Folate supplementation limits the tumourigenesis in rodent models of gliomagenesis.
A hallmark of cancer is the paradoxical co-presence, in the same tumour, of local and global DNA hypomethylation together with the regional hypermethylation of certain genes. Due to the oncogenic role of these different DNA methylation alterations, two therapeutic strategies are possible: the use of DNA methylating agents (DMA, such as folate) to inhibit global or local DNA hypomethylation or the use of DNA hypomethylating agents (DHA, such as 5-aza-2-deoxycytidine) to abrogate the accumulation of hypermethylated genes. Here we explored the use of folate to treat gliomas in a mouse model, using tumours induced by either PDGF-B or Ras/Akt overexpression, or by ethylnitrosourea (ENU) treatment. Under all conditions the volume of tumours were significantly less in folate treated mice than in untreated mice. Quantitative methylated DNA immunoprecipitation (qMeDIP) and quantitative methylated specific PCR (qMSP) analysis of methylation status showed that folate treatment, increased the methylation level of DNA repeat elements in tumour and in colorectal tissue and that of MGMT and specific oncogenes (PDGF-B or survivin) in tumours (but not in colorectal tissue), but had no effect on the expression of tumour suppressor genes (p53, PTENorbax) in tumours or in colorectal tissue. This suggests that folate has anti-neoplastic effects in gliomas and that no preneoplastic or neoplastic alterations were observed in unaffected colorectal tissue in response to the potential tumourigenic effects of folate. Collectively, our data support the proposal to include folate as a promising adjuvant in the design of anti-glioma therapeutic protocols in clinical studies.
Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Apoptose et Progression tumorale, Equipe labellisée Ligue Nationale Contre le Cancer, 8 quai moncousu, BP7021, 44007 Nantes, France. pierre-francois.cartron@univ-nantes.fr
Pierre-François
PF
Cartron
Eric
E
Hervouet
Emilie
E
Debien
Christophe
C
Olivier
Daniel
D
Pouliquen
Jean
J
Menanteau
Delphine
D
Loussouarn
Stephane A
SA
Martin
Mario
M
Campone
François M
FM
Vallette
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005492:Folic Acid / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D051379:Mice; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D005492:Folic Acid