Tumor Suppression by Targeting Senescent Cells with a Selective Singlet Oxygen Releasing Endoperoxide

Abstract Targeting senescent cells for cancer treatment is an important recent direction. In this work, we designed and synthesized a galactoside‐functionalized pyridone endoperoxide. The endoperoxide in this form, releases singlet oxygen at a relatively slow rate, but when transformed by β‐galactosidase activity, the pyridone endoperoxide releases singlet oxygen with a half‐life of 30 minutes at 37 °C. We also studied this compound with a variety of cell lines with differential β‐galactosidase expression levels. Cytotoxicity of the target compound is enhanced in high galactosidase‐expressing SKOV‐3 cells. In vivo tests with tumor models also showed significant suppression of tumor progression. Targeting singlet oxygen to senescent cells appears to be promising new approach for treating diseases concurrent with aging, including cancer.