Predicting effective pro-apoptotic anti-leukaemic drug combinations using co-operative dynamic BH3 profiling

PloS One
Martin GrundyMonica Pallis

Abstract

The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide. We found that a broad range of anti-leukaemic agents-notably MCL-1 inhibitors, DNA damaging agents and FLT3 inhibitors-sensitise leukaemia cells to BAD-BH3. We further analysed the BCL-2 inhibitors ABT-199 and JQ1, the MCL-1 inhibitors pladienolide B and torin1, the FLT3 inhibitor AC220 and the DNA double-strand break inducer etoposide to correlate priming responses with co-operative induction of apoptosis. ABT-199 in combination with pladienolide B, torin1, etoposide or AC220 strongly induced apoptosis within 4 hours, but the MCL-1 inhibitors did not co-operate with etoposide or AC220. In keeping with the long half-life of BCL-2, the BET domain inhib...Continue Reading

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Citations

Nov 6, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Haley E RamseyMichael R Savona
Sep 28, 2021·Frontiers in Cell and Developmental Biology·Albert Manzano-MuñozJoan Montero

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Datasets Mentioned

BETA
ABT-737

Methods Mentioned

BETA
FCS
flow cytometry
MDS
FACS

Software Mentioned

Genemapper
SPSS

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