Journal article
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
AIDS research and therapy, v 5(1), 12
10 Jun 2008
PMID: 18544167
Abstract
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 IC
50
(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.
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16 citations in Scopus
Details
- Title
- 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
- Creators
- Emmanuel Agbottah - George Washington UniversityWen-I Yeh - George Washington UniversityReem Berro - George Washington UniversityZachary Klase - George Washington UniversityCaitlin Pedati - George Washington UniversityKyleen Kehn-Hall - George Washington UniversityWeilin Wu - George Washington UniversityFatah Kashanchi - George Washington University
- Publication Details
- AIDS research and therapy, v 5(1), 12
- Publisher
- BioMed Central
- Number of pages
- 1
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Scopus ID
- 2-s2.0-48449105366
- Other Identifier
- 991021902503804721