Background
TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase) catalyse the
oxidation of tryptophan leading to the formation of immunesuppressive kynurenine pathway
(KP) metabolites and dampening the immune response in the tumour environment. IDO
is up-regulated in numerous cancers. Recently, TDO was shown to be up-regulated in
various tumour types. Hence, selective IDO inhibitors may have a limited effect in
cancers harbouring both TDO and IDO. To test this hypothesis we utilised novel dual-active
and selective TDO/IDO inhibitors to modulate kynurenine (Kyn) levels in cells expressing
TDO alone and both TDO and IDO.
Methods
Assays were developed to measure the effects of dual and selective TDO/IDO inhibitors
on Kyn levels in A172 glioma cells expressing TDO alone or both TDO and IDO following
IDO induction using Interferon (IFNg).
Findings
Dual-active and selective TDO/IDO inhibitors demonstrated distinct Kyn modulating
activities in A172 cells expressing TDO alone or both TDO and IDO (Fig. 1). Dual-active molecules ablated Kyn levels in both TDO-only and TDO/IDO-expressing
cells. IDO selective inhibitors were more active in cells following IDO induction.
TDO inhibitors were more active in TDO-only cells. Selective inhibitors did not fully
block Kyn in cells expressing IDO and TDO.
Discussion
These data demonstrate that dual-active TDO/IDO inhibitors are most effective at ablating
Kyn levels in cancer cells co-expressing TDO and IDO.
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