Lack of Cancer Specificity of Methionine Adenosyltransferase 2A (MAT2A) Inhibitor AG-270 in Combination With Recombinant Methioninase In Vitro

Background/aim: Methionine addiction is a fundamental and general hallmark of Cancer termed the Hoffman effect. Methionine restriction using recombinant methioninase (rMETase) has shown synergistic efficacy with numerous types of chemotherapeutic agents against Cancer cells and not normal cells. Methionine adenosyltransferase 2A (MAT2A) is a crucial enzyme converting methionine to S-adenosylmethionine (SAM). A MAT2A inhibitor, AG-270, has been proposed as a potential anti-cancer drug. The present study evaluated whether AG-270 is a cancer-specific agent by comparing its efficacy in combination with rMETase on Cancer and normal cells.

Materials and methods: The half-maximal inhibitory concentrations (IC₅₀) of rMETase and AG-270 were determined on HCT116 human colon-cancer cells and Hs-27 human normal fibroblasts in vitro. The efficacy of rMETase combined with AG-270, at their respective IC₅₀ values, on HCT116 and Hs-27 was also determined. Cell viability was evaluated using the WST-8 reagent.

Results: The IC₅₀ values of rMETase were 0.35 U/ml for HCT116 and 1.14 U/ml for Hs-27. The IC₅₀ values of AG-270 were 4.38 μM for HCT116 and 6.55 μM for Hs-27. The combination of rMETase and AG-270, at their respective IC₅₀, had synergistic efficacy on both Cancer and normal cells, reducing viability to approximately 20% in both cell lines (p<0.05).

Conclusion: AG-270 showed lack of Cancer specificity in combination with rMETase when tested on both Cancer and normal cells. The present results contrast with numerous chemotherapy agents, which in combination with rMETase are synergistic on Cancer cells but not on normal cells. The present findings suggest that MAT2A inhibition affects crucial metabolic pathways in normal as well as Cancer cell types and thus AG-270 may not be suitable as a cancer-specific therapeutic strategy.

AG-270; HCT116 colon cancer cells; Hoffman effect; Hs-27 normal fibroblasts; MAT2A; combination; methionine addiction; recombinant methioninase; synergy.