Accepted Manuscript

Invited review

Metformin in cancer

Ritwika Mallik, Tahseen A. Chowdhury

PII: S0168-8227(17)31410-9
DOI: https://doi.org/10.1016/j.diabres.2018.05.023
Reference: DIAB 7384

To appear in: Diabetes Research and Clinical Practice

Received Date: 7 September 2017

Revised Date: 27 March 2018
Accepted Date: 14 May 2018

Please cite this article as: R. Mallik, T.A. Chowdhury, Metformin in cancer, Diabetes Research and Clinical
Practice (2018), doi: https://doi.org/10.1016/j.diabres.2018.05.023

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 METFORMIN IN CANCER

Ritwika Mallik

International training fellow in Endocrinology and Diabetes

Tahseen A. Chowdhury

Consultant in Diabetes and Honorary Professor

Department of Diabetes and Metabolism, Barts and the London School of Medicine and Dentistry,

London, UK.

Address for Correspondence:

Professor Tahseen A. Chowdhury

Department of Diabetes and Metabolism

7th Floor, John Harrison House

The Royal London Hospital

Whitechapel

London E1 1BB

E-mail: Tahseen.Chowdhury@bartshealth.nhs.uk

Tel: 020 8223 8384

Fax: 020 8223 8806

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ABSTRACT

Metformin is a lipophilic biguanide which inhibits hepatic gluconeogenesis and improves peripheral
utilization of glucose. It is the first line pharmacotherapy for glucose control in patients with Type 2
diabetes due to its safety, efficacy and tolerability. Metformin exhibits pleotropic effects, which may
have beneficial effects on a variety of tissues independent of glucose control. A potential anti-
tumourigenic effect of metformin may be mediated by its role in activating AMP-kinase, which in turn
inhibits mammalian target of rapamycin (mTOR). Non-AMPK dependent protective pathways may
include reduction of insulin, insulin-like growth factor-1, leptin, inflammatory pathways and potentiation
of adiponectin, all of which may have a role in tumourigenesis. A role in inhibiting cancer stem cells is
also postulated. A number of large scale observational and cohort studies suggest metformin is
associated with a reduced risk of a number of cancers, although the data is not conclusive. Recent
randomised studies reporting use of metformin in treatment of cancer have revealed mixed results, and
the results of much larger randomised trials of metformin as an adjuvant therapy in breast and
colorectal cancers are awaited.

KEY WORDS

Metformin

Cancer

AMP-kinase

Mammalian Target of Rapamycin

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INTRODUCTION

As a result of sedentary lifestyles and calorie dense diets, the prevalence of type 2 diabetes mellitus
(T2D) is rapidly rising and has been deemed a global public health emergency, with the International
Diabetes Federation (IDF) projecting an increase in numbers of people living with the condition rising
from 415 million in 2015 to 642 million by 2040 [1]. Whilst the link between diabetes and vascular
complications is widely recognised, there is less awareness of the link between diabetes and cancer [2].
Cancer and diabetes are common conditions, and therefore the co-occurrence of diabetes and cancer in
a patient is not infrequent. Nevertheless, many observational studies suggest that the co-occurrence of
cancer and diabetes happens more frequently than would be expected by chance. It is widely
acknowledged that the diagnosis of diabetes is an important risk factor for a number of cancers,
independent of its association with obesity [3-5]. Strongest associations have been noted with cancer of
the liver, breast, pancreas, colorectum and endometrium with possible protective effects against
prostate cancer.

Metformin, a biguanide, is deemed first line therapy for T2D in many national and international
guidelines [6,7]. The drug also has established clinical efficacy in conditions characterised by
hyperinsulinaemia, such as polycystic ovarian syndrome, gestational diabetes, non-alcoholic
steatohepatitis and pre-diabetes [8]. Alongside its’ anti-hyperglycaemic effects, however, metformin
appears to have a number of pleotropic effects which may be clinically important. The drug may have
beneficial effects in cardiovascular and neurological protection, and reduction in inflammation [9]. The
drug may also have a potential role in conditions as diverse as pre-eclampsia [10], congestive heart
failure [11], multiple sclerosis [12] and renal tubulointerstitial fibrosis [13].

