Cell-specific regulation of apoptosis by designed enediynes.

AUTOR(ES)

Nicolaou, K C

RESUMO

The naturally occurring enediyne antibiotics are a unique class of antitumor drugs that combine reactive enediynes with additional structural features conferring affinity for DNA. Dynemicin A, in which an enediyne core is attached to an anthraquinone group capable of DNA intercalation, readily cleaves double-stranded DNA. This activity is thought to be the basis of its potent antitumor cytotoxicity. To investigate cell-specific mechanisms of cytotoxicity in the absence of DNA affinity, we have synthesized a variety of dynemicin-like enediynes that lack the anthraquinone moiety. We have found that the cytotoxicity of these compounds is dependent on their chemical instability and their enantiomeric form. Their selective toxicity results from a potent induction of apoptosis primarily in human leukemic cells. A group of synthetic enediynes were designed to be highly stable. These compounds were found to inhibit apoptotic cell death. This inhibition was observed in competition with the chemically unstable enediynes, including dynemicin and calicheamicin. The stable synthetic enediynes could also block the apoptotic morphology induced by unrelated cytotoxic agents such as cycloheximide, actinomycin D, and ultraviolet radiation. The results suggest that the cellular target(s) of synthetic enediynes may play a central role in regulating programmed cell death; a specific receptor-ligand interaction is proposed.

Documentos Relacionados

• Chemistry and biology of natural and designed enediynes.
• Regulation of differentiated cell-specific functions.
• Cell-Specific Proteins Synthesized by Salmonella typhimurium
• Glial Cell-Specific Regulation of the JC Virus Early Promoter by Histone Deacetylase Inhibitors
• Glial Cell-Specific Regulation of the JC Virus Early Promoter by Large T Antigen