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Osteosarcoma and rhabdomyosarcoma are the most common pediatric sarcomas, yet prognosis remains poor due to high relapse rates. This study investigates the repurposing of palbociclib (PB) and disulfiram (DS), alongside sodium selenite (SS), as potential therapeutic strategies. Using cell lines, we assessed antiproliferative effects via Sulforhodamine B, colony formation, and wound healing assays. Mechanisms of action were explored through protein expression of PARP-1 (apoptosis) and LC3β (autophagy), qPCR for stem cell markers, and ROS quantification. Finally, antitumor and anti-angiogenic efficacy was validated using the in ovo chicken chorioallantoic membrane (CAM) assay. Results demonstrated that all three compounds inhibited proliferation, migration, and spheroid growth while inducing apoptosis and autophagy. Notably, SS and PB elevated ROS levels, triggering parthanatos-mediated cell death via AIF nuclear translocation. SS also exhibited significant anti-angiogenic activity. Xenograft CAM models confirmed the in vivo efficacy of SS, PB, and DS against RD and MG63 cells. These findings suggest that SS, PB, and DS are promising candidates for pediatric sarcoma treatment, particularly as maintenance therapies to prevent relapse following conventional radical treatment.