ZGDHu-1 promotes apoptosis of chronic lymphocytic leukemia cells.

Abstract

Chronic lymphocytic leukemia (CLL) is a low-grade lymphoid malignancy incurable with conventional modalities of chemotherapy. We aimed to examine the proapoptotic effects of a novel proteasome inhibitor, N,N'-di-(m-methylphenyi)-3,6- dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1), on CLL cells. B lymphocytes were isolated from CLL patients and normal healthy controls, and treated with various concentrations of ZGDHu-1 for different days. CLL cell viability was detected by MTT assay. The apoptosis, mitochondrial membrane potential (∆ψm) and reactive oxidative species (ROS) were examined by flow cytometry. The expression of caspase-3 and Bcl-2/Bax ratio was detected by western blotting. ZGDHu-1 significantly reduced the viability of CLL cells and induced apoptosis in comparison to the control cells (both P<0.05). Normal peripheral B cells were resistant to the apoptosis-inducing effects of ZGDHu-1. Apoptosis induced by ZGDHu-1 was accompanied with generation of ROS, loss of ∆ψm, downregulation of Bcl-2 and increase of caspase-3 cleavage. Results of this study indicate that ZGDHu-1 is a promising specific treatment for CLL in the clinic.

• Authors: Lian-Nv Qiu, Yong-Lie Zhou, Zhen-Ni Wang, Qiang Huang, Wei-Xiao Hu
• Journal: International journal of oncology (Int J Oncol) Vol. 41 Issue 2 Pg. 533-40 (Aug 2012) ISSN: 1791-2423 [Electronic] Greece
• PMID: 22581170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BAX protein, human
• Heterocyclic Compounds, 1-Ring
• N,N-di-(m-methylphenyl)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboxamide
• Proteasome Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• CASP3 protein, human
• Caspase 3

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• B-Lymphocytes (drug effects)
• Caspase 3 (metabolism)
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Heterocyclic Compounds, 1-Ring (pharmacology)
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Middle Aged
• Mitochondrial Membranes (metabolism)
• Permeability
• Proteasome Inhibitors
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Tumor Cells, Cultured (drug effects)
• bcl-2-Associated X Protein (metabolism)