Characterisation of the anti-migratory activity of the 6-bromoindirubin-3’oxime (BIO) derivative VTIND42 in patient-derived GBM subpopulations

Samuel Peat, Anke Bruning-Richardson, Laurent Meijer, Sean Lawler, Valerie Thiery, Ruth Morton

Research output: Contribution to journalMeeting Abstract

Abstract

Introduction Targeting the infiltrative nature of GBMs with anti-migratory drugs as combination treatment for prevention of tumour recurrence is an attractive disease management option. One such class of drugs are the GSK-3 inhibitors 6-bromoindirubin-3′-oximes (BIO). BIO has been proposed for use in combination therapy, however, the administration of indirubins remains problematic due to low solubility causing low bioavailability. We describe the characterisation of a BIO derivative, VTIND42, identified from a screen of 450 compounds with improved solubility. Method The compounds were initially screened on the following criteria, selective anti-migratory effect with enhanced potency over the lead compound BIO. Effect on cell migration in two cell subpopulations (core obtained, edge obtained) from the patient derived GBM40 was assessed by 3D migration/invasion assays and for cytoskeletal rearrangements by immunofluorescence. Results VTIND42 (1 µM) showed the best performance overall in terms of specificity and efficacy in comparison to BIO with a pronounced effect on GBM40 edge cell populations. Anti-migratory effects over 72 hours in GBM40 edge (24h, 10.74% p=0.04; 48h, 6.52% p=0.06, 72h, 4.26% p=0.06) in comparison to the control were observed; BIO (5 µM) significantly reduced migration over 72 hours (24h, 12.79% p<0.001; 48h 5.43% p<0.001; 72h 4.26% p<0.001). Immunofluorescence assays revealed cytoskeletal rearrangements; cells treated with VTIND42 showed an increased ratio of cells with stress fibres to cortical fibres and elongated cells. Discussion VTIND42 displayed increased efficacy in comparison to BIO, further investigations will determine its potential as a bioavailable anti-migratory drug for glioblastoma treatment potentially improving disease outcome in patients.
Original languageEnglish
Pages (from-to)6-7
Number of pages2
JournalNeuro-Oncology
Volume21
Issue numberS4
DOIs
Publication statusPublished - 12 Oct 2019
EventBritish Neuro-Oncology Society Meeting - QEII Centre, London, United Kingdom
Duration: 3 Jul 20195 Jul 2019
https://www.bnos.org.uk/upcoming-bnos-conference/

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Solubility
Fluorescent Antibody Technique
Glycogen Synthase Kinase 3
Stress Fibers
Drug Combinations
Glioblastoma
Disease Management
6-bromoindirubin-3'-oxime
Pharmaceutical Preparations
Biological Availability
Cell Movement
Therapeutics
Recurrence
Population
Neoplasms
indirubin
Lead
antiglomerular basement membrane antibody

Cite this

@article{168bcb28b22e455382fdc301b234b474,
title = "Characterisation of the anti-migratory activity of the 6-bromoindirubin-3’oxime (BIO) derivative VTIND42 in patient-derived GBM subpopulations",
abstract = "Introduction Targeting the infiltrative nature of GBMs with anti-migratory drugs as combination treatment for prevention of tumour recurrence is an attractive disease management option. One such class of drugs are the GSK-3 inhibitors 6-bromoindirubin-3′-oximes (BIO). BIO has been proposed for use in combination therapy, however, the administration of indirubins remains problematic due to low solubility causing low bioavailability. We describe the characterisation of a BIO derivative, VTIND42, identified from a screen of 450 compounds with improved solubility. Method The compounds were initially screened on the following criteria, selective anti-migratory effect with enhanced potency over the lead compound BIO. Effect on cell migration in two cell subpopulations (core obtained, edge obtained) from the patient derived GBM40 was assessed by 3D migration/invasion assays and for cytoskeletal rearrangements by immunofluorescence. Results VTIND42 (1 µM) showed the best performance overall in terms of specificity and efficacy in comparison to BIO with a pronounced effect on GBM40 edge cell populations. Anti-migratory effects over 72 hours in GBM40 edge (24h, 10.74{\%} p=0.04; 48h, 6.52{\%} p=0.06, 72h, 4.26{\%} p=0.06) in comparison to the control were observed; BIO (5 µM) significantly reduced migration over 72 hours (24h, 12.79{\%} p<0.001; 48h 5.43{\%} p<0.001; 72h 4.26{\%} p<0.001). Immunofluorescence assays revealed cytoskeletal rearrangements; cells treated with VTIND42 showed an increased ratio of cells with stress fibres to cortical fibres and elongated cells. Discussion VTIND42 displayed increased efficacy in comparison to BIO, further investigations will determine its potential as a bioavailable anti-migratory drug for glioblastoma treatment potentially improving disease outcome in patients.",
keywords = "biological availability, glioblastoma, cell motility, combined modality therapy, cytoskeleton, flourescent antibody technique, oximes, solubility, stress fibers, disease management, neoplasms, glycogen synthase kinase 3, prevention",
author = "Samuel Peat and Anke Bruning-Richardson and Laurent Meijer and Sean Lawler and Valerie Thiery and Ruth Morton",
year = "2019",
month = "10",
day = "12",
doi = "10.1093/neuonc/noz167.026",
language = "English",
volume = "21",
pages = "6--7",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "S4",

}

Characterisation of the anti-migratory activity of the 6-bromoindirubin-3’oxime (BIO) derivative VTIND42 in patient-derived GBM subpopulations. / Peat, Samuel; Bruning-Richardson, Anke; Meijer, Laurent; Lawler, Sean; Thiery, Valerie; Morton, Ruth.

