The Combination of Methioninase and Ethionine Exploits Methionine Addiction to Selectively Eradicate Osteosarcoma Cells and Not Normal Cells and Synergistically Down-regulates the Expression of C-MYC

by Selleckchem | Jan 13 2024

Background/aim: The fundamental and general hallmark of cancer cells, methionine addiction, termed the Hoffman effect, is due to overuse of methionine for highly-increased transmethylation reactions. In the present study, we tested if the combination efficacy of recombinant methioninase (rMETase) and a methionine analogue, ethionine, could eradicate osteosarcoma cells and down-regulate the expression of c-MYC.

Materials and methods: 143B osteosarcoma cells and Hs27 normal human fibroblasts were tested. The efficacy of rMETase alone and ethionine, alone and in their combination, on cell viability was determined with the WST-8 assay on 143B cells and Hs27 cells. c-MYC expression was examined with western immunoblotting and compared in 143B cells treated with/without rMETase, ethionine, or the combination of both rMETase and ethionine.

Results: 143B cells were more sensitive to both rMETase and ethionine than Hs 27 cells, with the following IC50s: rMETase (143B: 0.22 U/ml; Hs27: 0.82 U/ml); ethionine (143B: 0.24 mg/ml; Hs27: 0.42 mg/ml). The combination of rMETase and ethionine synergistically eradicated 143B cells, lowering the IC50 for ethionine 14-fold compared to ethionine alone (p<0.001). In contrast, Hs27 fibroblasts were relatively resistant to the combination. The expression of c-MYC was significantly down-regulated only by the combination of rMETase and ethionine in 143B cells (p<0.001).

Conclusion: In the present study, we showed, for the first time, the synergistic combination efficacy of rMETase and ethionine on osteosarcoma cells in contrast to normal fibroblasts, which were relatively resistant. The combination of rMETase and ethionine down-regulated c-MYC expression in the cancer cells. The present results indicate the combination of rMETase and ethionine may reduce the malignancy of osteosarcoma cells and can be a potential future clinical strategy.

Comments:

This study seems to explore a promising strategy for combating osteosarcoma by targeting methionine addiction in cancer cells, termed the Hoffman effect. The combination of recombinant methioninase (rMETase) and the methionine analogue ethionine was investigated for its efficacy in eradicating osteosarcoma cells while minimizing impact on normal cells.

Key findings include:
- Greater sensitivity of osteosarcoma cells (143B) compared to normal human fibroblasts (Hs27) to both rMETase and ethionine.
- Synergistic eradication of 143B cells when rMETase and ethionine were combined, significantly reducing the concentration of ethionine required to kill the cancer cells.
- Relative resistance of Hs27 fibroblasts to the combination treatment.
- Down-regulation of c-MYC expression observed only in 143B cells when treated with the combination of rMETase and ethionine.

The results suggest a potential future clinical strategy involving the combination of rMETase and ethionine to reduce the malignancy of osteosarcoma cells. This approach demonstrates selectivity toward cancer cells while sparing normal cells, which is crucial for developing effective cancer therapies with minimal side effects.

Further research and clinical trials will likely be needed to validate these findings and explore the safety and efficacy of this combination treatment in a broader context, potentially paving the way for new therapeutic interventions against osteosarcoma.