دورية أكاديمية
BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models.
| العنوان: | BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models. |
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| المؤلفون: | Vervloessem T; KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut (LKI), Leuven, Belgium., Sasi BK; Molecular Hematology, International Center for Genetic Engineering & Biotechnology, Trieste, Italy., Xerxa E; Molecular Hematology, International Center for Genetic Engineering & Biotechnology, Trieste, Italy., Karamanou S; KU Leuven, Laboratory of Molecular Bacteriology, Rega Institute for Medical Research, Department of Microbiology and Immunology, Leuven, Belgium., Kale J; Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada., La Rovere RM; KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut (LKI), Leuven, Belgium., Chakraborty S; Molecular Hematology, International Center for Genetic Engineering & Biotechnology, Trieste, Italy., Sneyers F; KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut (LKI), Leuven, Belgium., Vogler M; Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany., Economou A; KU Leuven, Laboratory of Molecular Bacteriology, Rega Institute for Medical Research, Department of Microbiology and Immunology, Leuven, Belgium., Laurenti L; Hematology Institute, Catholic University Hospital 'A. Gemelli', Rome, Italy., Andrews DW; Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.; Sunnybrook Research Institute and Departments of Biochemistry and Medical Biophysics, University of Toronto, Toronto, ON, Canada., Efremov DG; Molecular Hematology, International Center for Genetic Engineering & Biotechnology, Trieste, Italy. efremov@icgeb.org., Bultynck G; KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut (LKI), Leuven, Belgium. geert.bultynck@kuleuven.be. |
| المصدر: | Cell death & disease [Cell Death Dis] 2020 Sep 17; Vol. 11 (9), pp. 769. Date of Electronic Publication: 2020 Sep 17. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London : Nature Pub. Group |
| مواضيع طبية MeSH: | Apoptosis*, Anthraquinones/*pharmacology , Ethanolamines/*pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy , Lymphoma, Large B-Cell, Diffuse/*drug therapy , Proto-Oncogene Proteins c-bcl-2/*metabolism, Calcium/metabolism ; Cell Line, Tumor ; Cytosol/metabolism ; Dose-Response Relationship, Drug ; Down-Regulation ; Drug Screening Assays, Antitumor ; Humans ; Liposomes/metabolism ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Neoplasms/metabolism ; Phosphorylation ; Protein Conformation ; Protein Domains ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Signal Transduction ; bcl-2-Associated X Protein/metabolism ; bcl-X Protein/metabolism |
| مستخلص: | Several cancer cell types, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL) upregulate antiapoptotic Bcl-2 to cope with oncogenic stress. BH3 mimetics targeting Bcl-2's hydrophobic cleft have been developed, including venetoclax as a promising anticancer precision medicine for treating CLL patients. Recently, BDA-366 was identified as a small molecule BH4-domain antagonist that could kill lung cancer and multiple myeloma cells. BDA-366 was proposed to switch Bcl-2 from an antiapoptotic into a proapoptotic protein, thereby activating Bax and inducing apoptosis. Here, we scrutinized the therapeutic potential and mechanism of action of BDA-366 in CLL and DLBCL. Although BDA-366 displayed selective toxicity against both cell types, the BDA-366-induced cell death did not correlate with Bcl-2-protein levels and also occurred in the absence of Bcl-2. Moreover, although BDA-366 provoked Bax activation, it did neither directly activate Bax nor switch Bcl-2 into a Bax-activating protein in in vitro Bax/liposome assays. Instead, in primary CLL cells and DLBCL cell lines, BDA-366 inhibited the activity of the PI3K/AKT pathway, resulted in Bcl-2 dephosphorylation and reduced Mcl-1-protein levels without affecting the levels of Bcl-2 or Bcl-xL. Hence, our work challenges the current view that BDA-366 is a BH4-domain antagonist of Bcl-2 that turns Bcl-2 into a pro-apoptotic protein. Rather, our results indicate that other mechanisms beyond switching Bcl-2 conformation underlie BDA-366's cell-death properties that may implicate Mcl-1 downregulation and/or Bcl-2 dephosphorylation. |
| التعليقات: | Comment in: Cell Death Differ. 2021 Mar;28(3):1130-1132. (PMID: 33469228) |
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(PMID: 2497428410.1016/B978-0-12-417158-9.00001-7) |
| معلومات مُعتمدة: | FDN143312 Canada CIHR |
| المشرفين على المادة: | 0 (Anthraquinones) 0 (BAX protein, human) 0 (BCL2 protein, human) 0 (BCL2L1 protein, human) 0 (BDA-366) 0 (Ethanolamines) 0 (Liposomes) 0 (MCL1 protein, human) 0 (Myeloid Cell Leukemia Sequence 1 Protein) 0 (Proto-Oncogene Proteins c-bcl-2) 0 (bcl-2-Associated X Protein) 0 (bcl-X Protein) SY7Q814VUP (Calcium) |
| تواريخ الأحداث: | Date Created: 20200918 Date Completed: 20210914 Latest Revision: 20210930 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC7498462 |
| DOI: | 10.1038/s41419-020-02944-6 |
| PMID: | 32943617 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 2041-4889 |
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| DOI: | 10.1038/s41419-020-02944-6 |