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Cell-specific regulation of apoptosis by designed enediynes
K C Nicolaou1, P Stabila, B Esmaeli-Azad
1Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037.
Summary
Chemically unstable enediynes induce apoptosis in leukemia cells, while stable synthetic versions inhibit programmed cell death, suggesting a role in regulating cell death pathways.
Area of Science:
- Natural Products Chemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- Naturally occurring enediyne antibiotics are potent antitumor agents.
- Dynemicin A, a DNA-intercalating enediyne, exhibits antitumor activity via DNA cleavage.
- Mechanisms of enediyne cytotoxicity independent of DNA affinity require investigation.
Purpose of the Study:
- To synthesize and evaluate dynemicin-like enediynes lacking DNA affinity.
- To investigate the role of chemical instability and enantiomeric form in enediyne cytotoxicity.
- To explore the potential of synthetic enediynes in modulating programmed cell death.
Main Methods:
- Synthesis of dynemicin-like enediynes with and without anthraquinone moieties.
- Assessment of cytotoxicity against human leukemic cells.
- Evaluation of apoptosis induction and inhibition by synthetic enediynes.
Main Results:
- Cytotoxicity of synthesized enediynes correlated with chemical instability and enantiomeric form.
- Unstable enediynes selectively induced apoptosis in human leukemic cells.
- Stable synthetic enediynes inhibited apoptosis induced by various agents, including other enediynes.
Conclusions:
- Enediyne-induced cytotoxicity is mediated by apoptosis, particularly in leukemic cells.
- Stable synthetic enediynes act as inhibitors of programmed cell death.
- Cellular targets of synthetic enediynes may regulate apoptosis, potentially via receptor-ligand interactions.