Mediating K+/H+ Transport on Organelle Membranes to Selectively Eradicate Cancer Stem Cells with a Small Molecule.
Fang-Fang ShenSheng-Yao DaiNai-Kei WongShan DengAlice Sze Tsai WongDan YangPublished in: Journal of the American Chemical Society (2020)
Molecules that are capable of disrupting cellular ion homeostasis offer unique opportunities to treat cancer. However, previously reported synthetic ion transporters showed limited value, as promiscuous ionic disruption caused toxicity to both healthy cells and cancer cells indiscriminately. Here we report a simple yet efficient synthetic K+ transporter that takes advantage of the endogenous subcellular pH gradient and membrane potential to site-selectively mediate K+/H+ transport on the mitochondrial and lysosomal membranes in living cells. Consequent mitochondrial and lysosomal damages enhanced cytotoxicity to chemo-resistant ovarian cancer stem cells (CSCs) via apoptosis induction and autophagy suppression with remarkable selectivity (up to 47-fold). The eradication of CSCs blunted tumor formation in mice. We believe this strategy can be exploited in the structural design and applications of next-generation synthetic cation transporters for the treatment of cancer and other diseases related to dysfunctional K+ channels.
Keyphrases
- cancer stem cells
- oxidative stress
- living cells
- small molecule
- papillary thyroid
- induced apoptosis
- cell cycle arrest
- cell death
- endoplasmic reticulum stress
- squamous cell
- fluorescent probe
- ionic liquid
- single molecule
- type diabetes
- lymph node metastasis
- photodynamic therapy
- childhood cancer
- radiation therapy
- high fat diet induced
- metabolic syndrome
- adipose tissue
- helicobacter pylori
- human health
- protein protein
- solid state
- wild type