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New Perspective for an Old Antidiabetic Drug: Metformin as Anticancer Agent

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Book cover Advances in Nutrition and Cancer

Part of the book series: Cancer Treatment and Research ((CTAR,volume 159))

Abstract

Metformin, an inexpensive, well-tolerated oral agent that is commonly used in the first-line treatment for type 2 diabetes, has become the focus of intense research as a potential anticancer agent. This research reflects a convergence of epidemiologic, clinical, and preclinical evidence, suggesting that metformin may lower cancer risk in diabetics and improve outcomes of many common cancers. Notably, metformin mediates an approximately 30 % reduction in the lifetime risk of cancer in diabetic patients. There is growing recognition that metformin may act (1) directly on cancer cells, primarily by impacting mitochondrial respiration leading to the activation of the AMP-activated protein kinase (AMPK), which controls energy homeostasis in cells, but also through other mechanisms or (2) indirectly on the host metabolism, largely through AMPK-mediated reduction in hepatic gluconeogenesis, leading to reduced circulating insulin levels and decreased insulin/IGF-1 receptor-mediated activation of the PI3K pathway. Support for this comes from the observation that metformin inhibits cancer cell growth in vitro and delays the onset of tobacco carcinogen-induced lung cancer in mice and that metformin and its analog phenformin delay spontaneous tumor development cancer-prone transgenic mice. The potential for both direct antitumor effects and indirect host-mediated effects has sparked enormous interest, but has led to added challenges in translating preclinical findings to the clinical setting. Nonetheless, the accumulation of evidence has been sufficient to justify initiation of clinical trials of metformin as an anticancer agent in the clinical setting, including a large-scale adjuvant study in breast cancer, with additional studies planned.

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Notes

  1. 1.

    http://provocativequestions.nci.nih.gov

Abbreviations

ACC:

Acetyl-CoA carboxylase

ACF:

Aberrant crypt foci

ACL:

ATP citrate lyase

AKT/PKB:

Protein kinase B

CaMKK2:

Ca2+/calmodulin-activated kinase kinase

cAMP:

Cyclic adenosine monophosphate

CI:

Confidence interval

CRTCS:

cAMP-responsive element binding protein (CREB)-regulated transcription coactivator

CSC:

Cancer stem cell

DM:

Diabetes mellitus

ER:

Estrogen receptor

ERK:

Extracellular signal-regulated kinase

FAS:

Fatty acid synthase

FOXO:

Forkhead box O

GLUT:

Glucose transporter

GPCR:

G-protein-coupled receptor

HCC:

Hepatocellular carcinoma

HIF-1α:

Hypoxia-inducible factor 1α

HOMA:

Homeostasis model assessment

IGF:

Insulin growth factor

IGFBP:

Insulin growth factor binding protein

IGF-R:

Insulin growth factor receptor

IR:

Insulin receptor

IRS:

Insulin receptor substrates

LKB1:

Liver kinase B1

MAPK:

Mitogen-activated protein kinase

MEF:

Mouse embryonic fibroblast

mTOR:

Mammalian target of rapamycin

mTORC1:

mTOR complex 1

NAFLD:

Non-alcoholic fatty liver disease

Nampt:

Nicotinamide phosphoribosyltransferase

OCT:

Organic cation transporter

PDK1-3:

Pyruvate dehydrogenase kinase 1 and 3

PET:

Positron emission tomography

PI3K:

Phosphatidylinositol 3 kinase

rag:

Recombination activating gene

RR:

Relative risk

SREBP-1:

Sterol regulator element binding protein 1

TSC:

Tuberous sclerosis

UMIN:

University Hospital Medical Information Network

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Experimental Pharmacology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazioni Giovanni Pascale - IRCCS, 80131, Naples, Italy

    Alessandra Leone, Elena Di Gennaro & Francesca Bruzzese

  2. Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazioni Giovanni Pascale - IRCCS, 80131, Naples, Italy

    Antonio Avallone

  3. Direttore U.O.C. Farmacologia Sperimentale, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazioni Giovanni Pascale - IRCCS, Via Mariano Semmola, 80131, Napoli, Italy

    Alfredo Budillon

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  1. Alessandra Leone
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  2. Elena Di Gennaro
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  3. Francesca Bruzzese
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  4. Antonio Avallone
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  5. Alfredo Budillon
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Correspondence to Alfredo Budillon .

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Editors and Affiliations

  1. Dept. of Biochemistry and Biophysics, Second University of Naples, Naples, Italy

    Vincenzo Zappia

  2. Clinical and Experimental Medicine, University of Naples "Federico II", Naples, Italy

    Salvatore Panico

  3. Institute of Food Sciences National Research Council, Avellino, Italy

    Gian Luigi Russo

  4. Dept. of Experimental Oncology, National Cancer Institute, Naples, Italy

    Alfredo Budillon

  5. Dept. of Biochemistry and Biophysics, Second University of Naples, Naples, Italy

    Fulvio Della Ragione

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Leone, A., Di Gennaro, E., Bruzzese, F., Avallone, A., Budillon, A. (2014). New Perspective for an Old Antidiabetic Drug: Metformin as Anticancer Agent. In: Zappia, V., Panico, S., Russo, G., Budillon, A., Della Ragione, F. (eds) Advances in Nutrition and Cancer. Cancer Treatment and Research, vol 159. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38007-5_21

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