This review focusses on the role of metformin in prevention of cancer amongst people with and without
diabetes, and the possible role of the drug in treatment of patients with cancer.

MECHANISM OF ACTION OF METFORMIN

Historical perspective
The anti-hyperglycaemic effect of metformin has been known for many centuries, and indeed was first
mentioned in the Ebers Papyrus in 1500 BCE. The drug is a synthetic biguanide derived from the French

3
lilac (Galega officinalis also known as goat’s rue or Italian Fitch), which was prescribed to treat polyuria
in the middle ages. In the early 20th century, it was discovered that guanidine was the active component
of the French lilac, implicated in its blood glucose lowering effect [14]. Mistakenly attributed for tetany
in parathyroidectomy patients, a study in 1918 demonstrated lowering of blood glucose on injecting
guanidine hydrochloride [15]. Toxicity of guanidine, however, inhibited its therapeutic potential, but
isoamylene guanidine was used for a time as an oral hypoglycaemic agent, until the development of
phenformin and buformin, both of which were withdrawn from production due to their tendency to
induce fatal lactic acidosis [16]. Initial interest in biguanides focused on their potential anti-malarial
effects, particularly of chloroguanide hydrochloride. It was noted, however, that this agent led to
hypoglycaemia, which led to the development of metformin as an anti-diabetic agent, which was also
called “glucophage” (glucose eater) [17].

Metformin was licensed for use as an oral anti-diabetic agent in the UK in 1958, but only licensed in the
USA in 1995, due to concerns about lactic acidosis and cardiac mortality. The safety of metformin is now
well established. Lactic acidosis is a rare occurrence, and indeed many observational studies and a
Cochrane review suggests that metformin is not linked with an excess risk of lactic acidosis [18].
Metformin is now widely advocated as first line therapy for patients with T2D based on data suggesting
reduced mortality in overweight patients with T2D in the seminal United Kingdom Prospective Diabetes
Study published in 1998 [19]. Whilst rare, lactic acidosis risk may be increased in circumstances where
tissue hypoxaemia may exist, for example in acute kidney injury, sepsis and acute cardiac or hepatic
disease, and this may be of particular relevance in patients with cancer, in whom these conditions may
occur during acute illness. Metformin is not licensed for use in stage 4 chronic kidney disease (estimated
glomerular filtration rate [eGFR] less than 30 mls/min/1.73m 2), although some authorities suggest there
may be circumstances where it may be used in lower eGFRs [20]. It has been suggest that metformin
prescription in patients with significant chronic kidney disease should be accompanied by “sick day
rules” which advise to cease therapy during acute illness.

Molecular mechanism of metformin action

The overall effect of metformin is to improve insulin sensitivity and reduce hepatic glucose output,
leading to a reduction in insulin and glucose levels (Figure 1). A number of mechanisms of action for
metformin are proposed. Improvement in insulin sensitivity may be modulated by increased insulin
receptor expression and tyrosine kinase activity, and also via the incretin pathway [21]. Metformin

4
appears to increase secretion of glucagon-like peptide-1 (GLP-1), and also increases beta-cell GLP-1
receptor expression, possibly via a perioxisome proliferator activated receptor- (PPAR-) mediated
pathway [22].

There is a growing body of evidence to suggest that the anti-hyperglycaemic effect of metformin may be
predominantly due to decreased hepatic gluconeogenesis, possibly by reduction in uptake of
gluconeogenic substrates, or inhibition of enzymes involved in gluconeogenesis [23]. Metformin appears
to have a preferential uptake in hepatic tissue due to their expression of organic cation transporter 1
(OCT1), which enables uptake of metformin into hepatic cells [24]. Metformin concentration is at its
highest in periportal tissues, and OCT1 deficient mouse models show significant resistance to the
glucose lowering effects of metformin [25].

