Modulating mitochondria-mediated apoptotic cell death through targeting of Bcl-2 family proteins.
Research demonstrated that the function of mitochondria extends well beyond that of being cell powerhouses and revealed that these organelles fulfil a dual role in both cellular life and death. In most vertebrates, execution of the mitochondrial pathway of apoptosis requires permeabilization of the mitochondrial outer membrane, an event which allows for the release of a variety of intramembrane space proteins, leading to the activation of caspases and ultimately cell demise. Bcl-2 family proteins, which include pro- and antiapoptotic members, positively or negatively regulate mitochondrial outer membrane permeabilization, i.e. a barrier to apoptosis induction. Over-expression of Bcl-2 and Bcl-x(L) is associated with tumor progression and may be responsible for drug resistance, making pro-survival Bcl-2 family members important targets for the development of anticancer agents. Pharmacological apoptosis modulation by manipulation of pro-apoptotic Bcl-2 family proteins, with the goal to treat disorders associated with uncontrolled cell death or to kill unwanted cells, is likely to represent an additional research focus in the coming years. The purpose of this review is to describe, with examples taken from recent patents, novel strategies for targeting the Bcl-2 family of apoptotic regulators through peptide-based approaches and selective delivery of functional nucleic acids.
Aouacheria
Abdel
A
Apoptosis and Oncogenesis Laboratory, Institute of Biology and Chemistry of Proteins (IBCP UMR 5086) CNRS-UCBL, IFR 128 Biosciences Lyon-Gerland, 69367 Lyon Cedex 07, France. a.aouacheria@ibcp.fr
Cibiel
Agnès
A
Guillemin
Yannis
Y
Gillet
Germain
G
Lalle
Philippe
P
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010330:Patents as Topic; D010455:Peptides / Q000494:pharmacology; D010957:Plasmids; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2