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  • For example nM MTX markedly stimulates the

    2019-12-03

    For example, 200nM MTX markedly stimulates the differentiation of the monocytic U937 Ispinesib [39], but only 10nM MTX is sufficient for the inhibition of clonogenicity in the ALL and APL cell lines [22]. Furthermore, an even lower concentration of MTX (2nM) selectively induces the expression of p27 and E-cadherin, which are markers of growth arrest and differentiation, in SCC13 and HEK1 carcinoma cell lines [2]. In contrast, 50μM MTX induces the expression of E-cadherin in A549 cells [17]. In addition to cell differentiation, other non-DHFR-mediated effects were also observed at various concentrations that can easily be achieved in human plasma. For example, 50nM MTX inhibits the activity of MAT in hepatocellular carcinoma Hep G2 cells [50], 1μM MTX induces demethylation and hyperacetylation of E2F1 in melanoma cells [36] and 50μM MTX induces histone H3 acetylation in A549 cells [55]. Regarding DNA methylation, treating CD4+ T cells with 50nM MTX leads to demethylation of the FoxP3 upstream enhancer [6], whereas 40μM MTX induces hypomethylation of DNA in osteosarcoma cells, although 1μM MTX is sufficient to decrease DNA methylation in osteosarcoma cells [44]. In contrast, a high concentration of MTX is needed to inhibit the glyoxalase system. The mean IC50 value of 125μM MTX was determined for Glo1 [4]. Altogether, it is obvious that some of the non-DHFR-mediated effects of MTX can be relevant in vivo only when patients are treated with high-dose MTX.
    Conclusion In human medicine, MTX has been used as a potent folate antagonist for almost 70years, especially for treating cancer diseases and autoimmune disorders. As described above, the effectiveness of MTX is undoubtedly caused by its capability to affect various intracellular pathways at many levels. Although the most important therapeutic mechanism of MTX is strongly based on the inhibition of DHFR, many other effects of this compound have been described and new studies bring new insights into the pharmacology of MTX every year. Identification of these new targets for MTX is especially important for a better understanding of MTX action in new protocols of combination therapy.
    Transparency document
    Introduction The Ortho- and Paramyxoviridae families comprise important respiratory pathogens, i.e. influenza A and B viruses and respiratory syncytial virus (RSV), respectively. The acute respiratory illnesses caused by these viruses represent major medical problems, given their significant morbidity and potential mortality, particularly in vulnerable populations such as small infants, elderly people or patients with underlying medical conditions [1]. Besides, the threat for new influenza A virus pandemics (such as that of 2009 [2]) is a reason for global and constant concern. Since the current arsenal of antiviral drugs to treat or prevent influenza or RSV infections is quite limited [1], [3], new therapeutics are highly needed. According to a recommendation by the World Health Organization [4], attention should be given to innovative agents with broad activity against diverse respiratory viruses. Viruses, as obligate intracellular parasites, encode multiple virus-specific proteins essential for replication, which also depends on critical interactions with host cell proteins. Most approved antiviral drugs target unique proteins encoded by one virus or a range of closely related viruses. This strategy is prone to selecting drug-resistance, particularly for viruses, which possess high mutability (such as influenza virus) or require long-term therapy. An alternative and relevant approach is to address host factors involved in the viral life cycle. This type of inhibitors is anticipated to possess a markedly higher barrier for selecting drug-resistant viruses and, furthermore, may display broad-spectrum antiviral activity when dealing with a cellular target that is recruited by different viruses. Two host-directed antiviral drugs are maraviroc, a CCR5 receptor antagonist approved for HIV therapy, and alisporivir, a cyclophylin inhibitor that is undergoing Phase III tests for hepatitis C treatment [5]. Specific host proteins were proven to be critical for the replication of diverse unrelated viruses [6], yet the array of possible cellular targets (the ‘virus-host interactome’) is continuously growing, as recently reviewed for influenza [7] and RSV [8].