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Predicting effective pro-apoptotic anti-leukaemic drug combinations using co-operative dynamic BH3 profiling
Martin Grundy1, Claire Seedhouse2, Thomas Jones2
1Clinical Haematology, Nottingham University Hospitals, Nottingham, United Kingdom.
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 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.
Insights
Dynamic BH3 profiling identifies anti-leukemic drugs that enhance apoptosis when combined with BCL-2 or MCL-1 inhibitors. This method predicts synergistic drug combinations for leukemia treatment.
Area of Science:
- Cellular Biology
- Molecular Biology
- Pharmacology
Background:
- The BH3-only proteins BAD and NOXA induce apoptosis by targeting BCL-2 and MCL-1, respectively.
- Combining drugs targeting BCL-2 and MCL-1 may enhance anti-leukemic activity.
- Understanding drug synergy is crucial for effective cancer therapy.
Purpose of the Study:
- To identify anti-leukemic drugs that sensitize cells to BCL-2 or MCL-1 antagonism.
- To evaluate the co-operative induction of apoptosis by drug combinations using dynamic BH3 profiling.
- To establish dynamic BH3 profiling as a tool for predicting synergistic drug lethality.
Main Methods:
- Dynamic BH3 profiling was used to assess cellular responses to BCL-2-targeting BAD-BH3 peptide and MCL-1-targeting MS1-BH3 peptide after priming with various anti-leukemic drugs.
- Specific drugs including BCL-2 inhibitors (ABT-199, JQ1), MCL-1 inhibitors (pladienolide B, torin1), FLT3 inhibitor (AC220), and etoposide were analyzed.
- Mitochondrial outer membrane permeabilization and apoptosis induction were measured to correlate priming effects with synergistic lethality.
Main Results:
- A wide range of anti-leukemic agents, including MCL-1 inhibitors, DNA damaging agents, and FLT3 inhibitors, sensitized leukemia cells to BAD-BH3 mediated apoptosis.
- The BCL-2 inhibitor ABT-199 showed strong cooperation with pladienolide B, torin1, etoposide, or AC220, inducing apoptosis rapidly.
- Prolonged priming with the BET inhibitor JQ1 downregulated BCL-2 and sensitized cells to MCL-1 inhibitors, etoposide, or AC220, leading to cytochrome C release.
Conclusions:
- Dynamic BH3 profiling is an effective mechanism-based tool for predicting co-operative lethality between drugs targeting BCL-2 and MCL-1.
- The study identified numerous agents that sensitize cells to BCL-2 antagonism, demonstrating potential for synergistic combinations with BCL-2 inhibitory compounds like ABT-199 or JQ1.
- These findings provide a foundation for developing novel combination therapies in leukemia treatment.
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