Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents.
Bottom Line: In this paper, we provide the first evidence supporting the presence of G4 in the mitochondrial DNA (mtDNA) of live cells.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.
Affiliation: Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei 10617, Taiwan.Show MeSH
Related in: MedlinePlus
Mentions: Developing G4 ligand for the targeting of mtDNA requires that the G4 ligand be able to reach the cell mitochondria. The carbazole derivative 3,6-bis(1-methyl-4-vinylpyridinium iodide)-9-(1-(1-methyl-piperidinium iodide)dodecyl) carbazole (BMVC-12C-P) is a fluorescent anticancer agent. Fluorescent images have previously illustrated the accumulation of BMVC-12C-P primarily in the mitochondria of cancer cells. Furthermore, as little as 0.5 μM BMVC-12C-P can induce mitochondrial dysfunction resulting in cancer cell death with no risk of harming normal cells. However, another fluorescent G4 ligand, 3,6-bis(1-methyl-2-vinylpyridinium) carbazole diiodide (o-BMVC), which also accumulates in mitochondria (23), presents no appreciable cytotoxic effects on cancer cells. Nonetheless, the large contrast in decay times of o-BMVC fluorescence between the interaction with G4s and calf thymus DNA may be applied to the visualization of G4s located in cells (23). To examine the difference in cytotoxicity between BMVC-12C-P and o-BMVC, we synthesized a number of o-BMVC derivatives, including -4C-P, -6C-P, -8C-P, -9C-P and -12C-P. The chemical structures of BMVC-12C-P, o-BMVC and o-BMVC derivatives are presented in Scheme 1. The synthesis of these molecules is described in the Supplementary material.
Affiliation: Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei 10617, Taiwan.