title: Ascorbic acid has superior ex vivo antiproliferative, cell death-inducing and immunomodulatory effects over IFN-α in HTLV-1-associated myelopathy.
abstract: BACKGROUND
  Clear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-α and high-dose ascorbic acid (AA) monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-α treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-α and high-dose AA in HAM/TSP.
  
  
  RESULTS
  Through thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-γ, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-α selectively up-regulated antiviral and immune-related genes.
  
  
  CONCLUSIONS
  In comparison to IFN-α, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.
authors: Rega Institute for Medical Research, K. U. Leuven, Leuven, Belgium. moensbritta@gmail.com
authors: Britta
authors: B
authors: Moens
authors: Daniele
authors: D
authors: Decanine
authors: Soraya Maria
authors: SM
authors: Menezes
authors: Ricardo
authors: R
authors: Khouri
authors: Gilvanéia
authors: G
authors: Silva-Santos
authors: Giovanni
authors: G
authors: Lopez
authors: Carolina
authors: C
authors: Alvarez
authors: Michael
authors: M
authors: Talledo
authors: Eduardo
authors: E
authors: Gotuzzo
authors: Ramon
authors: R
authors: de Almeida Kruschewsky
authors: Bernardo
authors: B
authors: Galvão-Castro
authors: Anne-Mieke
authors: AM
authors: Vandamme
authors: Johan
authors: J
authors: Van Weyenbergh
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D016898:Interferon-alpha / Q000494:pharmacology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009924:Organ Culture Techniques; D013118:Spinal Cord Diseases / Q000188:drug therapy; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007155:Immunologic Factors; D016898:Interferon-alpha; D001205:Ascorbic Acid