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Use of Human Cancer Cell Lines Mitochondria to Explore the Mechanisms of BH3 Peptides and ABT-737-Induced Mitochondrial Membrane Permeabilization
- Source :
- PLoS ONE, Vol 5, Iss 3, p e9924 (2010), Plos One 3 (5), Article Number: e9924. (2010), PLoS ONE, PLoS ONE, Public Library of Science, 2010, 5 (3), pp.Article Number: e9924. ⟨10.1371/journal.pone.0009924⟩
- Publication Year :
- 2010
- Publisher :
- Public Library of Science (PLoS), 2010.
-
Abstract
- International audience; Current limitations of chemotherapy include toxicity on healthy tissues and multidrug resistance of malignant cells. A number of recent anti-cancer strategies aim at targeting the mitochondrial apoptotic machinery to induce tumor cell death. In this study, we set up protocols to purify functional mitochondria from various human cell lines to analyze the effect of peptidic and xenobiotic compounds described to harbour either Bcl-2 inhibition properties or toxic effects related to mitochondria. Mitochondrial inner and outer membrane permeabilization were systematically investigated in cancer cell mitochondria versus non-cancerous mitochondria. The truncated (t-) Bid protein, synthetic BH3 peptides from Bim and Bak, and the small molecule ABT-737 induced a tumor-specific and OMP-restricted mitochondrio-toxicity, while compounds like HA-14.1, YC-137, Chelerythrine, Gossypol, TW-37 or EM20-25 did not. We found that ABT-737 can induce the Bax-dependent release of apoptotic proteins (cytochrome c, Smac/Diablo and Omi/HtrA2 but not AIF) from various but not all cancer cell mitochondria. Furthermore, ABT-737 addition to isolated cancer cell mitochondria induced oligomerization of Bax and/or Bak monomers already inserted in the mitochondrial membrane. Finally immunoprecipatations indicated that ABT-737 induces Bax, Bak and Bim desequestration from Bcl-2 and Bcl-xL but not from Mcl-1L. This study investigates for the first time the mechanism of action of ABT-737 as a single agent on isolated cancer cell mitochondria. Hence, this method based on MOMP (mitochondrial outer membrane permeabilization) is an interesting screening tool, tailored for identifying Bcl-2 antagonists with selective toxicity profile against cancer cell mitochondria but devoid of toxicity against healthy mitochondria.
- Subjects :
- Non-Clinical Medicine/Research Methods
[SDV]Life Sciences [q-bio]
Mitochondrion
Mitochondrial apoptosis-induced channel
Piperazines
Membrane Potentials
Nitrophenols
Mice
0302 clinical medicine
BIOLOGIE CELLULAIRE
Inner mitochondrial membrane
Mice, Inbred BALB C
Sulfonamides
0303 health sciences
Multidisciplinary
biology
Cytochrome c
Cell Biology/Cellular Death and Stress Responses
CANCER
Mitochondria
3. Good health
Cell biology
PROTEINE BCL-2
Gene Expression Regulation, Neoplastic
Cross-Linking Reagents
Proto-Oncogene Proteins c-bcl-2
Biochemistry
mitochondrie
protéine
030220 oncology & carcinogenesis
Mitochondrial Membranes
Medicine
Female
Biotechnology/Protein Chemistry and Proteomics
Biochemistry/Drug Discovery
biological phenomena, cell phenomena, and immunity
Bacterial outer membrane
Research Article
Science
Oncology/Oncology Agents
Permeability
03 medical and health sciences
Cell Line, Tumor
Proto-Oncogene Proteins
Animals
Humans
[INFO]Computer Science [cs]
030304 developmental biology
apoptose
Biphenyl Compounds
Peptide Fragments
CYTOCHROME-C RELEASE
BCL-2 FAMILY PROTEINS
MIMETIC ABT-737
OUTER-MEMBRANE
CASPASE ACTIVATION
BAX
APOPTOSIS
DEATH
INHIBITORS
DOMAINS
membrane cellulaire
Apoptosis
Cancer cell
biology.protein
Apoptosome
humain
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....dc5f9f365e149a0096ce5dcd20040ef4