Metformin and cancer: Quo vadis et cui bono?

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Abstract

How many lives have already been saved by the anti-cancer drug metformin? Inadvertently perhaps, among the millions of type 2 diabetics with occult or known cancers and who have been prescribed metformin since the 1950s, thousands may have benefited from the anticancer properties of this first-line pharmacotherapy. Quo vadis? Now, researchers aim to move metformin from a non-targeted stage of cancer therapy that has been mostly developed retrospectively and empirically into a targeted therapy by following a biological rationale and a predefined mechanism of action. But, who might benefit from metformin? Cui bono? Because metformin is on the leading edge of a new generation of cancer metabolism-targeted therapies, perhaps it is the right time to provide solutions to the challenges that metformin and other onco-biguanides will face in the coming years before becoming incorporated into the therapeutic armamentarium against cancer.

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Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study.

Pamela J Goodwin, Marguerite Ennis, Kathleen Pritchard … (2002)

Insulin, a member of a family of growth factors that includes insulin-like growth factor (IGF)-I and IGF-II, exerts mitogenic effects on normal and malignant breast epithelial cells, acting via insulin and IGF-I receptors. Because of this and because of its recognized association with obesity, an adverse prognostic factor in breast cancer, we examined the prognostic associations of insulin in early-stage breast cancer. A cohort of 512 women without known diabetes, who had early-stage (T1 to T3, N0 to N1, and M0) breast cancer, was assembled and observed prospectively. Information on traditional prognostic factors and body size was collected, and fasting blood was obtained. Fasting insulin was associated with distant recurrence and death; the hazard ratios and 95% confidence intervals (CI) for those in the highest (> 51.9 pmol/L) versus the lowest (< 27.0 pmol/L) insulin quartile were 2.0 (95% CI, 1.2 to 3.3) and 3.1 (95% CI, 1.7 to 5.7), respectively. There was some evidence to suggest that the association of insulin with breast cancer outcomes may be nonlinear. Insulin was correlated with body mass index (Spearman r = 0.59, P <.001), which, in turn, was associated with distant recurrence and death (P <.001). In multivariate analyses that included fasting insulin and available tumor- and treatment-related variables, adjusted hazard ratios for the upper versus lower insulin quartile were 2.1 (95% CI, 1.2 to 3.6) and 3.3 (95% CI, 1.5 to 7.0) for distant recurrence and death, respectively. Fasting insulin level is associated with outcome in women with early breast cancer. High levels of fasting insulin identify women with poor outcomes in whom more effective treatment strategies should be explored.

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Tumours with PI3K activation are resistant to dietary restriction

Nada Kalaany, David Sabatini (2009)

Dietary restriction (DR) delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown. We find that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of DR, while others are resistant. Cancer cells that form DR-resistant tumours carry mutations that cause constitutive activation of the PI3K pathway and in culture proliferate in the absence of insulin or IGF1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN-null cancer cell line, is sufficient to convert a DR-resistant tumour into one that is DR-sensitive. DR does not affect a PTEN-null mouse model of prostate cancer, but significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signaling. Thus, the PI3K pathway is a major determinant of the sensitivity of tumours to DR and activating mutations in the pathway may influence the response of cancers to DR-mimetic therapies.

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Metformin prevents tobacco carcinogen--induced lung tumorigenesis.

Regan Memmott, Jose Mercado, Colleen Maier … (2010)

Activation of the mammalian target of rapamycin (mTOR) pathway is an important and early event in tobacco carcinogen-induced lung tumorigenesis, and therapies that target mTOR could be effective in the prevention or treatment of lung cancer. The biguanide metformin, which is widely prescribed for the treatment of type II diabetes, might be a good candidate for lung cancer chemoprevention because it activates AMP-activated protein kinase (AMPK), which can inhibit the mTOR pathway. To test this, A/J mice were treated with oral metformin after exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Metformin reduced lung tumor burden by up to 53% at steady-state plasma concentrations that are achievable in humans. mTOR was inhibited in lung tumors but only modestly. To test whether intraperitoneal administration of metformin might improve mTOR inhibition, we injected mice and assessed biomarkers in liver and lung tissues. Plasma levels of metformin were significantly higher after injection than oral administration. In liver tissue, metformin activated AMPK and inhibited mTOR. In lung tissue, metformin did not activate AMPK but inhibited phosphorylation of insulin-like growth factor-I receptor/insulin receptor (IGF-1R/IR), Akt, extracellular signal-regulated kinase (ERK), and mTOR. This suggested that metformin indirectly inhibited mTOR in lung tissue by decreasing activation of insulin-like growth factor-I receptor/insulin receptor and Akt upstream of mTOR. Based on these data, we repeated the NNK-induced lung tumorigenesis study using intraperitoneal administration of metformin. Metformin decreased tumor burden by 72%, which correlated with decreased cellular proliferation and marked inhibition of mTOR in tumors. These studies show that metformin prevents tobacco carcinogen-induced lung tumorigenesis and support clinical testing of metformin as a chemopreventive agent.

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Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 23 August 2016

Publication date (Electronic): 23 June 2016

Volume: 7

Issue: 34

Pages: 54096-54101

Affiliations

¹ Metabolism and Cancer Group, ProCURE (Program Against Cancer Therapeutic Resistance), Catalan Institute of Oncology, Girona, Catalonia, Spain

² Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain

³ Unit of Clinical Research, Catalan Institute of Oncology, Girona, Catalonia, Spain

⁴ Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, Reus, Spain

Author notes

Correspondence to: Javier A. Menendez, jmenendez@ 123456idibgi.org

[*]

On behalf of the METTEN-01 Investigators (EudraClinicalTrial Number 2011-000490-30)

Article

Publisher ID: 10262

DOI: 10.18632/oncotarget.10262

PMC ID: 5342329

PubMed ID: 27356748

SO-VID: 51c8e907-7c3c-40e5-8eb3-243aabdbd8f7

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Metformin and cancer: Quo vadis et cui bono?

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Cancer Metabolism

Most cited references 23

Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study.

Tumours with PI3K activation are resistant to dietary restriction

Metformin prevents tobacco carcinogen--induced lung tumorigenesis.

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