Metformin Inhibits the Growth of Human Pancreatic Cancer... : Pancreas (original) (raw)

Original Article

Kisfalvi, Krisztina MD, PhD*; Moro, Aune MS†; Sinnett-Smith, James BSc*‡; Eibl, Guido MD†‡; Rozengurt, Enrique DVM, PhD, AGAF*‡

From the Departments of *Medicine, †Surgery, and ‡CURE: Digestive Diseases Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.

Received for publication July 12, 2012; accepted October 24, 2012.

Reprints: Enrique Rozengurt, DVM, PhD, AGAF, Division of Digestive Diseases, Department of Medicine, 900 Veteran Ave, Warren Hall Room 11-124, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1786 (e-mail: [email protected]).

This study was supported by the National Institutes of Health Grants R21CA137292, RO1DK55003, and P30DK41301 (Dr Rozengurt), P01AT003960 (Dr Eibl), P01 CA163200 (Dr Eibl), and funds from the endowed Hirshberg Chair of Pancreatic Cancer Research (Dr Rozengurt).

The authors declare no conflict of interest.

Abstract

Objective

Pancreatic ductal adenocarcinoma is a devastating disease, with an overall 5-year survival rate of only 3% to 5%. As the current therapies offer very limited survival benefits, novel therapeutic strategies are urgently required to treat this disease. Here, we determined whether metformin administration inhibits the growth of PANC-1 and MiaPaCa-2 tumor xenografts in vivo.

Methods

Different xenograft models, including orthotopic implantation, were used to determine whether intraperitoneal or oral administration of metformin inhibits the growth of pancreatic cancer in vivo.

Results

We demonstrate that metformin given once daily intraperitoneally at various doses (50-250 mg/kg) to nude mice inhibited the growth of PANC-1 xenografts in a dose-dependent manner. A significant effect of metformin was obtained at 50 mg/kg and maximal effect at 200 mg/kg. Metformin administration also caused a significant reduction in the phosphorylation of ribosomal S6 protein and ERK in these xenografts. Metformin also inhibited the growth of pancreatic cancer xenografts when administered orally (2.5 mg/mL) either before or after tumor implantation. Importantly, oral administration of metformin also inhibited the growth of MiaPaCa-2 tumors xenografted orthotopically.

Conclusions

The studies presented here provide further evidence indicating that metformin offers a potential novel approach for pancreatic ductal adenocarcinoma prevention and therapy.