Synergy of a Low-methionine Diet and Reduced-dose Cisplatinum Eradicates Experimental Lung-cancer Bone Metastases in a Nude-mouse Model

BACKGROUND/AIM: Bone metastasis of lung cancer is highly recalcitrant, and current treatment is palliative. Methionine addiction is a fundamental hallmark of cancer, known as the Hoffman effect, and is targeted by methionine restriction (MR). The present study aimed to evaluate the efficacy of MR combined with low-dose cisplatinum on an experimental nude-mouse model of bone metastasis of lung cancer. MATERIALS AND METHODS: The A549 human lung-adenocarcinoma cell line was used in the present study. An experimental bone-metastasis model was established by implanting A549 cells into the tibia of nude mice. The mice were then randomly assigned to four groups: untreated control; standard-dose cisplatinum (6 mg/kg, intraperitoneally, weekly); combination of low-dose cisplatinum (3 mg/kg, intraperitoneally, weekly) and an MR diet; and an MR diet only. Tumor growth and body weight were monitored during the 3-week treatment period. RESULTS: The combination of low-dose cisplatinum and an MR diet had the most tumor inhibition efficacy of all treatment groups, with tumors essentially being eradicated by the end of the treatment period. The combination of MR and low-dose cisplatinum showed superior efficacy compared to standard-dose cisplatinum. Furthermore, weight loss was observed only in the mice treated with standard-dose cisplatinum, whereas mice treated with the combination of low-dose cisplatinum and an MR diet maintained body weight comparable to that of the MR-alone group. CONCLUSION: MR enhanced the efficacy of low-dose cisplatinum, while mitigating treatment-associated toxicity in a lung-cancer experimental bone-metastasis model. The present findings suggest that metabolic targeting of methionine addiction is a promising therapeutic strategy enabling effective chemotherapy dose reduction in bone-metastatic lung cancer.