Two specific drugs, BMS-345541 and purvalanol A induce apoptosis of HTLV-1 infected cells through inhibition of the NF-kappaB and cell cycle pathways

被引：16

作者：

Agbottah E. ^{[1
]}

Yeh W.-I. ^{[1
]}

Berro R. ^{[1
]}

Klase Z. ^{[1
]}

Pedati C. ^{[1
]}

Kehn-Hall K. ^{[1
]}

Wu W. ^{[1
]}

Kashanchi F. ^{[1
,2
,3
]}

机构：

[1] Department of Microbiology and tropical Medicine, Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine, Washington

[2] Department of Microbiology, Institute for Proteomics Technology and Applications, The George Washington University, Washington

[3] The Institute for Genomic Research, TIGR, Rockville

来源：

AIDS Research and Therapy | / 5卷 / 1期

基金：

美国国家卫生研究院;

关键词：

Uninfected Cell; Arsenic Trioxide; Caffeic Acid Phenylethyl Ester;

D O I：

10.1186/1742-6405-5-12

中图分类号：

学科分类号：

摘要：

Human T-cell leukemia virus type-1 (HTLV-1) induces adult T-cell leukemia/lymphoma (ATL/L), a fatal lymphoproliferative disorder, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic progressive disease of the central nervous system after a long period of latent infection. Although the mechanism of transformation and leukemogenesis is not fully elucidated, there is evidence to suggest that the viral oncoprotein Tax plays a crucial role in these processes through the regulation of several pathways including NF-κB and the cell cycle pathways. The observation that NF-κB, which is strongly induced by Tax, is indispensable for the maintenance of the malignant phenotype of HTLV-1 by regulating the expression of various genes involved in cell cycle regulation and inhibition of apoptosis provides a possible molecular target for these infected cells. To develop potential new therapeutic strategies for HTLV-1 infected cells, in this present study, we initially screened a battery of NF-κB and CDK inhibitors (total of 35 compounds) to examine their effects on the growth and survival of infected T-cell lines. Two drugs namely BMS-345541 and Purvalanol A exhibited higher levels of growth inhibition and apoptosis in infected cell as compared to uninfected cells. BMS-345541 inhibited IKKβ kinase activity from HTLV-1 infected cells with an IC50 (the 50% of inhibitory concentration) value of 50 nM compared to 500 nM from control cells as measured by in vitro kinase assays. The effects of Purvalanol A were associated with suppression of CDK2/cyclin E complex activity as previously shown by us. Combination of both BMS-345541 and Purvalanol A showed a reduced level of HTLV-1 p19 Gag production in cell culture. The apparent apoptosis in these infected cells were associated with increased caspase-3 activity and PARP cleavage. The potent and selective apoptotic effects of these drugs suggest that both BMS-345541 and Purvalanol A, which target both NF-κB and CDK complex and the G1/S border, might be promising new agents in the treatment of these infected patients. © 2008 Agbottah et al; licensee BioMed Central Ltd.

引用

共 87 条

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