhibition of the nuclear factor κB (NF-κB) pathway by tetracyclic kaurene diterpenes in macrophages.  J Biol Chem. 2001;  276 15 854-60
• 13 Andrews G K. Cellular zinc sensors: MTF-1 regulation of gene expression.  BioMetals. 2001;  14 223-37
• 14 Hengartner M O. The biochemistry of apoptosis.  Nature. 2000;  407 770-6
• 15 Tewari M, Quan L T, O’Rourke K, Desnoyers S, Zeng Z, Beidler D R. et al . Yama/CPP32 β, a mammalian homolog of CED-3, is a crmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase.  Cell. 1995;  81 801-9
• 16 Yamaguchi S, Kamiya Y. Gibberellin biosynthesis: its regulation by endogenous and environmental signals.  Plant Cell Physiol. 2000;  41 251-7
• 17 Baker S J, Reddy E P. Modulation of life and death by the TNF receptor superfamily.  Oncogene. 1998;  17 3261-70