ABT-737, Synergistically Enhances Daunorubicin-Mediated Apoptosis in Acute Myeloid Leukemia Cell Lines

The anti-apoptotic proteins Bcl-XL and Bcl-2 are abundantly expressed in hematopoietic stem cells and/or progenitor cells. Furthermore, leukemic cells expressing these proteins are enriched in minimal residual disease cell populations. This prompted us to test the BH3-mimetic compound ABT-737 for its ability to eradicate putative leukemic stem cells. ABT-737 demonstrated potent cytotoxic effects in all patient samples tested. The efficacy of ABT-737 against AML blasts and the primitive CD34+/CD38− population was equal and independent of sensitivity to cytarabine/daunorubicin. These results, together with previously reported synergistic effects of ABT-737 with chemotherapeutics make BH3-mimetics promising candidates for future AML treatment regimens.

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The BH3-mimetic ABT-737 effectively kills acute myeloid leukemia initiating cells

Baev

Krawczyk

O’Dwyer

et al. 2014

Leukemia Research Reports

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The application of BH3 mimetics in myeloid leukemias

2021

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Execution of the intrinsic apoptotic pathway is controlled by the BCL-2 proteins at the level of the mitochondrial outer membrane (MOM). This family of proteins consists of prosurvival (e.g., BCL-2, MCL-1) and proapoptotic (e.g., BIM, BAD, HRK) members, the functional balance of which dictates the activation of BAX and BAK. Once activated, BAX/BAK form pores in the MOM, resulting in cytochrome c release from the mitochondrial intermembrane space, leading to apoptosome formation, caspase activation, and cleavage of intracellular targets. This pathway is induced by cellular stress including DNA damage, cytokine and growth factor withdrawal, and chemotherapy/drug treatment. A well-documented defense of leukemia cells is to shift the balance of the BCL-2 family in favor of the prosurvival proteins to protect against such intra- and extracellular stimuli. Small molecule inhibitors targeting the prosurvival proteins, named ‘BH3 mimetics’, have come to the fore in recent years to treat hematological malignancies, both as single agents and in combination with standard-of-care therapies. The most significant example of these is the BCL-2-specific inhibitor venetoclax, given in combination with standard-of-care therapies with great success in AML in clinical trials. As the number and variety of available BH3 mimetics increases, and investigations into applying these novel inhibitors to treat myeloid leukemias continue apace the need to evaluate where we currently stand in this rapidly expanding field is clear.

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Preferential targeting of cancer stem cells in the radiosensitizing effect of ABT-737 on HNSCC

et al. 2016

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Head and neck squamous cell carcinomas (HNSCC) are common human malignancies with poor clinical outcomes. The 5-year survival rates for patients with advanced stage HNSCC have not changed appreciably in the past few decades, underscoring a dire need for improved therapeutic options. HNSCC is frequently characterized by overexpression of anti-apoptotic Bcl-2 family members. Increased levels of these anti-apoptotic proteins have been associated with radio- and chemoresistance and poor clinical outcome. The aim of this study was to evaluate combined effects of radiation and ABT-737, a BH3-mimetic molecule, in HNSCC. Although ABT-737, as a single agent, was largely ineffective at promoting HNSCC cell death, we found that combining ABT-737 and radiation induced strong synergistic apoptosis in HNSCC cell lines and delayed tumoral growth in vivo. Moreover, we demonstrated for the first time that ABT-737, alone or in combination with radiation, can efficiently eliminate cancer stem cells (CSCs). Altogether, our results indicate that therapy targeting anti-apoptotic Bcl-2 family members could be a highly effective potential adjuvant to radiotherapy capable of targeting CSCs in HNSCC and therefore overcoming cancer recurrence and metastasis.

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ABT-737, Synergistically Enhances Daunorubicin-Mediated Apoptosis in Acute Myeloid Leukemia Cell Lines

Cited by 3 publications

References 24 publications

The BH3-mimetic ABT-737 effectively kills acute myeloid leukemia initiating cells

The BH3-mimetic ABT-737 effectively kills acute myeloid leukemia initiating cells

The application of BH3 mimetics in myeloid leukemias

Preferential targeting of cancer stem cells in the radiosensitizing effect of ABT-737 on HNSCC

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