Dehydroascorbic Acid Induces Cell Death in Sarcoma Stem Cells Under bFGF-Mediated Stemness-Supporting Conditions

The resilience of sarcomas, tumors characterized by resistance to therapy and high metastatic potential, is largely driven by the unique characteristics of a small population known as cancer stem cells (CSC). Although ascorbic acid (AA) and its oxidized form, dehydroascorbic acid (DHA), have shown potential for selectively targeting cancer cells, their effects on sarcoma CSCs remain insufficiently explored. Still, recent research indicates that AA can affect the specific characteristics of CSC and lead to their cytotoxicity. To investigate the sensitivity of sarcoma CSCs to ascorbate, CSCs were isolated from six sarcoma patient-derived samples using a sphere assay, and their stem identity was evaluated through gene expression profiling and dye-efflux assays. Cytotoxicity testing of AA and DHA showed that DHA has a selective cytotoxic effect on cancer stem cells. The presence of basic fibroblast growth factor (bFGF), which is commonly used to support the self-renewal of CSCs, had an influence on the cytotoxic effect of DHA. To evaluate the difference in the effect of AA and DHA, a seven-day treatment of CSCs with these forms of ascorbate was performed. The gene expression analysis revealed that DHA in the presence of bFGF had a stronger impact on response to oxidative stress and cellular metabolism. Also, investigation of somatic mutations of oncogenes and tumor suppressors revealed that in liposarcoma and rhabdomyosarcoma, there are mutations that induce proliferative signals. These proliferative signals, joined with bFGF in the presence of DHA, do not lead to proliferation but instead cause cell death.