title: Metformin reduces the Walker-256 tumor development in obese-MSG rats via AMPK and FOXO3a.
abstract: OBJECTIVE
  Studies have associated obesity with a wide variety of cancers. Metformin, an anti-diabetic drug, has recently received attention as a potentially useful therapeutic agent for treating cancer. Therefore, the objective of this study was to analyze the mechanisms involved in the increase in tumor development and the reduction of it by metformin in obesity using an experimental breast tumor model.
  
  
  METHODS
  Newborn male Wistar rats were subcutaneously injected with 400mg/kg monosodium glutamate (MSG) (obese) or saline (control) at 2, 3, 4, 5 and 6 days of age. After 16 weeks, 1 × 10(7) Walker-256 tumor cells were subcutaneously injected in the right flank of the rats and concomitantly the treatment with metformin 300 mg/kg/15 days, via gavage, started. The rats were divided into 4 groups: control tumor (CT), control tumor metformin (CTM), obese-MSG tumor (OT) and obese-MSG tumor metformin (OTM). On the 18th week the tumor development and metformin effect were analyzed.
  
  
  RESULTS
  Tumor development was higher in OT rats compared with CT rats. Activation of insulin-IR-ERK1/2 pathway and an anti-apoptotic effect might be the mechanisms involved in the higher development of tumor in obesity. The effect of metformin reducing the tumor development in obese rats might involve increased mRNA expression of pRb and p27, increased activity of AMPK and FOXO3a and decreased expression of p-ERK1/2 (Thr202/Tyr204) in Walker-256 tumor.
  
  
  CONCLUSIONS
  Our data allow us to suggest that metformin, reducing the stimulatory effect of obesity on tumor development, has a potential role in the management of cancers.
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Physiological Sciences, State University of Londrina, Londrina, Brazil. Electronic address: evefarma@yahoo.com.br.
authors.forename: Eveline A I F
authors.initials: EA
authors.lastname: de Queiroz
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Eliana H
authors.initials: EH
authors.lastname: Akamine
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Maria Helena C
authors.initials: MH
authors.lastname: de Carvalho
authors.affiliation: Laboratory of Pathophysiology, Butantan Institute, São Paulo, Brazil.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Sampaio
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: zbfortes@icb.usp.br.
authors.forename: Zuleica B
authors.initials: ZB
authors.lastname: Fortes
mesh_terms: D000818:Animals; D002279:Carcinoma 256, Walker / Q000188:drug therapy* / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D005503:Food Additives; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000627:therapeutic use*; D009765:Obesity / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D012970:Sodium Glutamate
chemical_list: C499515:FOXO3 protein, rat; D005503:Food Additives; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D008687:Metformin; D017868:Cyclic AMP-Dependent Protein Kinases; D012970:Sodium Glutamate
keywords: AMPK; Apoptosis; Breast cancer; FOXO3a; Metformin