VDAC1-based peptides: novel pro-apoptotic agents and potential therapeutics for B-cell chronic lymphocytic leukemia

The voltage-dependent anion channel 1 (VDAC1), localized in the outer mitochondrial membrane, mediates metabolic cross-talk between the mitochondrion and the cytoplasm and thus serves a fundamental role in cell energy metabolism. VDAC1 also plays a key role in mitochondria-mediated apoptosis, intera...

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Published in:	Cell death & disease Vol. 4; no. 9; p. e809
Main Authors:	Prezma, T, Shteinfer, A, Admoni, L, Raviv, Z, Sela, I, Levi, I, Shoshan-Barmatz, V
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-09-2013 Springer Nature B.V Nature Publishing Group
Subjects:	631/67/1990/283/1895 631/80/82/23 692/700/565/1331 Adenosine Triphosphate - metabolism Aged Amino Acid Sequence Antibodies Apoptosis - drug effects Biochemistry Biomedical and Life Sciences Cell Biology Cell Culture Cell Line, Tumor Cell-Penetrating Peptides - chemistry Cell-Penetrating Peptides - pharmacology Cell-Penetrating Peptides - therapeutic use Cytochromes c - metabolism Female Hexokinase - metabolism Humans Immunology Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy Leukemia, Lymphocytic, Chronic, B-Cell - pathology Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - pathology Life Sciences Male Membrane Potential, Mitochondrial - drug effects Mitochondria - drug effects Mitochondria - metabolism Mitochondria - ultrastructure Models, Biological Molecular Sequence Data Original original-article Protein Binding - drug effects Protein Multimerization - drug effects Voltage-Dependent Anion Channel 1 - chemistry apoptosis peptides CLL metabolism VDAC1 mitochondria
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Summary:	The voltage-dependent anion channel 1 (VDAC1), localized in the outer mitochondrial membrane, mediates metabolic cross-talk between the mitochondrion and the cytoplasm and thus serves a fundamental role in cell energy metabolism. VDAC1 also plays a key role in mitochondria-mediated apoptosis, interacting with anti-apoptotic proteins. Resistance of cancer cells to apoptosis involves quenching the mitochondrial apoptotic pathway by over-expression of anti-apoptotic/pro-survival hexokinase (HK) and Bcl-2 family proteins, proteins that mediate their anti-apoptotic activities via interaction with VDAC1. Using specifically designed VDAC1-based cell-penetrating peptides, we targeted these anti-apoptotic proteins to prevent their pro-survival/anti-apoptotic activities. Anti-apoptotic proteins are expressed at high levels in B-cell chronic lymphocytic leukemia (CLL), an incurable disease requiring innovative new approaches to improve therapeutic outcome. CLL is characterized by a clonal accumulation of mature neoplastic B cells that are resistant to apoptosis. Specifically, we demonstrate that the VDAC1-based peptides (Antp-LP4 and N-Terminal-Antp) selectively kill peripheral blood mononuclear cells (PBMCs) obtained from CLL patients, yet spare those obtained from healthy donors. The cell death induction competence of the peptides was well correlated with the amount of double positive CD19/CD5 cancerous CLL PBMCs, further illustrating their selectivity toward cancer cells. Moreover, these VDAC1-based peptides induced apoptosis by activating the mitochondria-mediated pathway, reflected in membrane blebbing, condensation of nuclei, DNA fragmentation, release of mitochondrial cytochrome c , loss of mitochondrial membrane potential, decreased cellular ATP levels and detachment of HK, all leading to apoptotic cell death. Thus, the mode of action of the peptides involves decreasing energy production and inducing apoptosis. Over 27 versions of cell-penetrating VDAC1-based peptides were designed and screened to identify the most stable, short and apoptosis-inducing peptides toward CLL-derived lymphocytes. In this manner, three optimized peptides suitable for in vivo studies were identified. This study thus reveals the potential of VDAC1-based peptides as an innovative and effective anti-CLL therapy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	2041-4889 2041-4889
DOI:	10.1038/cddis.2013.316