Ultra-low Concentrations of Cisplatinum Down to the IC 10 in Combination With Recombinant Methioninase Are Synergistically Effective Against Lung Cancer Cells In Vitro and In Vivo

Background/Aim: To determine whether methionine restriction using recombinant methioninase (rMETase) enhances the efficacy of ultra-low-dose cisplatinum against lung cancer cells in vitro, and whether combining a methionine-restricted (MR) diet with low-dose cisplatinum can inhibit lung cancer growth in vivo with reduced toxicity. Materials and Methods: Human A549 lung adenocarcinoma cells were treated with rMETase and cisplatinum in vitro. Cell viability was assessed after 72 hours using the WST-8 reagent. The IC50 value of rMETase was determined, and synergy was evaluated by combining rMETase at its IC50 with cisplatinum at its determined IC10-IC50. For in vivo analysis, A549 xenografts were established in nude mice and assigned to four groups: control: standard-dose cisplatinum 6 mg/kg, intraperitoneally (i.p.), weekly; low-dose cisplatinum (3 mg/kg, i.p., weekly) + a methionine-restricted (MR) diet; or the MR diet alone. Treatments were administered for two weeks, with tumor size and body weight were monitored. Results: For A549 lung-cancer cells the IC50 value of rMETase was 0.64 U/ml. Combination treatment with rMETase (IC50) and cisplatinum (IC10-IC50) synergistically reduced cell viability compared with either agent alone, even at the IC10 of cisplatinum. In vivo, A549 tumor eradication was observed only in the low-dose cisplatinum + MR diet group. Standard-dose cisplatinum alone and MR-alone showed delayed or limited efficacy. Body-weight loss was minimal in the low-dose cisplatinum + MR group compared with the standard-dose cisplatinum group, indicating reduced systemic toxicity. Conclusion: Methionine restriction enhances the efficacy of ultra-low-dose cisplatinum on lung cancer cells in vitro. Low-dose cisplatinum in combination with an MR diet prevented lung-cancer growth in nude mice. The present approach of cancer therapy may help reduce platinum-related toxicity and improve treatment outcomes, suggesting further investigation for clinical translation.