Once in the cell, the predominant site of action of metformin is the mitochondria. Metformin is a
positively charged molecule and interacts with the mitochondrial membrane by virtue of it’s negative
charge. On entry into the mitochondria, metformin inhibits the mitochondrial electron transport system,
resulting in a decrease in cellular adenosine triphosphate (ATP), leading to a rise in the adenosine
monophosphate (AMP)/ATP ratio within the cell. For many years the mechanism behind this inhibition
was unknown, but it is now recognised that activation of AMP-activated protein kinase (AMPK) appears
to be implicated in the cellular action of metformin [26]. AMPK plays a central role in cellular energy
homeostasis in energy deplete conditions, and is activated on increase of the AMP/ATP ratio. In order to
be activated, AMPK must be phosphorylated on the Thr172 residue of its -subunit by liver-kinase b1
(LKB1), and calcium/calmodulin-dependent protein-kinase (CaMKK) [27]. Activated AMPK converts the
cell from an anabolic state to a catabolic state by switching off ATP consumption, and restoring cellular
homeostasis. This leads to inhibition of protein, lipid and glucose synthesis, and increase in glucose and
fatty acid uptake into the cell, leading to cellular energy balance.

A number of observations suggest that metformin does not directly activate LKB1 or AMPK, but that it
activates AMPK secondary to its effects on the mitochondrion; specifically effects on the mitochondrial
respiratory complex 1, through an as yet unknown mechanism.

5
MOLECULAR MECHANISMS BY WHICH METFORMIN MAY INHIBIT CANCER

Tumorigenesis requires a number of steps, and hyperglycaemia may modulate some of these processes.
Metformin acts via direct (insulin independent) and indirect (insulin dependent) pathways although they
are not mutually exclusive [28] (Figure 2).

AMPK activation
AMPK has a central role as regulator of multiple processes within the cell, and its dysregulation may
have an important role in the pathogenesis of cancer [27]. As described above, the anti-hyperglycaemic
effects of metformin appear to be modulated through activation of AMPK. Activation of AMPK appears
to have a multitude of important effects on cancer cell metabolism, including inhibition of cellular
proliferation by inhibiting cell division by mitosis [27]. By virtue of its activation of AMPK, metformin
appears to induce G1-phase arrest of the cell cycle by inhibiting cyclin D1 protein expression, leading to
loss of proliferation, although no induction of apoptosis [29]. Metformin may also promote activation of
the multidrug resistance 1 (MDR1) gene suggesting that metformin may be a useful adjunctive therapy
to reduce drug failure in cancer chemotherapy [30].

AMPK activation also inhibits lipogenic enzymes including fatty acid synthase and acetyl CoA carboxylase
which leads to reduced fatty acid availability for tumour cells. Tumour cells appear to prefer anaerobic
glycolysis as a method of energy production – the so called “Warburg” effect [31]. AMPK activation
appears to oppose this effect leading to a cytostatic effect on cancer cells. Activation of AMPK also
appears to have an anti-inflammatory effect leading to reduction in pro-inflammatory cytokines such as
tumour necrosis factor alpha (TNF-), inteleukin-6 and 8 (IL-6, IL-8) and vascular endothelial growth
factor (VEGF) [32]. Production of IL-6 activates signal transducer and activator of transcription protein
(STAT), leading to cell proliferation and hence inhibition of IL-6 will reduce cellular proliferation [33].

Mammalian target of Rapamycin (mTOR) inhibition

MTOR plays an important role in cellular energy homeostasis, and in angiogenesis by modulation of
hypoxia-inducible factor 1 (HIF-1) and VEGF [34]. mTOR responds to multiple signals cascades from
nutrients, growth factors, and cellular energy status to regulate protein synthesis and thereby modulate
control cell growth and proliferation [35]. Over-expression of mTOR is linked with many conditions,
including, diabetes, cancer and neurodegeneration [36]. In cancer, overactivation of mTOR is linked with

6
tumour progression, resistance to pharmacotherapy and poorer prognosis. Metformin activation of
AMPK appears to inhibit the mTOR pathway possibly by down regulation of specificity protein (Sp)
transcription factors and reduction in levels of insulin-like growth factors [36]. Metformin has been
shown to inhibit mTOR activation in various cancer types, including leukaemia, lung, breast and thyroid
cancer.

