In vivo (Athens, Greece) · 2026
Ultra-low Concentrations of Cisplatinum Down to the IC10 in Combination With Recombinant Methioninase Are Synergistically Effective Against Lung Cancer Cells In Vitro and In Vivo.
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Asano Yohei, Han Qinghong, Li Shukuan, Kang Byung Mo, Kim Jin Soo, Miyashi Yuta, Bouvet Michael, Yamamoto Norio, Hayashi Katsuhiro, Kimura Hiroaki, Miwa Shinji, Igarashi Kentaro, Higuchi Takashi, Morinaga Sei, Tsuchiya Hiroyuki, Demura Satoru, Hoffman Robert M
Аннотация
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.
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.