Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents
Journal
Nucleic Acids Research
Journal Volume
43
Journal Issue
21
Pages
10102-10113
Date Issued
2015
Author(s)
Huang W.-C.
Tseng T.-Y.
Chen Y.-T.
Chang C.-C.
Wang Z.-F.
Wang C.-L.
Hsu T.-N.
Li P.-T.
Chang T.-C.
Abstract
G-quadruplex (G4) is a promising target for anticancer 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. ? The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
SDGs
Other Subjects
3,6 bis(1 methyl 2 vinylpyridinium)carbazole diiodide; 3,6 bis(1 methyl 4 vinylpyridinium iodide) 9 [1 (1 methyl piperidinium iodide)dodecyl]carbazole; 3,6 bis(1 methyl 4 vinylpyridinium)carbazole diiodide; antineoplastic agent; guanine quadruplex; mitochondrial DNA; unclassified drug; 3,6-bis(1-methyl-2-vinylpyridinium)carbazole; antineoplastic agent; carbazole derivative; fluorescent dye; guanine quadruplex; mitochondrial DNA; o-BMVC-12C-P; pyridinium derivative; animal experiment; animal model; antineoplastic activity; Article; cancer cell; cell death; cell nucleus; controlled study; cytoplasm; DNA determination; drug DNA interaction; drug structure; fluorescence; gene expression; HeLa cell line; lung cancer; mitochondrial gene; mitochondrion; mouse; nonhuman; priority journal; tumor xenograft; animal; Bagg albino mouse; cell line; chemistry; fluorescence microscopy; human; Animals; Antineoplastic Agents; Carbazoles; Cell Line; DNA, Mitochondrial; Fluorescent Dyes; G-Quadruplexes; HeLa Cells; Humans; Mice, Inbred BALB C; Microscopy, Fluorescence; Pyridinium Compounds
Publisher
Oxford University Press
Type
journal article