The anti-angiogenic effect of metformin may be promoted through inhibition of mTOR. Metformin
appears to reduce VEGF, plasminogen activator inhibitor-1 (PAI-1) and HIF-1, all of which are potent
angiogenic stimuli in cancer cells [37].

Insulin and Insulin-like growth factors

Insulin itself is a growth factor, and elevated levels of insulin are independently associated with a
number of cancers, including colorectal, pancreatic and breast cancers [38]. Elevated plasma insulin may
also be associated with poorer outcomes and disease recurrence. Insulin exerts a mitogenic effect on
various tissues including breast cancer cell lines, which are oestrogen receptor positive. Breast cancer
cells appear to have high levels of insulin receptors, compared to normal breast tissue, and in such cells,
insulin induces aromatase activity and reduces sex hormone binding globulin (SHBG), leading to
increased free oestrogen levels, which in turn increases mitogenicity [39].

Insulin may exert a mitogenic effect through insulin like growth factor-1 (IGF-1) receptors with the latter
being a more potent mitogen compared to insulin alone. Prospective studies suggest that people with
circulating IGF-1 have an increased risk of a number of common epithelial cancers such as breast, colon
and prostate cancers, and population based surveys showed that women with high plasma
concentrations of IGF-1 are more likely than those with low concentrations to develop breast cancer
[40]. Hyperinsulinaemia reduces levels of IGF Binding Protein-1 (IGFBP-1), thus increasing levels of
bioactive IGF-1, and furthermore overexpression of IGF-1 receptors can lead to neoplasia or metastasis
development.

Hyperinsulinemia develops due to insulin resistance or exogenous administration of insulin. Insulin binds
to insulin receptors (IR) and IGF-1 binds to its growth factor receptor (IGF-1R), especially isoform A,
which are expressed and upregulated in cancer cells, initiating the signaling pathways of mTOR leading
to promotion of cancer cell proliferation, invasion and metastasis [41]. The receptor isoform-A can

7
stimulate insulin-mediated mitogenesis, even in cells deficient in IGF-I receptors. Insulin and IGF-1 also
have stimulatory effects on vascular smooth muscle cell proliferation and growth of abnormal vessels.

There is some evidence to suggest that metformin may exhibit anti-cancer properties by reducing levels
of insulin and IGF-1. As an insulin sensitizer, metformin reduces plasma insulin and insulin-binding
proteins which can indirectly reduce IGF-1 levels. In rodent models, metformin reduced circulating levels
of insulin and IGF-1 and hence reducing cell proliferation and invasion [42]. In addition, metformin
mediated activation of AMPK can reduce the phosphorylation of insulin receptor substrate-1 (IRS-1)
leading to reduced activation of the mTOR cascade.

Leptin and Adiponectin

Leptin and adiponectin are two adipokines (cytokines produced by adipocytes), which exhibit opposing
molecular effects. Epidemiological studies have highlighted associations between increased serum leptin
levels and increased tumour growth and metastasis [43], whilst adiponectin appears to exhibit an
inhibitory effect on cancer development, and appears to exert anti-proliferative effects in cancer cells
[44]. Metformin inhibitsleptin production and stimulatesadiponectin production, which may be of
importance in its anti-cancer effect.

Other signaling pathways

The Ras/Raf/Mitogen activated protein kinase (MAPK) is involved a number of intracellular signaling
pathways regulating cellular growth, proliferation and apoptosis. Metformin induces apoptosis through
a MAPK pathway and enhancing expression of a growth inhibition and DNA damage inducible gene 153
(GADD153) [45].