In: Neuro-Oncology, Vol. 21, No. S4, 12.10.2019, p. 6-7.

Research output: Contribution to journalMeeting Abstract

TY - JOUR

T1 - Characterisation of the anti-migratory activity of the 6-bromoindirubin-3’oxime (BIO) derivative VTIND42 in patient-derived GBM subpopulations

AU - Peat, Samuel

AU - Bruning-Richardson, Anke

AU - Meijer, Laurent

AU - Lawler, Sean

AU - Thiery, Valerie

AU - Morton, Ruth

PY - 2019/10/12

Y1 - 2019/10/12

N2 - Introduction Targeting the infiltrative nature of GBMs with anti-migratory drugs as combination treatment for prevention of tumour recurrence is an attractive disease management option. One such class of drugs are the GSK-3 inhibitors 6-bromoindirubin-3′-oximes (BIO). BIO has been proposed for use in combination therapy, however, the administration of indirubins remains problematic due to low solubility causing low bioavailability. We describe the characterisation of a BIO derivative, VTIND42, identified from a screen of 450 compounds with improved solubility. Method The compounds were initially screened on the following criteria, selective anti-migratory effect with enhanced potency over the lead compound BIO. Effect on cell migration in two cell subpopulations (core obtained, edge obtained) from the patient derived GBM40 was assessed by 3D migration/invasion assays and for cytoskeletal rearrangements by immunofluorescence. Results VTIND42 (1 µM) showed the best performance overall in terms of specificity and efficacy in comparison to BIO with a pronounced effect on GBM40 edge cell populations. Anti-migratory effects over 72 hours in GBM40 edge (24h, 10.74% p=0.04; 48h, 6.52% p=0.06, 72h, 4.26% p=0.06) in comparison to the control were observed; BIO (5 µM) significantly reduced migration over 72 hours (24h, 12.79% p<0.001; 48h 5.43% p<0.001; 72h 4.26% p<0.001). Immunofluorescence assays revealed cytoskeletal rearrangements; cells treated with VTIND42 showed an increased ratio of cells with stress fibres to cortical fibres and elongated cells. Discussion VTIND42 displayed increased efficacy in comparison to BIO, further investigations will determine its potential as a bioavailable anti-migratory drug for glioblastoma treatment potentially improving disease outcome in patients.

AB - Introduction Targeting the infiltrative nature of GBMs with anti-migratory drugs as combination treatment for prevention of tumour recurrence is an attractive disease management option. One such class of drugs are the GSK-3 inhibitors 6-bromoindirubin-3′-oximes (BIO). BIO has been proposed for use in combination therapy, however, the administration of indirubins remains problematic due to low solubility causing low bioavailability. We describe the characterisation of a BIO derivative, VTIND42, identified from a screen of 450 compounds with improved solubility. Method The compounds were initially screened on the following criteria, selective anti-migratory effect with enhanced potency over the lead compound BIO. Effect on cell migration in two cell subpopulations (core obtained, edge obtained) from the patient derived GBM40 was assessed by 3D migration/invasion assays and for cytoskeletal rearrangements by immunofluorescence. Results VTIND42 (1 µM) showed the best performance overall in terms of specificity and efficacy in comparison to BIO with a pronounced effect on GBM40 edge cell populations. Anti-migratory effects over 72 hours in GBM40 edge (24h, 10.74% p=0.04; 48h, 6.52% p=0.06, 72h, 4.26% p=0.06) in comparison to the control were observed; BIO (5 µM) significantly reduced migration over 72 hours (24h, 12.79% p<0.001; 48h 5.43% p<0.001; 72h 4.26% p<0.001). Immunofluorescence assays revealed cytoskeletal rearrangements; cells treated with VTIND42 showed an increased ratio of cells with stress fibres to cortical fibres and elongated cells. Discussion VTIND42 displayed increased efficacy in comparison to BIO, further investigations will determine its potential as a bioavailable anti-migratory drug for glioblastoma treatment potentially improving disease outcome in patients.

KW - biological availability

KW - glioblastoma

KW - cell motility

KW - combined modality therapy

KW - cytoskeleton

KW - flourescent antibody technique

KW - oximes

KW - solubility

KW - stress fibers

KW - disease management

KW - neoplasms

KW - glycogen synthase kinase 3

KW - prevention

U2 - 10.1093/neuonc/noz167.026

DO - 10.1093/neuonc/noz167.026

M3 - Meeting Abstract

VL - 21

SP - 6

EP - 7

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - S4

ER -