Synergistic induction of apoptosis by the Bcl‐2 inhibitor ABT‐737 and imatinib mesylate in gastrointestinal stromal tumor cells

Reynoso, David; Nolden, Laura K.; Yang, Dan; Dumont, Sarah; Conley, Anthony P.; Agathe, Dumont; Zhou, Kim; Duensing, Anette; Trent, Jonathan C.

doi:10.1016/j.molonc.2010.10.003

Cited by 26 publications

(19 citation statements)

References 47 publications

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“…Our synergy experiments are similar to those in BCR-ABL models of CML or gastrointestinal stromal cell tumor cells in which combinatorial treatment with TKIs and BH3 mimetics like navitoclax has been shown to be synergistic. 26,55,56 MCL-1 is a critical prosurvival molecule required to promote the survival of B-cell progenitor populations during BCR-ABL transformation as well as for the continued survival of the BCR-ABL B-ALL cells. These findings highlight the potential for targeting MCL-1 protein expression and function in treating this BCR-ABL B-ALL.…”

Section: Discussionmentioning

confidence: 99%

Requirement for antiapoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia

Koss

Morrison

Perciavalle

et al. 2013

Blood

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The response of Philadelphia chromosome (Ph(+)) acute lymphoblastic leukemia (ALL) to treatment by BCR-ABL tyrosine kinase inhibitors (TKIs) has been disappointing, often resulting in short remissions typified by rapid outgrowth of drug-resistant clones. Therefore, new treatments are needed to improve outcomes for Ph(+) ALL patients. In a mouse model of Ph(+) B-lineage ALL, MCL-1 expression is dysregulated by the BCR-ABL oncofusion protein, and TKI treatment results in loss of MCL-1 expression prior to the induction of apoptosis, suggesting that MCL-1 may be an essential prosurvival molecule. To test this hypothesis, we developed a mouse model in which conditional allele(s) of Mcl-1 can be deleted either during leukemia transformation or later after the establishment of leukemia. We report that endogenous MCL-1's antiapoptotic activity promotes survival during BCR-ABL transformation and in established BCR-ABL(+) leukemia. This requirement for MCL-1 can be overcome by overexpression of other antiapoptotic molecules. We further demonstrate that strategies to inhibit MCL-1 expression potentiate the proapoptotic action of BCL-2 inhibitors in both mouse and human BCR-ABL(+) leukemia cell lines. Thus, strategies focused on antagonizing MCL-1 function and expression would be predicted to be effective therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Requirement for antiapoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia

Koss

Morrison

Perciavalle

et al. 2013

Blood

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“…It acts like a BH3-only protein to antagonize anti-apoptotic Bcl-2 family members, thereby diminishing their ability to inhibit apoptosis (Oltersdorf et al, 2005). Many groups have reported on the high efficacy of ABT-737 either as a single agent or as a chemo-potentiator in combination with other chemotherapeutic agents to treat multiple types of cancers (Adams et al, 2005; Oltersdorf et al, 2005; Certo et al, 2006; Konopleva et al, 2006; Shoemaker et al, 2006; van Delft et al, 2006; Chauhan et al, 2007; Chen et al, 2007; Kang et al, 2007; Kohl et al, 2007; Olberding et al, 2010; Reynoso et al, 2010; Song et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

