Mediating K⁺/H⁺ Transport on Organelle Membranes to Selectively Eradicate Cancer Stem Cells with a Small Molecule

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Disrupting cellular ion homeostasis presents a therapeutic strategy for cancer treatment.
• Previous synthetic ion transporters lacked selectivity, causing indiscriminate toxicity to healthy and cancerous cells.

Purpose of the Study:

• To develop a selective synthetic potassium (K+) transporter for cancer therapy.
• To investigate the mechanism of selective ion transport and its effect on cancer stem cells (CSCs).

Main Methods:

• Utilized endogenous pH gradients and membrane potential for site-selective K+/H+ transport.
• Targeted mitochondrial and lysosomal membranes in living cells.
• Assessed cytotoxicity in chemo-resistant ovarian cancer stem cells (CSCs) and tumor formation in mice.

Main Results:

• The synthetic K+ transporter demonstrated site-selective K+/H+ transport on mitochondrial and lysosomal membranes.
• Induced mitochondrial and lysosomal damage, enhancing cytotoxicity to chemo-resistant ovarian cancer stem cells (CSCs) with up to 47-fold selectivity.
• Suppressed autophagy and induced apoptosis in CSCs.
• Eradication of CSCs led to blunted tumor formation in vivo.

Conclusions:

• The developed synthetic K+ transporter offers a selective approach to target cancer cells by exploiting cellular ion gradients.
• This strategy shows potential for developing next-generation synthetic cation transporters for cancer treatment and other diseases involving ion channel dysfunction.