A novel Bim-BH3-derived Bcl-XL inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity

Ponassi, Raffaella; Biasotti, Barbara; Tomati, Valeria; Bruno, Silvia; Poggi, Alessandro; Malacarne, Davide; Cimoli, Guido; Salis, Annalisa; Pozzi, Sarah; Miglino, Maurizio; Damonte, Gianluca; Cozzini, Pietro; Spyrakis, Francesca; Campanini, Barbara; Bagnasco, Luca; Castagnino, Nicoletta; Tortolina, Lorenzo; Mumot, Anna; Frassoni, Francesco; Daga, Antonio; Cilli, Michele; Piccardi, Federica; Monfardini, Ilaria; Perugini, Miriam; Zoppoli, Gabriele; D’Arrigo, Cristina; Pesenti, Raffaele; Parodi, Silvio

doi:10.4161/cc.7.20.6830

Cited by 30 publications

(33 citation statements)

References 45 publications

(70 reference statements)

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“…Anti-apoptotic Bcl-2 family proteins Acts as BH3-only mimetic to induce release of mitochondrial pro-apoptotic proteins [124] 072RB Anti-apoptotic Bcl-2 family proteins Acts as BH3-only mimetic to induce release of mitochondrial pro-apoptotic proteins [110] HA14-1 Anti-apoptotic Bcl-2 family proteins Acts as BH3-only mimetic to induce release of mitochondrial pro-apoptotic proteins [112] GX15-070 Anti-apoptotic Bcl-2 family proteins Acts as BH3-only mimetic to induce release of mitochondrial pro-apoptotic proteins [113] Arsenic trioxide Permeability transition pore Inhibition of ANT and VDAC [98] Lonidamine Permeability transition pore Hexokinase and ANT inhibitor [125] 2 Szeto-Schiller peptides IMM Prevents MPT, efficient in animal models of ischemiareperfusion, neurodegeneration, and renal fibrosis [70] Edaravone Hydroxyl radicals Scavenger of radicals, efficient for acute ischemic stroke [72] Lamotrigine Complex I of respiratory chain Protects from rotenone toxicity [73] Coenzyme Q10 Mitochondria Scavenger of free radicals, prevents lipid peroxidation [75] Creatine Mitochondria Protects from neurotoxicity of glutamate and Ab [87] L-Carnitine Mitochondria Essential for b-oxidation of long-chain fatty acids in mitochondria, restores mitochondrial dysfunction [90] Apoptosis (2009) 14:624-640 635 contrast, stabilization of mitochondria in tumor cells is responsible for resistance of a variety of tumors to treatment. Thus, stimulation of destructive processes in cancer cell mitochondria could be a useful approach, facilitating mitochondrial collapse and stimulating cell death processes.…”

Section: Discussionmentioning

confidence: 99%

“…Another BH3-mimetic, 072RB, is localized to mitochondria and was shown to cause cell death in various cultured leukemic cells, as well as in cells derived from acute myeloid leukemia (AML) patients [110]. Intravenous administration of 072RB to xenografts of human AML cells in NOD/SCID mice caused a significant delay of leukemic cell growth with no evidence of toxicity to normal tissue.…”

Section: Induction Of Mptmentioning

confidence: 99%

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Mitochondria as targets for chemotherapy

2009

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Mitochondrial malfunctioning is implicated in the pathogenesis of a variety of disorders, including cancer and multiple neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. Disturbance of mitochondrial vital functions, e.g., production of ATP, calcium buffering capacity, and generation of reactive oxygen species, can be potentially involved in disease pathogenesis. Neurological disorders caused by mitochondrial deterioration are often associated with cell loss within specific brain regions. In contrast, mitochondrial alterations in tumor cells and the "Warburg effect" might lead to cell survival and resistance of tumor cells to chemotherapy. This review is devoted to the role of mitochondria in neurodegeneration and tumor formation, and describes how targeting of mitochondria can be beneficial in the therapy of these diseases, which affect a large human population.

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Section: Discussionmentioning

confidence: 99%

Section: Induction Of Mptmentioning

confidence: 99%

Mitochondria as targets for chemotherapy

2009

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“…For example ‘hydrocarbon-stapled’ peptides containing BH3 domains (stabilized α-helices of Bcl-2 family proteins [SAHBs]; Bim-SAHB) are currently being developed as anticancer agents [75,76]. In addition, modifications of the BH3 domain using natural and non-natural amino acids to improve stability and enhance target specificity have been used as with the Bim-BH3 mimic, 072RB [77]. As certain neoplasias are likely the consequence of mutations or aberrant regulation exclusively of Bim [78], the restoration of a ‘therapeutic’ Bim is an attractive possibility.…”

