Combined Methionine Deprivation and Chloroethylnitrosourea Have Time-Dependent Therapeutic Synergy on Melanoma Tumors That NMR Spectroscopy-Based Metabolomics Explains by Methionine and Phospholipid Metabolism Reprogramming

摘要

Methionine (Met) deprivation stress (MDS) is proposed in as-nsociation with chemotherapy in the treatment of some cancers. Ansynergistic effect of this combination is generally acknowledged.nHowever, little is known on the mechanism of the response to thisntherapeutic strategy. A model of B16 melanoma tumor in vivonwas treated by MDS alone and in combination with chloroethylni-ntrosourea (CENU). It was applied recent developments in proton-nNMR spectroscopy-basedmetabolomics for providing informationnon themetabolic response of tumors toMDS and combination withnchemotherapy. MDS inhibited tumor growth during the depriva-ntion period and growth resumption thereafter. The combinationnof MDS with CENU induced an effective time-dependent synergynon growth inhibition. Metabolite profiling during MDS showedna decreased Met content (P < 0.01) despite the preservation ofnthe protein content, disorders in sulfur-containing amino acids,nglutamine/proline, and phospholipid metabolism [increase of glyc-nerophosphorylcholine (P < 0.01), decrease in phosphocholine (Pn< 0.05)]. The metabolic profile of MDS combined with CENU andnANOVA analysis revealed the implication ofMet and phospholipidnmetabolism in the observed synergy, which may be interpretednas a Met–sparing metabolic reprogramming of tumors. It followsnthat combination therapy of MDS with CENU seems to intensify adaptive processes, which may set limitations to this therapeuticnstrategy.