Selective Protection of Normal Cells during Chemotherapy by RY4 Peptides

Abstract Mitochondrial targeted Szeto-Schiller (SS) peptides have recently gained attention for their antioxidative stress ability; however, the functional variations between normal and cancer cells have not been determined. Here, we report the results of such experiments conducted with a newly designed class of peptide called RY4, which is based on SS peptide sequence characteristics. The RY4 peptide exhibits distinct differences in antioxidative stress response between normal and cancer cells when challenged with chemotherapeutics like the glycolytic inhibitor dichloroacetate (DCA), the platinating agent carboplatin, and the DNA damage inducer doxorubicin. Interestingly, only normal human cells were protected by the RY4 peptide and catalase (CAT) activity was significantly enhanced in normal but not tumor cells when incubated with RY4. Pull-down, coimmunoprecipitation, and LC/MS-MS proteomic analysis demonstrated that RY4 and catalase are capable of forming protein complexes. Finally, in vivo efficacy was evaluated by intraperitoneal administration of RY4 into a lung cancer xenograft model, which revealed significant myocardiocyte protection from doxorubicin-induced cardiotoxicity without diminishing doxorubicin's tumoricidal effects. Taken together, RY4 offers selective protection to normal cells from chemotherapy-induced toxicity by enhancing the activity of cellular antioxidant enzymes. Implications: RY4 peptides selectively reduce chemotherapeutic-induced oxidative stress and represent a new class of chemoprotective agents with clinical potential. Mol Cancer Res; 12(10); 1365–76. ©2014 AACR.