Super Methotrexate-resistant Osteosarcoma Cells Retain Their Sensitivity to Recombinant Methioninase: Targeting Methionine Addiction to Overcome Extreme Cancer-Chemotherapy Resistance

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Abstract
Background/Aim: Drug-resistance in osteosarcoma results in a very poor clinical prognosis and has been a recalcitrant problem over many decades. We have previously reported the development of super methotrexate (MTX)-resistant osteosarcoma cells (143B-MTXSR), selected from parental 143B osteosarcoma cells (143B-P) 143B-MTXSR cells were previously selected by culturing the cells with increasing concentrations of MTX, resulting in osteosarcoma cells which are 5,500 times more MTX-resistant than the parental cells, due to extreme over-expression of dihydrofolate reductase (DHFR). In the present study, the potential therapeutic efficacy of methionine restriction, using recombinant methioninase (rMETase), was explored to overcome super MTX-resistant osteosarcoma cells. Materials and Methods: Previously-selected 143B-MTXSR cells were used for the present study. Sensitivity to methionine restriction by rMETase was determined using the WST-8 assay and compared between 143B-MTXSR and parental 143B-P cells. Results: 143B-MTXSR cells (rMETase IC50: 0.38 U/ml) were very sensitive to methionine restriction by rMETase, very similar to 143B-P (rMETase IC50: 0.36 U/ml). Conclusion: rMETase overcame a 5,500-fold MTX-resistance of osteosarcoma cells. The present results suggest methionine restriction by rMETase can be a potential clinical strategy to overcome recalcitrant drug-resistance in osteosarcoma.

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