PMID- 24052077
OWN - NLM
STAT- MEDLINE
DCOM- 20140312
LR  - 20211021
IS  - 2041-4889 (Electronic)
VI  - 4
IP  - 9
DP  - 2013 Sep 19
TI  - VDAC1-based peptides: novel pro-apoptotic agents and potential therapeutics for 
      B-cell chronic lymphocytic leukemia.
PG  - e809
LID - 10.1038/cddis.2013.316 [doi]
AB  - 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.
FAU - Prezma, T
AU  - Prezma T
AD  - Department of Life Sciences and the National Institute for Biotechnology in the 
      Negev, BeerSheva, Israel.
FAU - Shteinfer, A
AU  - Shteinfer A
FAU - Admoni, L
AU  - Admoni L
FAU - Raviv, Z
AU  - Raviv Z
FAU - Sela, I
AU  - Sela I
FAU - Levi, I
AU  - Levi I
FAU - Shoshan-Barmatz, V
AU  - Shoshan-Barmatz V
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130919
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Cell-Penetrating Peptides)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 1.6.- (Voltage-Dependent Anion Channel 1)
RN  - EC 2.7.1.1 (Hexokinase)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Aged
MH  - Amino Acid Sequence
MH  - Apoptosis/*drug effects
MH  - Cell Line, Tumor
MH  - Cell-Penetrating Peptides/chemistry/*pharmacology/*therapeutic use
MH  - Cytochromes c/metabolism
MH  - Female
MH  - Hexokinase/metabolism
MH  - Humans
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy/*pathology
MH  - Leukocytes, Mononuclear/drug effects/pathology
MH  - Male
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mitochondria/drug effects/metabolism/ultrastructure
MH  - Models, Biological
MH  - Molecular Sequence Data
MH  - Protein Binding/drug effects
MH  - Protein Multimerization/drug effects
MH  - Voltage-Dependent Anion Channel 1/*chemistry
PMC - PMC3789174
EDAT- 2013/09/21 06:00
MHDA- 2014/03/13 06:00
PMCR- 2013/09/01
CRDT- 2013/09/21 06:00
PHST- 2013/04/30 00:00 [received]
PHST- 2013/07/15 00:00 [revised]
PHST- 2013/07/19 00:00 [accepted]
PHST- 2013/09/21 06:00 [entrez]
PHST- 2013/09/21 06:00 [pubmed]
PHST- 2014/03/13 06:00 [medline]
PHST- 2013/09/01 00:00 [pmc-release]
AID - cddis2013316 [pii]
AID - 10.1038/cddis.2013.316 [doi]
PST - epublish
SO  - Cell Death Dis. 2013 Sep 19;4(9):e809. doi: 10.1038/cddis.2013.316.