Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells
Direct co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have applied to the measurement of complementarity between...
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Impact Journals
2016
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| Online Access: | https://eprints.nottingham.ac.uk/43288/ |
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| author | Pallis, Monica Burrows, Francis Ryan, Jeremy Grundy, Martin Seedhouse, Claire Abdul-Aziz, Amina Montero, Joan Letai, Anthony Russell, Nigel |
| author_facet | Pallis, Monica Burrows, Francis Ryan, Jeremy Grundy, Martin Seedhouse, Claire Abdul-Aziz, Amina Montero, Joan Letai, Anthony Russell, Nigel |
| author_sort | Pallis, Monica |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Direct co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have applied to the measurement of complementarity between sensitiser BH3 peptide mimetics and therapeutic agents. Using dynamic BH3 profiling, we show that the agent TG02, which downregulates MCL-1, sensitises to the BCL-2-inhibitory BAD-BH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide in acute myeloid leukaemia (AML) cells. At the concentrations used, the peptides did not trigger mitochondrial outer membrane permeabilisation in their own right, but primed cells to release Cytochrome C in the presence of an appropriate trigger of a complementary pathway. In KG-1a cells TG02 and ABT-199 synergised to induce apoptosis. In heterogeneous AML patient samples we noted a range of sensitivities to the two agents. Although some individual samples markedly favoured one agent or the other, in the group as a whole the combination of TG02 + ABT-199 was significantly more cytotoxic than either agent individually. We conclude that dynamic NOXA and BAD BH3 profiling is a sensitive methodology for investigating molecular pathways of drug action and complementary mechanisms of chemoresponsiveness. |
| first_indexed | 2025-11-14T19:51:26Z |
| format | Article |
| id | nottingham-43288 |
| institution | University of Nottingham Malaysia Campus |
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| last_indexed | 2025-11-14T19:51:26Z |
| publishDate | 2016 |
| publisher | Impact Journals |
| recordtype | eprints |
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| spelling | nottingham-432882020-05-04T17:46:33Z https://eprints.nottingham.ac.uk/43288/ Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells Pallis, Monica Burrows, Francis Ryan, Jeremy Grundy, Martin Seedhouse, Claire Abdul-Aziz, Amina Montero, Joan Letai, Anthony Russell, Nigel Direct co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have applied to the measurement of complementarity between sensitiser BH3 peptide mimetics and therapeutic agents. Using dynamic BH3 profiling, we show that the agent TG02, which downregulates MCL-1, sensitises to the BCL-2-inhibitory BAD-BH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide in acute myeloid leukaemia (AML) cells. At the concentrations used, the peptides did not trigger mitochondrial outer membrane permeabilisation in their own right, but primed cells to release Cytochrome C in the presence of an appropriate trigger of a complementary pathway. In KG-1a cells TG02 and ABT-199 synergised to induce apoptosis. In heterogeneous AML patient samples we noted a range of sensitivities to the two agents. Although some individual samples markedly favoured one agent or the other, in the group as a whole the combination of TG02 + ABT-199 was significantly more cytotoxic than either agent individually. We conclude that dynamic NOXA and BAD BH3 profiling is a sensitive methodology for investigating molecular pathways of drug action and complementary mechanisms of chemoresponsiveness. Impact Journals 2016-04-15 Article PeerReviewed Pallis, Monica, Burrows, Francis, Ryan, Jeremy, Grundy, Martin, Seedhouse, Claire, Abdul-Aziz, Amina, Montero, Joan, Letai, Anthony and Russell, Nigel (2016) Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells. Oncotarget, 8 (10). pp. 16220-16232. ISSN 1949-2553 BAD NOXA TG02 ABT-199 AML http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=8742 doi:10.18632/oncotarget.8742 doi:10.18632/oncotarget.8742 |
| spellingShingle | BAD NOXA TG02 ABT-199 AML Pallis, Monica Burrows, Francis Ryan, Jeremy Grundy, Martin Seedhouse, Claire Abdul-Aziz, Amina Montero, Joan Letai, Anthony Russell, Nigel Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells |
| title | Complementary dynamic BH3 profiles predict co-operativity
between the multi-kinase inhibitor TG02 and the BH3 mimetic
ABT-199 in acute myeloid leukaemia cells |
| title_full | Complementary dynamic BH3 profiles predict co-operativity
between the multi-kinase inhibitor TG02 and the BH3 mimetic
ABT-199 in acute myeloid leukaemia cells |
| title_fullStr | Complementary dynamic BH3 profiles predict co-operativity
between the multi-kinase inhibitor TG02 and the BH3 mimetic
ABT-199 in acute myeloid leukaemia cells |
| title_full_unstemmed | Complementary dynamic BH3 profiles predict co-operativity
between the multi-kinase inhibitor TG02 and the BH3 mimetic
ABT-199 in acute myeloid leukaemia cells |
| title_short | Complementary dynamic BH3 profiles predict co-operativity
between the multi-kinase inhibitor TG02 and the BH3 mimetic
ABT-199 in acute myeloid leukaemia cells |
| title_sort | complementary dynamic bh3 profiles predict co-operativity
between the multi-kinase inhibitor tg02 and the bh3 mimetic
abt-199 in acute myeloid leukaemia cells |
| topic | BAD NOXA TG02 ABT-199 AML |
| url | https://eprints.nottingham.ac.uk/43288/ https://eprints.nottingham.ac.uk/43288/ https://eprints.nottingham.ac.uk/43288/ |