Nuclear factor kappa (NF-k) is a transcription factor that has a role in regulation of cellular
proliferation and apoptosis. Its inhibition can lead to reduced cancer cell proliferation and sensitization
to chemotherapeutic agents. Metformin appears to reduce NF-k expression and hence this may lead to
reduced cellular proliferation [46].

Human epidermal growth factor receptor-2 (HER2) is overexpressed in around 30% of breast cancers.
Via mTOR inhibition, metformin appears to suppress HER2 overexpression. Combination of metformin

8
with the anti-HER2 monoclonal antibody trastuzumab can reduce stem cell populations in HER2-
amplified breast cancer cells [47].

Whilst the mTOR and AMPK pathways are most frequently cited as the mechanism by which metformin
exhibits anti-cancer properties, further pathways independent of mTOR and AMPK have been described,
such as that mediated by RAG GTPase or via the induction of Regulated in Damage and DNA response 1
(REDD1) expression [48].

Anti-angiogenic effects of Metformin

Metformin may have an important role in angiogenic pathways in cancer tumorigenesis [49].
Angiogenesis is increasingly recognised as important in tumour growth, invasion and metastasis.
Metformin is able to attenuate pro-angiogenic stimuli such as Tumour Necrosis Factor-a (TNF-a) and NF-
kb [50]. Metformin has, however, also been associated with Vascular Endothelial Growth Factor (VEGF)
up-regulation, associated with enhanced angiogenesis [51]. More recent data suggests that metformin
may increase expression of several angiogenesis associated genes, with short term increased expression
of VEGF, but suppression of other angiogenic factors such as IL-8, angiogenin and TIMP-1 [52]. The
overall effect is that metformin has anti-angiogenic activity, associated with a contradictory short-term
enhancement of pro-angiogenic mediators, as well as with a differential regulation in endothelial and
breast cancer cells. Further study of metformin in HER2+ breast cancer cells has shown inhibition of
several angiogenic proteins [53].

Other effects of Metformin on tumour cells

Metformin has been postulated as having many other effects on tumour cells independent of AMPK and
mTOR. It may have a role in inhibiting cancer stem cells (CSCs), which are cancer cells which have a
capacity to renew indefinitely to result in tumour formation. These cells are often resistant to chemo-
and radiotherapy. Metformin appears to improve response to chemotherapy by removing CSCs in a
variety of cancers [54], possibly by activating AMPK and suppressing mTOR in CSCs. Metformin also
appears to have an immunomodulatory effect on cancers cells, by stimulating CD8+ tumour infiltrating
lymphocytes (TILs) leading to a cytotoxic response against cancer cells [55]. Metformin appears to
inhibit DNA damage by inhibition of reactive oxygen species and activation of Ataxia Telangiectasia
Mutation (ATM), an important component of DNA repair [56]. Metformin has also been shown to

9
suppress a biological process called epithelial-mesenchymal transition (EMT), which may be important in
metastasis formation, especially in epithelial cancers such as breast and colorectal cancer [57].

METFORMIN IN CANCER THERAPY

In the following section we will discuss recent in vitro, observational and randomised studies, and meta-
analyses of metformin use in various cancer types.

Lung cancer
Lung cancer is common, with non-small cell lung cancer (NSCLC) accounting for the majority. Metformin
has been studied in NSCLC, with in vitro and in vivo studies demonstrating that metformin monotherapy
or combination therapy results in decreased proliferation of lung cancer cells and increased apoptosis
[58]. A cohort study in the US military health system showed that metformin was associated with
improved survival after NSCLC with the greatest risk reduction amongst patients with longest duration
of metformin exposure (> two years) (Hazard Ratio [HR] = 0.19; 95% Confidence Intervals [CI] = 0.09-
0.40) [59]. A randomised pilot study in chemotherapy naïve, non-diabetic patients with stage IV NSCLC
evaluated gemcitabine/cisplatin with or without 500mg of Metformin [60]. There was an improvement
in the objective response rate (ORR) and median overall survival (OS) although thiswas not statistically
significant, and there was no improvement in the median progression free survival (PFS). The dose of
metformin in this study was low, and a more recent pilot study, the Metformin in Advanced Lung Cancer
(METAL) study concluded that the recommended phase 2 dose of metformin should be 1500mg/day
combined with erlotinib (a tyrosine kinase inhibitor) in stage IV NSCLC harboring the wild type EGFR
gene as second line agents [61].

