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Sirnikova, Diana; Reynisson, Johannes; Brüning-Richardson, Anke; Kirby, Catherine


Diana Sirnikova

Anke Brüning-Richardson

Catherine Kirby


AIMS The kynurenine (Kyn) pathway plays an important role in the pathogenesis of many cancers including glioblastomas (GBMs). The enzymes, indoleamine-2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO2), regulate the first and rate-limiting step resulting in the formation of N-formyl-kynurenine, which is then readily converted into Kyn by kynurenine formaldehyde. Cancers expressing the IDO1 and TDO2 enzymes can produce immunosuppressive tryptophan metabolites that compromise the host immune system leading to poor patient prognosis. The inhibitors TD12, TD18 and TD34 were recently developed due to the lack of TDO2 and IDO1/TDO2 inhibitors, of which TD34 can block both IDO1 and TDO2 activity. Here, we investigated the ability of these novel inhibitors to also target cell migration in GBM as part of our ongoing research interest in this area. METHOD Two established brain tumour cell lines, U87 and U251 and one patient-derived cell line, E55, were used to determine IC50 values and anti-migratory concentrations by MTT for application in 2D and 3D migration/invasion assays. RESULTS Cell migration in all cell lines was significantly reduced in the presence of the TD12, TD18 and TD34 inhibitors. E55 appeared to be 100-fold more sensitive to drug activity; immunofluorescence analysis indicates changes in the actin cytoskeleton and cell adhesion CONCLUSIONS Initial results suggest that TDO2 and the IDO1 enzymes play also a role in cell migration in GBM and provide further evidence for the involvement of the Kyn pathway in the pathology of GBMs. This also supports the application of inhibitors targeting TDO2 and IDO1 as novel complementary treatment options in GBM.

Journal Article Type Conference Paper
Conference Name BNOS Manchester 2023 Conference
Conference Location Manchester, UK
Acceptance Date Sep 16, 2023
Online Publication Date Sep 16, 2023
Publication Date 2023-10
Deposit Date Oct 3, 2023
Journal Neuro-Oncology
Print ISSN 1522-8517
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 25
Issue Supplement_3
Pages iii21-iii21
Keywords Cancer Research, Neurology (clinical), Oncology