Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents.

Abstract

G-quadruplex (G4) is a promising target for anti-cancer treatment. In this paper, we provide the first evidence supporting the presence of G4 in the mitochondrial DNA (mtDNA) of live cells. The molecular engineering of a fluorescent G4 ligand, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC), can change its major cellular localization from the nucleus to the mitochondria in cancer cells, while remaining primarily in the cytoplasm of normal cells. A number of BMVC derivatives with sufficient mitochondrial uptake can induce cancer cell death without damaging normal cells. Fluorescence studies of these anti-cancer agents in live cells and in isolated mitochondria from HeLa cells have demonstrated that their major target is mtDNA. In this study, we use fluorescence lifetime imaging microscopy to verify the existence of mtDNA G4s in live cells. Bioactivity studies indicate that interactions between these anti-cancer agents and mtDNA G4 can suppress mitochondrial gene expression. This work underlines the importance of fluorescence in the monitoring of drug-target interactions in cells and illustrates the emerging development of drugs in which mtDNA G4 is the primary target.

• Authors: Wei-Chun Huang, Ting-Yuan Tseng, Ying-Ting Chen, Cheng-Chung Chang, Zi-Fu Wang, Chiung-Lin Wang, Tsu-Ning Hsu, Pei-Tzu Li, Chin-Tin Chen, Jing-Jer Lin, Pei-Jen Lou, Ta-Chau Chang
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 43 Issue 21 Pg. 10102-13 (Dec 02 2015) ISSN: 1362-4962 [Electronic] England
• PMID: 26487635 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• 3,6-bis(1-methyl-2-vinylpyridinium)carbazole
• Antineoplastic Agents
• Carbazoles
• DNA, Mitochondrial
• Fluorescent Dyes
• Pyridinium Compounds
• o-BMVC-12C-P

Topics

• Animals
• Antineoplastic Agents (chemistry, toxicity)
• Carbazoles (chemistry, toxicity)
• Cell Line
• DNA, Mitochondrial (chemistry)
• Fluorescent Dyes (chemistry)
• G-Quadruplexes
• HeLa Cells
• Humans
• Mice, Inbred BALB C
• Microscopy, Fluorescence
• Pyridinium Compounds (chemistry, toxicity)