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2015 ; 10
(7
): e0130078
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Methotrexate Is a JAK/STAT Pathway Inhibitor
#MMPMID26131691
Thomas S
; Fisher KH
; Snowden JA
; Danson SJ
; Brown S
; Zeidler MP
PLoS One
2015[]; 10
(7
): e0130078
PMID26131691
show ga
BACKGROUND: The JAK/STAT pathway transduces signals from multiple cytokines and
controls haematopoiesis, immunity and inflammation. In addition, pathological
activation is seen in multiple malignancies including the myeloproliferative
neoplasms (MPNs). Given this, drug development efforts have targeted the pathway
with JAK inhibitors such as ruxolitinib. Although effective, high costs and side
effects have limited its adoption. Thus, a need for effective low cost treatments
remains. METHODS & FINDINGS: We used the low-complexity Drosophila melanogaster
pathway to screen for small molecules that modulate JAK/STAT signalling. This
screen identified methotrexate and the closely related aminopterin as potent
suppressors of STAT activation. We show that methotrexate suppresses human
JAK/STAT signalling without affecting other phosphorylation-dependent pathways.
Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells
expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate
acts independently of dihydrofolate reductase (DHFR) and is comparable to the
JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still
retain their ability to respond to physiological levels of the ligand
erythropoietin. CONCLUSIONS: Aminopterin and methotrexate represent the first
chemotherapy agents developed and act as competitive inhibitors of DHFR.
Methotrexate is also widely used at low doses to treat inflammatory and
immune-mediated conditions including rheumatoid arthritis. In this low-dose
regime, folate supplements are given to mitigate side effects by bypassing the
biochemical requirement for DHFR. Although independent of DHFR, the
mechanism-of-action underlying the low-dose effects of methotrexate is unknown.
Given that multiple pro-inflammatory cytokines signal through the pathway, we
suggest that suppression of the JAK/STAT pathway is likely to be the principal
anti-inflammatory and immunosuppressive mechanism-of-action of low-dose
methotrexate. In addition, we suggest that patients with JAK/STAT-associated
haematological malignancies may benefit from low-dose methotrexate treatments.
While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost
precludes widespread adoption. With an annual methotrexate cost of around £32,
our findings represent an important development with significant future
potential.
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