Placzek WJ, Wei J, Kitada S et al.A survey of the anti-apoptotic Bcl-2 subfamily expression in cancer types provides a platform to predict the efficacy of Bcl-2 antagonists in cancer therapy. Cell Death Dis 1:e40

Sanford/Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Cell Death & Disease (Impact Factor: 5.01). 05/2010; 1(5):e40. DOI: 10.1038/cddis.2010.18
Source: PubMed


We investigated the mRNA expression levels of all six antiapoptotic Bcl-2 subfamily members in 68 human cancer cell lines using qPCR techniques and measured the ability of known Bcl-2 inhibitors to induce cell death in 36 of the studied tumor cell lines. Our study reveals that Mcl-1 represents the anti-apoptotic Bcl-2 subfamily member with the highest mRNA levels in the lung, prostate, breast, ovarian, renal, and glioma cancer cell lines. In leukemia/lymphoma and melanoma cancer cell lines, Bcl-2 and Bfl-1 had the highest levels of mRNA, respectively. The observed correlation between the cell killing properties of known Bcl-2 inhibitors and the relative mRNA expression levels of anti-apoptotic Bcl-2 proteins provide critical insights into apoptosis-based anticancer strategies that target Bcl-2 proteins. Our data may explain current challenges of selective Bcl-2 inhibitors in the clinic, given that severe expression of Bcl-2 seems to be limited to leukemia cell lines. Furthermore, our data suggest that in most cancer types a strategy targeted to Mcl-1 inhibition, or combination of Bfl-1 and Mcl-1 inhibition for melanoma, may prove to be more successful than therapies targeting only Bcl-2.

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Available from: William Placzek, Feb 10, 2014
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    • "Many cancers feature overexpression of pro-survival members of the Bcl-2 family [24]. In follicular lymphoma, constitutive high level expression of Bcl-2 results from a translocation that brings it under the control of the immunoglobulin heavy chain enhancer [25] [26], but expression of Bcl-2 or its pro-survival relatives Bcl-x L and Mcl-1 is also elevated in other cancers [27]. Enhanced activity of pro-survival Bcl-2 family proteins contributes to oncogenesis and can also result in resistance to chemotherapy and poor clinical outcome. "
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    ABSTRACT: Chemotherapy and radiotherapy can cause permanent damage to the genomes of surviving cells, provoking severe side effects such as second malignancies in some cancer survivors. Drugs that mimic the activity of death ligands, or antagonise pro-survival proteins of the Bcl-2 or IAP families have yielded encouraging results in animal experiments and early phase clinical trials. Because these agents directly engage apoptosis pathways, rather than damaging DNA to indirectly provoke tumour cell death, we reasoned that they may offer another important advantage over conventional therapies: minimisation or elimination of side effects such as second cancers that result from mutation of surviving normal cells. Disappointingly, however, we previously found that concentrations of death receptor agonists like TRAIL that would be present in vivo in clinical settings provoked DNA damage in surviving cells. In this study, we used cell line model systems to investigate the mutagenic capacity of drugs from two other classes of direct apoptosis-inducing agents: the BH3-mimetic ABT-737 and the IAP antagonists LCL161 and AT-406. Encouragingly, our data suggest that IAP antagonists possess negligible genotoxic activity. Doses of ABT-737 that were required to damage DNA stimulated Bax/Bak-independent signalling and exceeded concentrations detected in the plasma of animals treated with this drug. These findings provide hope that cancer patients treated by BH3-mimetics or IAP antagonists may avoid mutation-related illnesses that afflict some cancer survivors treated with conventional DNA-damaging anti-cancer therapies. Copyright © 2015 Elsevier B.V. All rights reserved.
    04/2015; 777:23-32. DOI:10.1016/j.mrfmmm.2015.04.005
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    • "The anti-apoptotic BCL-2 protein family contributes to melanoma's resistance to apoptosis (Eberle and Hossini, 2008; Haass and Schumacher, 2014; Mohana-Kumaran et al., 2014; Placzek et al., 2010; Soengas and Lowe, 2003), and clinical trials targeting anti-apoptotic Bcl-2 family members are currently underway (Thomas et al., 2013). ABT-737 and its oral bioactive form, ABT-263, are small molecule "
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    ABSTRACT: Investigations from multiple laboratories support the existence of melanoma initiating cells (MICs) that potentially contribute to melanoma's drug resistance. ABT-737, a small molecule BCL-2/BCL-XL/BCL-W inhibitor, is promising in cancer treatments, but not very effective against melanoma, with the anti-apoptotic protein MCL-1 as the main contributor to resistance. The synthetic retinoid fenretinide (4-HPR) has shown promise for treating breast cancers. Here, we tested whether the combination of ABT-737 with 4-HPR is effective in killing both the bulk of melanoma cells and MICs. The combination synergistically decreased cell viability and caused cell death in multiple melanoma cells lines (carrying either BRAF or NRAS mutations), but not in normal melanocytes. The combination increased the NOXA expression and caspase-dependent MCL-1 degradation. Knocking-down NOXA protected cells from combination-induced apoptosis, implicating the role of NOXA in the drug synergy. The combination treatment also disrupted primary spheres (a functional assay for MICs) and decreased the percentage of ALDH(high) cells (a marker of MICs) in melanoma cell lines. Moreover, the combination inhibited the self-renewal capacity of MICs, measured by secondary sphere forming assays. In vivo, the combination inhibited tumor growth. Thus, this combination is a promising treatment strategy for melanoma, regardless of mutation status of BRAF or NRAS.Journal of Investigative Dermatology accepted article preview online, 28 October 2014. doi:10.1038/jid.2014.464.
    Journal of Investigative Dermatology 10/2014; 135(3). DOI:10.1038/jid.2014.464 · 7.22 Impact Factor
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    • "All the antiapoptotic proteins are playing essential roles on regulating/resisting apoptosis. Moreover, each of the proteins plays unique roles in various biological processes, notwithstanding similar 3D structures of the proteins (Placzek et al., 2010). However, exact structureactivity relationships of the proteins have not yet well addressed to our best knowledge. "
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    ABSTRACT: We have herein computationally examined binding affinities and specificity of 2-hydroxy-3,5-dinitrobenzamide (HDNB), a small chemical molecular BH3-mimetic identified by means of 'peptidodynmimetic method', on the BH3-binding grooves of six anti-apoptotic proteins (Bcl-2, Bcl-B, Bcl-W, Bcl-XL, Bfl-1 and Mcl-1) from human beings. The HDNB ligand was found to interact on the BH3-binding grooves of Bcl-2, Bcl-B, Bcl-XL, Bfl-1 and Mcl-1, whereas it did not act as BH3-mimetic to Bcl-W. Moreover, binding affinities of the HDNB towards the anti-apoptotic proteins were significantly different from each other. The differential binding affinities and specificity of the HDNB towards the anti-apoptotic proteins have been chiefly attributed to the differences in the chemical properties of BH3-binding grooves of the proteins. Implications of the study to design efficient de novo antagonists to the antiapoptotic proteins using the HDNB as seed molecule have been discussed.
    Bangladesh Journal of Pharmacology 07/2014; 9(3). DOI:10.3329/bjp.v9i3.18965 · 1.05 Impact Factor
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