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 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.
Highlights
Screening of various inhibitors on Human T-cell leukemia virus type 1 (HTLV-1) infected and uninfected cells Despite its tight control in normal T cells, NF-κB is constitutively activated in both HTLV-I-transformed T-cell lines and freshly isolated adult T-cell leukemia (ATL) cells suggesting that activation of NF-κB is an important part of the oncogenic mechanism of HTLV-I
This pathologic action may largely rely on the viral transforming protein Tax, at least for many of the cell lines to date that are isolated for in vitro analysis and not necessarily are ATL samples, which up-regulates the expressions and activities of cyclin E/CDK2 which is important in cell cycle transition from G1 to S phase
Inhibition of cyclin/cyclin dependent kinases (CDKs) complexes by Purvalanol A We have previously shown that cyclin E/CDK2 kinase activity is de-regulated in HTLV-1 infected cells and these cells are especially susceptible to Purvalanol A treatment [62]
Summary
In the canonical pathway, proceeding the stimulation of TNF-R, the activated IκB kinase (IKK) complex containing IKKα/IKKβ/NEMO phosphorylates inhibitor of NF-κB (IκBα) [22,23]. The IKK complex with two IKKα subunits is activated through NIK by other stimuli such as lymphotoxin β (LTβ) and CD40 ligand, and mediates the processing of NF-κB complex to p52/RelB [25,26]. This IKK complex phosphorylates p100 at C-terminal domain and promotes the ubiquitination of p100 and the proteasomal processing of the complex to p52/RelB [2729]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
