Mechanism of DNA Intercalation by Chloroquine Provides Insights into Toxicity.
Joha JoshiMicah J McCauleyMichael MorseMichael R MuccioJoseph G KanlongMárcio S RochaIoulia RouzinaKarin Musier-ForsythMark C WilliamsPublished in: International journal of molecular sciences (2024)
Chloroquine has been used as a potent antimalarial, anticancer drug, and prophylactic. While chloroquine is known to interact with DNA, the details of DNA-ligand interactions have remained unclear. Here we characterize chloroquine-double-stranded DNA binding with four complementary approaches, including optical tweezers, atomic force microscopy, duplex DNA melting measurements, and isothermal titration calorimetry. We show that chloroquine intercalates into double stranded DNA (dsDNA) with a K D ~ 200 µM, and this binding is entropically driven. We propose that chloroquine-induced dsDNA intercalation, which happens in the same concentration range as its observed toxic effects on cells, is responsible for the drug's cytotoxicity.
Keyphrases
- circulating tumor
- single molecule
- plasmodium falciparum
- cell free
- nucleic acid
- dna binding
- atomic force microscopy
- high resolution
- high speed
- binding protein
- induced apoptosis
- emergency department
- oxidative stress
- drug induced
- endothelial cells
- cell death
- endoplasmic reticulum stress
- signaling pathway
- cell cycle arrest
- electronic health record