Section: Malignant Mitochondria (The Tumor Signature)mentioning

confidence: 99%

Targeting Malignant Mitochondria With Therapeutic Peptides

Constance

Lim

2012

Therapeutic Delivery

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The current status of peptides that target the mitochondria in the context of cancer is the focus of this review. Chemotherapy and radiotherapy used to kill tumor cells are principally mediated by the process of apoptosis that is governed by the mitochondria. The failure of anticancer therapy often resides at the level of the mitochondria. Therefore, the mitochondrion is a key pharmacological target in cancer due to many of the differences that arise between malignant and healthy cells at the level of this ubiquitous organelle. Additionally, targeting the characteristics of malignant mitochondria often rely on disruption of protein-protein interactions that are not generally amenable to small molecules. We discuss anticancer peptides that intersect with pathological changes in the mitochondrion.The mitochondrion holds importance among cellular organelles in consideration of selective anticancer therapy because it is the nexus for propagating malignant transformation and controls cell death. The mitochondrion is a universal target in all cancer cells, and new information about functional and structural differences between healthy and malignant cells continues to emerge [1]. Peptides that specifically target malignant mitochondria offer advantages of low toxicity, high specificity and generally increase the range of interactions that are difficult to target with small molecules (e.g., protein-protein, protein-lipid and protein-DNA) [2]. However, the benefits of peptides are offset by difficulties in delivery, such as degradation by proteases and rapid clearance. As such, the delivery of peptide/ protein therapeutics is almost exclusively by the parenteral route, but the status quo is actively being challenged by broad efforts (e.g., liposomes, microparticles, nanoparticles, 'smart' polymers, hydrogels and chemical modifications to the peptide/protein) to achieve more convenient routes of administration (i.e., oral, nasal and transdermal) and improved pharmacokinetics [3][4][5]. However, peptides, in many cases, are far from passive in the delivery process and through the maze that is drug delivery (from route of administration to perhaps a target residing within a specific organelle), peptides are employed as the vehicle, homing motif and trans-/intra-cellular passport [6].There is an emerging view in cancer therapy that the way in which a cancer cell dies (i.e., immunogenic cell death) is important for a durable response [7]. However, traditional chemo therapy and immune response are in conflict because chemotherapy (e.g., DNA-© 2012 Future Science Ltd * Author for correspondence: Tel.: +1 801 581 7120 Fax: +1 801 585 3614 carol.lim@pharm.utah.edu. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript....

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“…From a clinical translational standpoint, BIM induction appears essential for cell death responses to a host of chemotherapeutic agents, and BIM suppression by genetic deletion, miRNA-based suppression, or protein interaction-based neutralization or degradation accounts for the emergence of drug resistance (13)(14)(15). Therefore, harnessing the BIM BH3 helix to promote a death response and, in particular, chemical replacement of this death functionality, in the context of drug resistance, are logical pharmacologic goals (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers

et al. 2012

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Cancer cells subvert the natural balance between cellular life and death, achieving immortality through pathologic enforcement of survival pathways and blockade of cell death mechanisms. Pro-apoptotic BCL-2 family proteins are frequently disarmed in relapsed and refractory cancer through genetic deletion or interactionbased neutralization by overexpressed antiapoptotic proteins, resulting in resistance to chemotherapy and radiation treatments. New pharmacologic strategies are urgently needed to overcome these formidable apoptotic blockades. We harnessed the natural killing activity of BCL-2-interacting mediator of cell death (BIM), which contains one of the most potent BH3 death domains of the BCL-2 protein family, to restore BH3-dependent cell death in resistant hematologic cancers. A hydrocarbon-stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity, blocked inhibitory antiapoptotic interactions, directly triggered proapoptotic activity, and induced dose-responsive and BH3 sequence-specific cell death of hematologic cancer cells. The therapeutic potential of stapled BIM BH3 was highlighted by the selective activation of cell death in the aberrant lymphoid infiltrates of mice reconstituted with BIM-deficient bone marrow and in a human AML xenograft model. Thus, we found that broad and multimodal targeting of the BCL-2 family pathway can overcome pathologic barriers to cell death. IntroductionThe BCL-2 family interaction network lies at the crossroads of the cell's life-death decision (1, 2). Among the oncogenic signals that drive the development and maintenance of cancer, the pathologic reprogramming of the BCL-2 family interaction network has emerged as a formidable barrier to modern day anticancer treatment. Antiapoptotic members of the BCL-2 family contain a surface hydrophobic groove that can bind, sequester, and neutralize the critical BH3 death domains of proapoptotic members (3). Small molecules, such as ABT-737 and ABT-263, that selectively inhibit the antiapoptotic proteins BCL-2 and BCL-X L induce apoptosis of tumors that are especially dependent upon this subset of survival proteins (4, 5). However, the compounds are rendered ineffective by cellular expression of alternate antiapoptotic proteins, such as MCL-1 and BFL1/A1, which lie outside the molecules' range of binding specificity or by the relative or absolute absence of proapoptotic effectors, such as BAX and BAK (6, 7). Thus, a pharmacologic quest is underway to develop nextgeneration agents that simulate broader spectrum BH3-dependent killing activities and effectively deactivate the deflector shields of relapsed and refractory cancers.Chief among the killer BH3-only proteins, Bcl-2-interacting mediator of cell death (BIM) exhibits the most broad-ranging BCL-2 protein interactions, engaging all of the antiapoptotic proteins with high affinity (8, 9) and also directly triggering death effectors, such as BAX (10,11). A recent genetic analysis elegantly demonstrated that only BIM BH3, but not oth...

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A novel Bim-BH3-derived Bcl-XL inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity

Cited by 30 publications

References 45 publications

Mitochondria as targets for chemotherapy

Mitochondria as targets for chemotherapy

Targeting Malignant Mitochondria With Therapeutic Peptides

A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers

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