The induction of G2/M cell-cycle arrest and apoptosis by cucurbitacin E is associated with increased phosphorylation of eIF2alpha in leukemia cells.

Abstract

The antiproliferative and apoptotic effects of cucurbitacin E, a natural product isolated from Cucurbitaceae, were determined in human leukemia HL-60 cells. Cucurbitacin E at low concentrations (3-50 nmol/l) inhibited the growth of HL-60 cells, which was associated with G2/M cell-cycle arrest, decrease in the levels of cyclin-dependent kinase1, and increase in the levels of p21. Cucurbitacin E at high concentrations (1-10 mol/l) induced apoptosis of HL-60 cells and activation of caspase-3, caspase-8, and caspase-9. Jurkat leukemia cells with or without caspase-8 expression were nearly equally sensitive to cucurbitacin E-induced apoptosis. Cucurbitacin E did not increase the levels of reactive oxygen species and antioxidants, N-acetylcysteine and catalase, did not block cucurbitacin E-induced apoptosis. Cucurbitacin E decreased the levels of the antiapoptotic proteins XIAP, survivin, and Mcl-1, but increased the level of the proapoptotic protein, Bax. The levels of phosphorylated eukaryotic translation initiation factor 2 subunit (eIF2) were induced in cells undergoing both apoptosis and cell-cycle arrest. As phosphorylated eIF2 is an inhibitor of protein translation initiation, our data suggest that cucurbitacin E induces cell growth arrest and apoptosis through the induction of eIF2 phosphorylation, which leads to the inhibition of cyclin-dependent kinase 1, Mcl-1, survivin, and/or XIAP protein synthesis and that cucurbitacin E induces apoptosis mainly through a mitochondrial-mediated pathway.

• Authors: Yanchun Li, Rui Wang, Enlong Ma, Yihui Deng, Xiaolong Wang, Jinfang Xiao, Yongkui Jing
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 21 Issue 4 Pg. 389-400 (Apr 2010) ISSN: 1473-5741 [Electronic] England
• PMID: 20110807 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Eukaryotic Initiation Factor-2
• Growth Inhibitors
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• Survivin
• Triterpenes
• X-Linked Inhibitor of Apoptosis Protein
• Catalase
• Caspase 3
• Caspase 8
• Caspase 9
• cucurbitacin E
• Acetylcysteine

Topics

• Acetylcysteine (metabolism)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Catalase (metabolism)
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Eukaryotic Initiation Factor-2 (drug effects, metabolism)
• G2 Phase (drug effects)
• Growth Inhibitors (pharmacology, therapeutic use)
• Humans
• Inhibitor of Apoptosis Proteins
• Jurkat Cells
• Leukemia (drug therapy, metabolism)
• Microtubule-Associated Proteins (metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Survivin
• Triterpenes (pharmacology, therapeutic use)
• X-Linked Inhibitor of Apoptosis Protein (metabolism)