Abstract 107P
Background
Methionine (MET) addiction is a fundamental and general hallmark of cancer cells, including osteosarcoma cells, which is termed the Hoffman effect, due to overuse of exogenous MET for highly increased transmethylation reactions. The beta catenin/cyclin-D1 pathway is associated with tumor progression, including osteosarcoma. In the present study, we targeted MET addiction with the combination of methioninase (rMETase), and the MET analogue, ethionine (ETH), to eradicate osteosarcoma cells and down regulate beta catenin/cyclin-D1 pathway.
Methods
The efficacy of rMETase, ETH, or the combination of both rMETase and ETH on cell viability was compared with the WST-8 assay in 143B osteosarcoma cells and Hs27 normal human foreskin fibroblasts. The expression of beta catenin and cyclin-D1 was determined with Western immunoblotting and compared in 143B cells treated with/without rMETase, ETH, or the combination of both rMETase and ETH.
Results
143B cells were more sensitive toboth rMETase and ETH than Hs 27 cells, with the following IC50: rMETase (143B: 0.2 U/ml, Hs27: 1.17 U/ml); ETH (143B: 0.29 mg/ml, Hs27: 0.82 mg/ml). 143B cells were synergistically eradicated by the combination of rMETase and ETH (p<0.001). In contrast, Hs27 fibroblasts were relatively resistant to the combination. The expression of both beta catenin and cyclin-D1 was significantly down-regulated by the combination of rMETase and ETH in 143B cells (p<0.001, p=0.04, respectively).
Conclusions
In the present study, the synergistic combination efficacy of rMETase and ETH on osteosarcoma cells was shown, in contrast to normal fibroblasts, which were relatively resistant. The combination of rMETase and ETH down regulated the expression of both beta catenin and cyclin-D1 in osteosarcoma cells, which may be epigenetically dysregulated via suppression of transmethylation reactions by the combination therapy. The present results indicate the combination of rMETase and ETH can be a potential future clinical strategy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.