Prevention of pancreatic cancer induction in hamsters by metformin

Schneider, Matthias; Matsuzaki, Hiromitsu; Haorah, James; Ulrich, Alexis; Standop, Jens; Ding, Xianzhong; Adrian, Thomas E.; Pour, Parviz M.

doi:10.1053/gast.2001.23258

Cited by 296 publications

(219 citation statements)

References 38 publications

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“…Recent data suggest that metformin could protect from cancer (Schneider et al, 2001;Evans et al, 2005) and inhibit breast and glial cancer cell proliferation in vitro (Zakikhani et al, 2006). Here we show that metformin not only is a very potent inhibitor of human prostate cancer cell growth, but also inhibits tumorigenesis in a xenograft model when it is administrated orally or i.p.…”

Section: Discussionmentioning

confidence: 48%

“…This result is of particular importance since it is the first time that metformin is shown to inhibit prostate tumor growth in a xenograft model. Schneider et al (2001) showed that metformin reduced the number of pancreatic malignant lesions in hamsters treated with metformin. However, the concentration administrated to the animal is 120 times higher than the concentration used in our study (Schneider et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Schneider et al (2001) showed that metformin reduced the number of pancreatic malignant lesions in hamsters treated with metformin. However, the concentration administrated to the animal is 120 times higher than the concentration used in our study (Schneider et al, 2001). Here, with the dosage used for patients, we obtained a strong inhibition of tumor growth.…”

Section: Discussionmentioning

confidence: 99%

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The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

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Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G 0 /G 1 . This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27 kip protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

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“…Notably, retrospective studies of diabetics taking metformin have suggested a significant decrease in cancer risk compared to diabetics receiving insulin therapy (Evans et al, 2005). Metformin administration also prevented pancreatic tumor development in a hamster model (Schneider et al, 2001). It will be of interest to determine whether this protective effect of Lkb1-AMPK signaling involves systemic metabolic effects, metabolic effects in evolving tumor cells, maintenance of cell polarity, or a combination of these processes.…”

Section: Mechanisms Of Neoplastic Suppressionmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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“…Unfortunately, there are few established risk factors, the exception being cigarette smoking (IARC, 1986). Experiments using a hamster model have suggested that insulin and insulin resistance may play a role in the aetiology of pancreatic cancer (Schneider et al, 2001). This is supported by human studies, with a meta-analysis of 20 studies concluding that diabetes mellitus is associated with increased risk (Everhart and Wright, 1995).…”

mentioning

confidence: 99%

Physical activity, body weight, and pancreatic cancer mortality

et al. 2003

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In a study of 32 687 subjects with data on physical activity and body mass index (BMI) collected serially over time, we examined associations with pancreatic cancer mortality (n ¼ 212). Despite plausible biologic mechanisms, neither physical activity (multivariate relative risks for increasing levels: 1.00, 0.98, 0.92, and 1.31, respectively) nor BMI (corresponding findings: 1.00, 0.84, 1.08, and 0.99, respectively) significantly predicted pancreatic cancer mortality.

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Prevention of pancreatic cancer induction in hamsters by metformin

Cited by 296 publications

References 38 publications

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

LKB1; linking cell structure and tumor suppression

Physical activity, body weight, and pancreatic cancer mortality

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