Streptomycin targets tumor-initiating cells by disrupting oxidative phosphorylation

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Tumor-initiating cells (TICs) drive cancer metastasis and treatment resistance.
• Current therapies are limited in effectively eradicating TICs.
• Understanding TIC metabolism is crucial for developing novel treatments.

Purpose of the Study:

• To identify novel therapeutic agents targeting TICs.
• To elucidate the mechanism of action of streptomycin (SM) against TICs.
• To explore the potential of SM in advanced and metastatic cancer treatment.

Main Methods:

• Screening of compounds for TIC-targeting activity.
• Utilizing colon and breast cancer cell lines.
• Investigating cell death pathways, including ROS and ferroptosis.
• Analyzing mitochondrial morphology and function.
• Assessing the role of SM's aldehyde group.

Main Results:

• Streptomycin (SM) specifically targets non-adherent TICs from colon and breast cancer.
• SM induces iron-dependent, ROS-mediated cell death distinct from ferroptosis.
• SM causes significant mitochondrial morphology alterations via COX1 inhibition.
• The aldehyde group of SM is essential for its anti-TIC activity.

Conclusions:

• Streptomycin exhibits a novel mechanism of action against TICs.
• COX1 inhibition and subsequent mitochondrial ROS production are key to SM's efficacy.
• SM's ability to target TIC metabolism and overcome resistance holds promise for cancer therapy.