[PMID]: | 29298347 |
[Au] Autor: | Grundy M; Seedhouse C; Jones T; Elmi L; Hall M; Graham A; Russell N; Pallis M |
[Ad] Endereço: | Clinical Haematology, Nottingham University Hospitals, Nottingham, United Kingdom. |
[Ti] Título: | Predicting effective pro-apoptotic anti-leukaemic drug combinations using co-operative dynamic BH3 profiling. |
[So] Source: | PLoS One;13(1):e0190682, 2018. |
[Is] ISSN: | 1932-6203 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | 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 inhibitor JQ1 was found to downregulate BCL-2 and to prime cells to respond to MS1-BH3 at 48, but not at 4 hours: prolonged priming with JQ1 was then shown to induce rapid cytochrome C release when pladienolide B, torin1, etoposide or AC220 were added. In conclusion, dynamic BH3 profiling is a useful mechanism-based tool for understanding and predicting co-operative lethality between drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism. A plethora of agents sensitised cells to BAD-BH3-mediated mitochondrial outer membrane permeabilisation in the dynamic BH3 profiling assay and this was associated with effective co-operation with the BCL-2 inhibitory compounds ABT-199 or JQ1. |
[Mh] Termos MeSH primário: |
Antineoplásicos/farmacologia Apoptose/efeitos dos fármacos Leucemia/patologia
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[Mh] Termos MeSH secundário: |
Azepinas/farmacologia Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia Linhagem Celular Tumoral Combinação de Medicamentos Seres Humanos Indóis/farmacologia Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores Sulfonamidas/farmacologia Triazóis/farmacologia
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 ((+)-JQ1 compound); 0 (A-1210477); 0 (Antineoplastic Agents); 0 (Azepines); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Drug Combinations); 0 (Indoles); 0 (Myeloid Cell Leukemia Sequence 1 Protein); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Sulfonamides); 0 (Triazoles); N54AIC43PW (venetoclax) |
[Em] Mês de entrada: | 1802 |
[Cu] Atualização por classe: | 180215 |
[Lr] Data última revisão:
| 180215 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 180104 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1371/journal.pone.0190682 |
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