Metformin suppresses intestinal polyp growth in <i>Apc</i><sup>Min/+</sup> mice

Tomimoto, Ayako; Endo, Hideki; Sugiyama, Michiko; Fujisawa, Toshio; Hosono, Kunihiro; Takahashi, Hirokazu; Nakajima, N.; Nagashima, Yoji; Wada, Koichiro; Nakagama, Hitoshi; Nakajima, Atsushi

doi:10.1111/j.1349-7006.2008.00933.x

Cited by 178 publications

(145 citation statements)

References 24 publications

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“…We showed that metformin suppressed the development of intestinal polyps in adenomatous polyposis coli (APC Min/+ ) mice, a murine model of familial adenomatous polyposis (16). Furthermore, we showed that metformin suppressed the azoxymethaneinduced formation of colorectal aberrant crypt foci (ACF) by activating AMPK (17).…”

Section: Introductionmentioning

confidence: 85%

Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial

Hosono

Endo

Takahashi

et al. 2010

Cancer Prevention Research

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The biguanide metformin is widely used for treating diabetes mellitus. We previously showed the chemopreventive effect of metformin in two rodent models of colorectal carcinogenesis. However, besides epidemiologic studies, little is known about the effects of metformin on human colorectal carcinogenesis. The objective of this pilot study was to evaluate the chemopreventive effect of metformin on rectal aberrant crypt foci (ACF), which are an endoscopic surrogate marker of colorectal cancer. We prospectively randomized 26 nondiabetic patients with ACF to treatment with metformin (250 mg/d, n = 12) or no treatment (control, n = 14); 23 patients were evaluable for end point analyses (9 metformin and 14 control); the two groups were similar in ACF number and other baseline clinical characteristics. Magnifying colonoscopy determined the number of rectal ACF in each patient at baseline and after 1 month in a blinded fashion (as were all laboratory end point analyses). We also examined proliferative activity in colonic epithelium (via proliferating cell nuclear antigen labeling index) and apoptotic activity (via terminal deoxynucleotidyl transferase dUTP nick-end labeling). At 1 month, the metformin group had a significant decrease in the mean number of ACF per patient (8.78 ± 6.45 before treatment versus 5.11 ± 4.99 at 1 month, P = 0.007), whereas the mean ACF number did not change significantly in the control group (7.23 ± 6.65 versus 7.56 ± 6.75, P = 0.609). The proliferating cell nuclear antigen index was significantly decreased and the apoptotic cell index remained unaltered in normal rectal epithelium in metformin patients. This first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer. Cancer Prev Res; 3(9);

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Section: Introductionmentioning

confidence: 85%

Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial

Hosono

Endo

Takahashi

et al. 2010

Cancer Prevention Research

Self Cite

286

207

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“…Another example of metformin action on the development of in situ tumors was observed in the Apc (Min/+) mice models. Administration of metformin at 250 mg/kg in the diet significantly reduced the number of large polyps (41). Finally, we and others showed that metformin efficiently inhibits tumor growth in prostate, colon, or lung cancer cell xenografts (25,31,42).…”

Section: Preclinical Studies and Antitumor Growth Action Of Metforminmentioning

confidence: 95%

Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug?

Sahra

Marchand-Brustel

Tanti

et al. 2010

Molecular Cancer Therapeutics

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Metformin is the most widely used antidiabetic drug in the world, and there is increasing evidence of a potential efficacy of this agent as an anticancer drug. First, epidemiological studies show a decrease in cancer incidence in metformin-treated patients. Second, metformin decreases insulin resistance and indirectly reduces insulin level, a beneficial effect because insulin promotes cancer cell growth. Third, several reports outline a direct inhibitory effect of metformin on cancer cell growth and an antitumoral action. Finally, metformin activates the AMP activated protein kinase (AMPK) pathway, a major sensor of the energetic status of the cell, which has been proposed as a promising therapeutic target in cancer. Mol Cancer Ther; 9(5);

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“…For example, it has been shown that metformin suppresses polyp formation in ApcMin/ þ mice (Tomimoto et al, 2008), inhibits in vivo growth of p53 null cancers (Buzzai et al, 2007), attenuates tumorigenesis in phosphatase and tensin homolog-deficient mice (Huang et al, 2008) and slows proliferation of triple-negative breast cancer cells (Liu et al, 2009); however, these studies did not investigate the anti-neoplastic effects of metformin in the context of variation of dietary energy intake or insulin levels. This issue is critical as all epidemiological evidence for an anti-neoplastic action of metformin is derived from type II diabetic patients and metformin has important endocrine effects at the whole organism level in the setting of type II diabetes, apart from any direct effects on neoplastic cells.…”

Section: Introductionmentioning

confidence: 99%

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

et al. 2010

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Hypothesis-generating epidemiological research has suggested that cancer burden is reduced in diabetics treated with metformin and experimental work has raised questions regarding the role of direct adenosine monophosphate-activated protein kinase (AMPK)-mediated antineoplastic effects of metformin as compared with indirect effects attributable to reductions in circulating insulin levels in the host. We treated both tumor LKB1 expression and host diet as variables, and observed that metformin inhibited tumor growth and reduced insulin receptor activation in tumors of mice with diet-induced hyperinsulinemia, independent of tumor LKB1 expression. In the absence of hyperinsulinemia, metformin inhibited only the growth of tumors transfected with short hairpin RNA against LKB1, a finding attributable neither to an effect on host insulin level nor to activation of AMPK within the tumor. Further investigation in vitro showed that cells with reduced LKB1 expression are more sensitive to metformin-induced adenosine triphosphate depletion owing to impaired ability to activate LKB1-AMPK-dependent energy-conservation mechanisms. Thus, loss of function of LKB1 can accelerate proliferation in contexts where it functions as a tumor suppressor, but can also sensitize cells to metformin. These findings predict that any clinical utility of metformin or similar compounds in oncology will be restricted to subpopulations defined by host insulin levels and/or loss of function of LKB1.

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Metformin suppresses intestinal polyp growth in Apc^Min/+ mice

Cited by 178 publications

References 24 publications

Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial

Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial

Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug?

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

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Metformin suppresses intestinal polyp growth in ApcMin/+ mice

Cited by 178 publications

References 24 publications

Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial

Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial

Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug?

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

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Metformin suppresses intestinal polyp growth in Apc^Min/+ mice