Apoptosis in Leukemias: Regulation and Therapeutic Targeting

Samudio, Ismael; Konopleva, Marina; Carter, Bing Z.; Andreeff, Michael

doi:10.1007/978-0-387-69259-3_12

Cited by 22 publications

(28 citation statements)

References 117 publications

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“…Because the induction of apoptosis in leukemia cells is largely controlled by dimerization of proapoptotic and antiapoptotic proteins (11), we hypothesized that, in addition to the inhibition of mTOR/MEK signaling, the inhibition of binding of Bax or Bim with their respective partners, Bcl-2 and Bcl-xL would further enhance apoptosis induction. We, and others, have reported previously that the Bcl-2 antagonist ABT-737 can bind to Bcl-2 family members resulting in leukemic cell death (12,24).…”

Section: Resultsmentioning

confidence: 99%

“…The anti-apoptotic Bcl-2 proteins Bcl-2, Bcl-xL, and myeloid cell leukemia sequence 1 (Mcl-1) prevent cellular apoptosis via their expression and dimerization with the pro-apoptotic Bcl-2 proteins Bim and Bax. The overexpression of the anti-apoptotic Bcl-2 proteins correlates with an overall lower overall survival rates for AML patients (10,11). Several small-molecule Bcl-2 inhibitors have been developed, and they have shown encouraging single-agent activity in preclinical and clinical trials (12,13).…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Apoptosis Induction by Concomitant Inhibition of MEK, mTOR, and Bcl-2 in Human Acute Myelogenous Leukemia Cells

Zhang¹,

Ruvolo²,

Chen³

et al. 2014

Molecular Cancer Therapeutics

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Aberrant activation of multiple signaling pathways is common in acute myeloid leukemia (AML) cells, which can be linked to a poor prognosis for patients with this disease. Previous research with mTOR or MEK inhibitors revealed cytostatic, rather than cytotoxic, effects in in vitro and in vivo AML models. We evaluated the combination effect of the mTOR inhibitor AZD8055 and the MEK inhibitor selumetinib on human AML cell lines and primary AML samples. This combination demonstrated synergistic proapoptotic effects in AML cells with high basal activation of MEK and mTOR. We next incorporated the BH3 mimetic ABT-737 into this combination regimen to block Bcl-2, which further enhanced the apoptogenic effect of MEK/mTOR inhibition. The combination treatment also had a striking proapoptotic effect in CD33+/CD34+ AML progenitor cells from primary AML samples with NRAS mutations. Mechanistically, up-regulation of the proapoptotic protein Bim, accompanied by the down-regulation of the antiapoptotic protein Mcl-1 (mainly via protein degradation), appeared to play critical roles in enhancing the combination drug effect. Furthermore, the modulation of survivin, Bax, Puma, and XIAP expression suggested a role for mitochondria-mediated apoptosis in the cytotoxicity of the drug combination. Consequently, the concomitant blockade of pro-survival MEK/mTOR signaling and the deactivation of Bcl-2 could provide a mechanism-based integrated therapeutic strategy for the eradication of AML cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of Apoptosis Induction by Concomitant Inhibition of MEK, mTOR, and Bcl-2 in Human Acute Myelogenous Leukemia Cells

Zhang¹,

Ruvolo²,

Chen³

et al. 2014

Molecular Cancer Therapeutics

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“…Recent studies have demonstrated that the true “Achilles heel” of leukemia may be exploited by targeting both signal transduction and apoptotic programs simultaneously (synthetic lethality) . Indeed, apoptosis has been established as a mechanism of anticancer defense and several components of the apoptotic machinery are being currently targeted in clinical trials of leukemia .…”

Section: Discussionmentioning

confidence: 99%

Apoptosis: A biomarker of high‐risk phenotype in pediatric acute myeloid leukemia?

Tyagi

Pramanik

Bakhshi

et al. 2018

Int J Lab Hematology

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Introduction Dysregulation of apoptosis has been explored in acute myeloid leukemia (AML); yet, its correlation with clinical outcomes in pediatric AML is unknown. This study was aimed to analyze percentage of apoptosis and apoptosis mediated through the intrinsic pathway with clinical outcomes in patients with pediatric AML. Methods This prospective study included pediatric AML patients enrolled from July 2013 to August 2016. Annexin‐V (marker of total apoptosis) and caspase‐9 expression (marker of intrinsic pathway) was determined in baseline bone marrow (BM) samples by flow cytometery and compared with controls (unaffected BM of solid tumors and peripheral blood [PB] of unaffected siblings). Overall survival (OS) and event‐free survival (EFS) were compared using log‐rank test. Results A total of 151 AML patients were enrolled, median age 10 (range: 0.7‐18 years). Annexin‐V expression in blast cells was significantly high in AML patients as compared to BM of subjects with solid tumors (P = 0.01) and PB of healthy subjects (P = 0.04). Caspase‐9 expression in blast cells was not significantly different. Median annexin‐V expression was significantly higher in patients with WBC count ≥11 000/mm3 (P = 0.02), poor‐risk cytogenetics (P = 0.02), the absence of RUNX1‐RUNX1T1 translocation (P = 0.004), and the absence of NPM1 mutation (P = 0.05). Patients with high annexin‐V expression had significantly inferior OS (P = 0.05) in univariate analysis but not in multivariate analysis (P = 0.32). Conclusion Apoptosis as a whole was found to be activated in baseline BM samples of AML patients. High apoptosis may be associated with high‐risk phenotype in this disease.

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“…Some members of the TNFfamily (three ligands TNF-α, FasL and TRAIL) directly trigger apoptosis and together with their respective four receptors (TNF-R1, Fas, TRAIL-R1 and TRAIL-R2) have been considered as potential anticancer therapeutics (Testa & Riccioni, 2007). According to Samudio et al (2009) the majority of leukemia cells express TRAIL receptors, but these samples are notoriously resistant to apoptosis induction by TRAIL. However, in different types of leukemia, especially in AML, many directions in apoptosis mediation and induction are described.…”

Section: Development Of New Therapeutic Models Based On Modulation Ofmentioning

confidence: 99%

Triggering apoptosis in tumors: an overview of potential approaches in treatment of leukemia

Hadžić

Haverić

Pojskić

2019

GenApp

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Apoptosis, as a well-studied process of a programmed cell death, is essential for the maintenance of cell homeostasis and integrity of organisms. This process occurs normally during development and aging and it is a balance of the sustainability of the tissue cell population. In addition, apoptosis also occurs as a defensive mechanism such as an immune response or after cell damage as a consequence of a pathological condition or the action of harmful agents. Apoptotic activation tends to be less responsive with aging, causing accumulation of non-functional cells and pathological changes such are degenerative diseases or tumor transformation. This overview aims to provide summarized facts about different approaches of apoptosis research, targeting and regulation in tumors especially in leukemic cells as a way of pharmacological manipulation with a potential therapeutic benefit.

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Apoptosis in Leukemias: Regulation and Therapeutic Targeting

Cited by 22 publications

References 117 publications

Evaluation of Apoptosis Induction by Concomitant Inhibition of MEK, mTOR, and Bcl-2 in Human Acute Myelogenous Leukemia Cells

Evaluation of Apoptosis Induction by Concomitant Inhibition of MEK, mTOR, and Bcl-2 in Human Acute Myelogenous Leukemia Cells

Apoptosis: A biomarker of high‐risk phenotype in pediatric acute myeloid leukemia?

Triggering apoptosis in tumors: an overview of potential approaches in treatment of leukemia

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