Dr. Weeks’ Comment: No longer so sexy, vitamin C (ascorbic acid) far from yesterday’s news, remains so essential and ought not be taken for granted. Vitamin C is the original “centsible” remedy: safe, effective and cost-effective.
Ascorbic Acid Has Superior Ex Vivo Antiproliferative, Cell Death-Inducing and Immunomodulatory Effects over IFN-a in HTLV-1-Associated Myelopathy
Britta Moens1*, Daniele Decanine2¤a, Soraya Maria Menezes1, Ricardo Khouri1,2, Gilvane ́ia Silva- Santos2¤b, Giovanni Lopez3, Carolina Alvarez1,3, Michael Talledo3, Eduardo Gotuzzo3,4, Ramon de Almeida Kruschewsky5, Bernardo Galva ̃o-Castro2,5, Anne-Mieke Vandamme1,6, Johan Van Weyenbergh1,2
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-a 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-a 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-a and high-dose AA in HAM/TSP.
Principal Findings: 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-a in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-a, 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-c, 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-a selectively up-regulated antiviral and immune-related genes.
Conclusions: In comparison to IFN-a, 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.