ABT-737 synergizes with Bortezomib to kill melanoma cells

et al. 2011

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SummaryThe BH3 mimetic ABT-737 is a potent inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-XL, and Bcl-w. The Bcl-2 family modulates sensitivity to anticancer drugs in many cancers, including melanomas. In this study, we examined whether ABT-737 is effective in killing melanoma cells either alone or in combination with a proteasome inhibitor already in clinical use (Bortezomib) in vitro and in vivo, and further evaluated the mechanisms of action. Results showed that ABT-737 alone induced modest cytotoxicity in melanoma cells, but only at higher doses. Knock-down of the anti-apoptotic proteins Bcl-2, Bcl-XL, or Mcl-1 with siRNAs demonstrated that Mcl-1 is the critical mediator of melanoma's resistance to ABT-737 treatment. However, ABT-737 displayed strong synergistic lethality when combined with Bortezomib. Immunoblot analyses demonstrated that Bortezomib increased expression of Noxa, a pro-apoptotic Bcl-2 member that antagonizes Mcl-1. Additionally, siRNA-mediated inhibition of Noxa expression protected melanoma cells from cytotoxicity induced by the combination treatment. These results demonstrate that Bortezomib synergizes with ABT-737 by neutralizing Mcl-1's function via increased levels of Noxa. In a xenograft mouse model, although drug doses were limited due to toxicity, ABT-737 or Bortezomib slowed melanoma tumor growth compared to the control, and the drug combination significantly decreased growth compared to either drug alone. These data imply that less toxic drugs fulfilling a function similar to Bortezomib to neutralize Mcl-1 are promising candidates for combination with ABT-737 for treating melanomas.

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“…Cell cycle assay was performed by propidium iodide (PI) staining (Roche, Indianapois, IN, USA) to identify the sub‐G1 population and analyzed by a FACS Canto II flow cytometer and FACS Diva 6.1 software (BD Biosciences, San Jose, CA), as previously described. (Reynoso et al., 2011) To assess apoptosis by flow cytometry, cells were stained with alexa fluor 488 annexin V and PI (Invitrogen, Carlsbad, CA USA), whereas caspase 3 and 7 activities were measured using the Apo‐One homogeneous Capase‐3/7 kit (Promega Inc., Madison, WI, USA) according to manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Targeted polytherapy in small cell sarcoma and its association with doxorubicin

et al. 2014

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A paradigm shift has occurred in the last decade from chemotherapy to targeted therapy for the management of many patients with advanced sarcoma. This work identifies a combination of targeted agents and doxorubicin that are effective against small cell sarcoma cell lines. Three small cell sarcoma cell lines were studied: RD18 (rhabdomyosarcoma), A204 (undifferentiated sarcoma) and TC 71 (Ewing's sarcoma). Each cell line was exposed to increasing concentrations of vorinostat (HDAC inhibitor), 17-DMAG (HSP90 inhibitor), abacavir (anti-telomerase) or sorafenib (tyrosine kinase inhibitor) alone, combined with one another, or combined with doxorubicin. Cell viability, cell cycle analysis and apoptosis were assessed by MTS assay, propidium iodide-Annexin V staining, and caspase 3/7 activity, respectively. The Chou and Talalay combination index (CI) was used to determine whether the effects were additive (CI = 1), synergistic (CI < 1) or antagonistic (CI > 1). In monotherapy, targeted agents achieved 30-90% reductions in viability, with the exception of abacavir. Dual-targeted combination therapies with vorinostat, sorafenib and 17-DMAG demonstrated synergy. Abacavir was antagonistic with every other drug and was not further studied. Both vorinostat and 17-DMAG synergized with doxorubicin, achieving 60% cell killing compared to 12% with doxorubicin alone. No synergy was observed for sorafenib with doxorubicin. The triple therapy vorinostat, 17-DMAG and doxorubicin did not show synergy, but increased the subG1 population at 24H, from 30% to 70% compared to monotherapies with an increase in apoptosis. This work provides evidence of synergy of combinations of vorinostat, 17-DMAG and sorafenib in small cell sarcoma. In addition to doxorubicin, these combinations enhance doxorubicin cytotoxicity at therapeutically relevant concentrations.

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Synergistic induction of apoptosis by the Bcl‐2 inhibitor ABT‐737 and imatinib mesylate in gastrointestinal stromal tumor cells

Abstract: We provide the first preclinical evidence that Bcl-2/Bcl-x(L) inhibition with ABT-737 synergistically enhances imatinib-induced cytotoxicity via apoptosis, and that direct engagement of apoptotic cell death may be an effective approach to circumvent imatinib-resistance in GIST.

Cited by 26 publications

References 47 publications

Requirement for antiapoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia

Requirement for antiapoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia

ABT-737 synergizes with Bortezomib to kill melanoma cells

Targeted polytherapy in small cell sarcoma and its association with doxorubicin

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