Reference : Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and in...
Scientific journals : Article
Human health sciences : Oncology
Valproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo.
Achachi, Amine* [> > > >]
Florins, Arnaud-Francois* [Université de Liège - ULiège > > Gembloux Agro-Bio Tech >]
Gillet, Nicolas* mailto [Université de Liège - ULiège > Chimie et bio-industries > Biologie cell. et moléc. >]
Debacq, Christophe [> > > >]
Urbain, Patrice [> > > >]
Foutsop, Germain Manfouo [> > > >]
Vandermeers, Fabian [Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement >]
Jasik, Agnieszka [> > > >]
Reichert, Michal [> > > >]
Kerkhofs, Pierre [> > > >]
Lagneaux, Laurence [> > > >]
Burny, Arsene [> > > >]
Kettmann, Richard mailto [Université de Liège - ULiège > Chimie et bio-industries > Centre de Bio. Fond. - Section de Biologie cell. et moléc. >]
Willems, Luc mailto [Université de Liège - ULiège > > GIGA-Research >]
* These authors have contributed equally to this work.
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
Yes (verified by ORBi)
[en] Animals ; Apoptosis/drug effects ; B-Lymphocytes/metabolism ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Gene Expression Regulation, Viral/drug effects ; Hela Cells ; Histone Deacetylases/antagonists & inhibitors ; Humans ; Leukemia Virus, Bovine/metabolism ; Leukemia, Lymphoid/therapy ; Leukocytes, Mononuclear/metabolism ; Luciferases ; Lymphocyte Count ; Proviruses/metabolism ; Remission Induction ; Sheep ; Valproic Acid/pharmacology/therapeutic use
[en] Leukemogenic viruses like human T-lymphotropic virus and bovine leukemia virus (BLV) presumably persist in the host partly by latent integration of the provirus in a fraction of infected cells, leading to accumulative increase in the outgrowth of transformed cells. Furthermore, viral infection also correlates with a blockade of the apoptotic mechanisms concomitant with an apparent latency of the host cell. Conceptually, induction of viral or cellular gene expression could thus also be used as a therapeutic strategy against retroviral-associated leukemia. Here, we provide evidence that valproate, an inhibitor of deacetylases, activates BLV gene expression in transient transfection experiments and in short-term cultures of primary B-lymphocytes. In vivo, valproate injection into newly BLV-inoculated sheep did not abrogate primary infection. However, valproate treatment, in the absence of any other cytotoxic drug, was efficient for leukemia/lymphoma therapy in the sheep model leading to decreased lymphocyte numbers (respectively from 25.6, 35.7, and 46.5 x 10(3) cells per mm3 to 1.0, 10.6, and 24.3 x 10(3) cells per mm3 in three leukemic sheep) and tumor regression (from >700 cm3 to undetectable). The concept of a therapy that targets the expression of viral and cellular genes might be a promising treatment of adult T cell leukemia or tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy, diseases for which no satisfactory treatment exists so far.
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