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Phosphorothioate oligonucleotides reduce mitochondrial outer membrane permeability to ADP
Wenzhi Tan1, Johnathan C Lai, Paul Miller
1Department of Biology, University of Maryland, College Park, MD 20742, USA.
American Journal of Physiology. Cell Physiology
|December 1, 2006
Summary
G3139, a novel antisense agent, triggers cancer cell death by blocking mitochondrial outer membrane permeability. This action, mediated by voltage-dependent anion-selective channels (VDAC), occurs early in apoptosis and is independent of Bcl-2.
Area of Science:
- Mitochondrial biology
- Cancer cell death pathways
- Oligonucleotide therapeutics
Background:
- Antisense phosphorothioate oligodeoxynucleotides like G3139 induce apoptosis in cancer cells.
- The mechanism appears independent of Bcl-2 downregulation.
- G3139's interaction with mitochondrial voltage-dependent anion-selective channels (VDAC) is hypothesized.
Purpose of the Study:
- To investigate the mechanism of G3139-induced apoptosis.
- To determine if G3139 interacts with VDAC to alter mitochondrial function.
- To establish the role of VDAC in G3139's apoptotic effects.
Main Methods:
- Assessing G3139's effect on mitochondrial outer membrane permeability to ADP.
- Measuring inhibition constants (K(i)) for G3139's interaction with VDAC.
- Evaluating the impact of G3139 on other mitochondrial respiration components.
- Comparing G3139's effects with other phosphorothioate oligonucleotides.
Main Results:
- G3139 significantly reduces mitochondrial outer membrane permeability to ADP (K(i) 0.2-0.5 microM).
- This effect is attributed to VDAC closure, strengthening the initial hypothesis.
- Mitochondrial respiration is unaffected at low G3139 concentrations but inhibited at higher levels.
- Phosphorothioate oligonucleotides, particularly those with specific lengths and linkages, induce VDAC closure.
Conclusions:
- G3139 acts early in the apoptotic cascade by modulating VDAC function and reducing mitochondrial outer membrane permeability.
- VDAC closure by G3139 is a key mechanism preceding cytochrome c release.
- Phosphorothioate oligonucleotides are identified as specific tools for restricting mitochondrial outer membrane permeability.
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