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.
Methionine (Met) deprivation stress (MDS) is proposed in association with chemotherapy in the treatment of some cancers. A synergistic effect of this combination is generally acknowledged. However, little is known on the mechanism of the response to this therapeutic strategy. A model of B16 melanoma tumor in vivo was treated by MDS alone and in combination with chloroethylnitrosourea (CENU). It was applied recent developments in proton-NMR spectroscopy-based metabolomics for providing information on the metabolic response of tumors to MDS and combination with chemotherapy. MDS inhibited tumor growth during the deprivation period and growth resumption thereafter. The combination of MDS with CENU induced an effective time-dependent synergy on growth inhibition. Metabolite profiling during MDS showed a decreased Met content (P < 0.01) despite the preservation of the protein content, disorders in sulfur-containing amino acids, glutamine/proline, and phospholipid metabolism [increase of glycerophosphorylcholine (P < 0.01), decrease in phosphocholine (P < 0.05)]. The metabolic profile of MDS combined with CENU and ANOVA analysis revealed the implication of Met and phospholipid metabolism in the observed synergy, which may be interpreted as a Met-sparing metabolic reprogramming of tumors. It follows that combination therapy of MDS with CENU seems to intensify adaptive processes, which may set limitations to this therapeutic strategy.
Guénin
Samuel
S
Inserm UMR 484, Clermont-Ferrand, France.
Morvan
Daniel
D
Thivat
Emilie
E
Stepien
Georges
G
Demidem
Aicha
A
D000222:Adaptation, Physiological / Q000187:drug effects*; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D016001:Confidence Intervals; D006131:Growth Inhibitors / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000737:chemistry / Q000178:diet therapy / Q000378:metabolism / Q000628:therapy*; D055442:Metabolome / Q000187:drug effects; D008715:Methionine / Q000032:analysis / Q000172:deficiency* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009607:Nitrosourea Compounds / Q000627:therapeutic use*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009929:Organ Size / Q000187:drug effects; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000378:metabolism; D010743:Phospholipids / Q000032:analysis / Q000378:metabolism*; D011897:Random Allocation; D013312:Stress, Physiological / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D009607:Nitrosourea Compounds; D010743:Phospholipids; C051263:N'-(2-chloroethyl)-N-(2-(methylsulfonyl)ethyl)-N'-nitrosourea; D008715:Methionine; D050918:Phosphatidylethanolamine N-Methyltransferase