Affiliation:
1. College of Biology College of Chemistry and Chemical Engineering State Key Laboratory of Chemo/Biosensing and Chemometrics Hunan University Changsha 410082 P. R. China
2. Eye Center of Xiangya Hospital Hunan Key Laboratory of Ophthalmology Central South University Changsha 410008 P. R. China
Abstract
AbstractTransmembrane ion transport modality has received a widespread attention due to its apoptotic activation toward anticancer cell activities. In this study, G‐quadruplex‐based potassium‐specific transmembrane channels have been developed to facilitate the intracellular K+ efflux, which perturbs the cellular ion homeostasis thereby inducing cancer cell apoptosis. Cholesterol‐tag, a lipophilic anchor moiety, serves as a rudiment for the G‐quadruplex immobilization onto the membrane, while G‐quadruplex channel structure as a transport module permits ion binding and migration along the channels. A c‐Myc sequence tagged with two‐cholesterol is designed as a representative lipophilic G‐quadruplex, which forms intramolecular parallel G‐quadruplex with three stacks of G‐quartets (Ch2‐Para3). Fluorescence transport assay demonstrates Ch2‐Para3 a high transport activity (EC50 = 10.9 × 10−6 m) and an ion selectivity (K+/Na+ selectivity ratio of 84). Ch2‐Para3 mediated K+ efflux in cancer cells is revealed to purge cancer cells through K+ efflux‐mediated cell apoptosis, which is confirmed by monitoring the changes in membrane potential of mitochondria, leakage of cytochrome c, reactive oxygen species yield, as well as activation of a family of caspases. The lipophilic G‐quadruplex exhibits obvious antitumor activity in vivo without systemic toxicity. This study provides a functional scheme aimed at generating DNA‐based selective artificial membrane channels for the purpose of regulating cellular processes and inducing cell apoptosis, which shows a great promising for anticancer therapy in the future.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Hunan Province