期刊
MOLECULAR PHARMACOLOGY
卷 83, 期 2, 页码 470-480出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.112.081075
关键词
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资金
- Cancer Research UK Program [C129/A4489]
- Philipp Brown Trust
- Deutsche Krebshilfe-Tumorstammzellverbund
- BMBF (Bundesministerium fur Forschung und Technik) UV-A Konsortium
- National Institutes of Health National Cancer Institute [HHSN261200800001E]
G-quadruplexes are higher-order nucleic acid structures that can form in G-rich telomeres and promoter regions of oncogenes. Telomeric quadruplex stabilization by small molecules can lead to telomere uncapping, followed by DNA damage response and senescence, as well as chromosomal fusions leading to deregulation of mitosis, followed by apoptosis and downregulation of oncogene expression. We report here on investigations into the mechanism of action of tetra-substituted naphthalene diimide ligands on the basis of cell biologic data together with a National Cancer Institute COMPARE study. We conclude that four principal mechanisms of action are implicated for these compounds: 1) telomere uncapping with subsequent DNA damage response and senescence; 2) inhibition of transcription/translation of oncogenes; 3) genomic instability through telomeric DNA end fusions, resulting in mitotic catastrophe and apoptosis; and 4) induction of chromosomal instability by telomere aggregate formation.
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