Cell Chem Biol. 2025 Apr 08. pii: S2451-9456(25)00098-4. [Epub ahead of print]
Hélène Guillorit,
Sébastien Relier,
Benjamin Zagiel,
Audrey Di Giorgio,
Chris Planque,
Bastien Felipe,
Hélène Hérault,
Lucile Bansard,
Céline Bouclier,
Béatrice Chabi,
François Casas,
Ornella Clara,
Béatrice Bonafos,
Xavier Mialhe,
Chantal Cazevieille,
Szimonetta Hideg,
Armelle Choquet,
Amandine Bastide,
Julie Pannequin,
Maria Duca,
Françoise Macari,
Alexandre David.
Tumor initiating cells (TICs) are the roots of current shortcomings in advanced and metastatic cancer treatment. Endowed with self-renewal and multi-lineage differentiation capacity, TICs can disseminate and seed metastasis in distant organ. Our work identified streptomycin (SM), a potent bactericidal antibiotic, as a molecule capable of specifically targeting non-adherent TIC from colon and breast cancer cell lines. SM induces iron-dependent, reactive oxygen species (ROS)-mediated cell death, which is mechanistically distinct from RSL3-induced ferroptosis. SM-induced cell death is associated with profound alterations in mitochondrial morphology. This effect results from COX1 inhibition, which disrupts the regulation of the cytochrome c oxidase complex and triggers mitochondrial ROS production. SM's aldehyde group is essential, as its reduction into dihydrostreptomycin (DSM) abolishes its activity. These findings reveal a mechanism of action for streptomycin, shedding light on TIC metabolism and resistance, with potential implications for advanced cancer treatment.
Keywords: Cytochrome C oxidase; OXPHOS activity; RSL3; aminoglycoside; mitochondria; sphere-forming ability; streptomycin; tumor initiating cells