Bcl-2 resistant mitochondrial toxicity mediated by the isoquinoline carboxamide PK11195 involves de novo generation of reactive oxygen species

Resistance to apoptosis is a major obstacle preventing effective therapy for malignancy. Mitochondria localized anti-death proteins of the Bcl-2 family play a central role in inhibiting apoptosis and therefore present valid targets for novel therapy. The peripheral benzodiazepine receptor (PBR) shar...

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Bibliographic Details
Published in:British journal of cancer 2001-05, Vol.84 (10), p.1397-1404
Main Authors: FENNELL, D. A, CORBO, M, PALLASKA, A, COTTER, F. E
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - toxicity
Apoptosis
Benzodiazepines
Biological and medical sciences
Cancer research
Cancer therapies
Cell culture
Cell death
Cell Death - drug effects
Cytotoxicity
Dose-Response Relationship, Drug
General aspects
Genes, bcl-2
HL-60 Cells
Humans
Hydrogen Peroxide - metabolism
Intracellular Membranes - drug effects
Intracellular Membranes - physiology
Isoquinolines - toxicity
K562 Cells
Ligands
Lymphoma
Medical research
Medical sciences
Membrane Potentials - drug effects
Mitochondria - drug effects
Mitochondria - physiology
Mitochondrial DNA
Oxidative stress
Permeability
Pharmacology. Drug treatments
Physiology
PK 11195
Proteins
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Reactive Oxygen Species - physiology
Receptors, GABA-A - drug effects
Receptors, GABA-A - physiology
Regular
Toxicity
Transfection
Tumor Cells, Cultured
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Summary:Resistance to apoptosis is a major obstacle preventing effective therapy for malignancy. Mitochondria localized anti-death proteins of the Bcl-2 family play a central role in inhibiting apoptosis and therefore present valid targets for novel therapy. The peripheral benzodiazepine receptor (PBR) shares a close physical association with the permeability transition pore complex (PTPC), a pivotal regulator of cell death located at mitochondrial contact sites. In this study we investigated the cytotoxicity of the PBR ligand, PK11195, in the micromolar concentration range. PK11195 induced antioxidant inhibitable collapse of the inner mitochondrial membrane potential (DeltaPsi(m)) and mitochondrial swelling in HL60 human leukaemia cells, but not in SUDHL4 lymphoma cells (which exhibited a higher level of reduced glutathione and relative tolerance to chemotherapy or pro-oxidant induced DeltaPsi(m)dissipation). PK11195 induced the production of hydrogen peroxide that was not inhibited by Bcl-2 transfection, nor depletion of mitochondrial DNA. ROS production was however blocked by protonophore, implicating a requirement for DeltaPsi(m). Our findings suggest that PK11195-induced cytotoxicity relies upon Bcl-2 resistant generation of oxidative stress; a process only observed at concentrations several orders of magnitude higher that required to saturate its receptor.
ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1054/bjoc.2001.1788