Elucidation of the drug resistance mechanisms of osteosarcoma cancer stem cells with PET tracers

Cells stem cells (CSCs) have been identified in several types of malignancies and referred as the responsible for driving tumor growth and resistance to chemotherapy. Previous studies have identified CSCs in a human osteosarcoma cell line that is relatively resistant to doxorubicin. We aimed to identify the mechanisms underlying this resistant phenotype and to assess the functional alterations occurring during differentiation of CSCs using PET radiotracers. CSCs were isolated using the sphere-formation assay and incubated with different concentrations of DOX during 48h, with and without verapamil. Cells´ viability was measured using the MTT-colorimetric assay. Metabolic and osteoblastic activity was assessed with [¹⁸F]FDG and [¹⁸F]NaF, respectively during differentiation of CSCs. The half-maximal inhibitory concentrations of DOX was higher in CSCs (IC₅₀=0.90±0.10μM) than in the MNNG/HOS (IC₅₀=0.61±0.05μM) and decreased to 0.29μM with verapamil. Cellular uptake of [¹⁸F]FDG was lower in CSCs and increased progressively during differentiation, whereas [¹⁸F]NaF accumulation was higher in undifferentiated CSCs.