Metformin reduces the Walker-256 tumor development in obese-MSG rats via AMPK and FOXO3a

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 deve...

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Published in:	Life sciences (1973) Vol. 121; pp. 78 - 87
Main Authors:	de Queiroz, Eveline A.I.F., Akamine, Eliana H., de Carvalho, Maria Helena C., Sampaio, Sandra C., Fortes, Zuleica B.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Inc 15-01-2015
Subjects:	AMPK Animals Apoptosis Breast cancer Carcinoma 256, Walker - drug therapy Carcinoma 256, Walker - pathology Cyclic AMP-Dependent Protein Kinases - metabolism Female Food Additives Forkhead Box Protein O3 Forkhead Transcription Factors - metabolism FOXO3a Hypoglycemic Agents - therapeutic use Male Mammary Neoplasms, Experimental - drug therapy Mammary Neoplasms, Experimental - metabolism Mammary Neoplasms, Experimental - pathology Metformin Metformin - therapeutic use Obesity - chemically induced Obesity - complications Obesity - pathology Rats Rats, Wistar Signal Transduction - drug effects Sodium Glutamate AMPK Breast cancer Metformin FOXO3a Apoptosis
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Summary:	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. Newborn male Wistar rats were subcutaneously injected with 400mg/kg monosodium glutamate (MSG) (obese) or saline (control) at 2, 3, 4, 5 and 6days of age. After 16weeks, 1×107 Walker-256 tumor cells were subcutaneously injected in the right flank of the rats and concomitantly the treatment with metformin 300mg/kg/15days, 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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0024-3205 1879-0631
DOI:	10.1016/j.lfs.2014.11.028