A meta-analysis of 17 individual studies showed that metformin was associated with an improved
disease-free survival (DFS) (HR = 0.65, 95%CI = 0.52-0.83) and OS (HR = 0.78, 95%CI = 0.64-0.93) [62].
Sub group analysis showed similar association in the Asian population, small cell cancer and NSCLC. A
prior meta-analysis of six studies had shown the pooled HR of OS was 0.90 (95 % CI 0.84-0.96; P = 0.003)
and sub-group analysis once again favored Asians and small cell cancer but not NSCLC [63]. A further
meta-analysis involving eight retrospective studies and 17,997 patients showed a 16% reduction of lung
cancer risk in metformin users as compared to other medications [64]. Not all studies have shown an
association, however. A systematic review and meta-analysis of 11 cohort and four case-control studies

10
published in 2014, did not show benefit or harm associated with metformin or other antidiabetic
medication in the risk of developing lung cancer [65]. There was, however significant heterogeneity
between the studies examined in this meta-analysis.

Colorectal cancer (CRC)

Epithelial-mesenchymal transition (EMT) as described above, is associated with progression of CRC.
Metformin appears to interfere with this process [57]. A Markov model analysis showed that T2D
patients on metformin had a lower rate of CRC than non-metformin users (1.670% vs. 2.146%, P=0.016)
with a statistically significant cumulative tumour free survival [66].

In a meta-analysis of seven cohort studies of patients with CRC and diabetes, metformin users had an
improved OS than non-users (HR 0.75; 95% CI 0.65 to 0.87) but no improvement in CSS [67]. As a result,
metformin has also been advocated as an adjuvant therapy in early stage colorectal cancer due to the
significant beneficial effect in all outcomes observed. A more recent meta-analysis showed not only an
improvement in OS, but also CSS but not DFS [68]. Metformin has been shown to synergistically
potentiate the cytotoxic action of Imatinib, a tyrosine kinase inhibitor, in CRC [69]. A gender dependent
association has been noted in one study of CRC and metformin users as compared to non-metformin
users with advanced CRC, with a significant benefit of metformin seen in females but not males [70].

Colorectal adenoma is postulated as a precursor to CRC in a number of patients. In a systematic review

and meta-analysis of 10 studies, metformin appeared to significantly reduce the risk of colorectal
adenoma in general and in the high-risk population (pooled OR = 0.61, 95% CI = 0.34-1.10, I2 = 79%) [71].
One study has demonstrated a reduction in risk of colorectal adenoma with metformin therapy
(adjusted OR = 0.75, 95% CI: 0.59-0.97, p=0.03), and a significant reduction of CRC (unadjusted OR=0.73,
95% CI: 0.62-0.86, p=0.0002) [72].

Prostate Cancer
The diagnosis of diabetes appears to be associated with a lower risk of prostate cancer. In vitro studies
have shown that metformin therapy reduces viability and increases apoptosis of prostate cancer cells via
the androgen receptor (AR) signaling pathway, thus repressing androgen dependent and androgen
independent prostate cancers [73]. A further proposed mechanism for inhibiting proliferation, migration

11
and invasion of prostate cancer cells is via up-regulation of pigment epithelium-derived factor (PEDF)
expression in prostate cancer cells [74].

In a Finnish randomized study (FinRSPC), there was a dose dependent decreased risk of prostate cancer
in metformin users (HR 0.81, 95% CI 0.69-0.95), as well as any antidiabetic treatment (HR 0.85, 95% CI
0.79-0.92), although there was noted an increased risk of metastatic prostate cancer in the sulfonylurea
treated group (HR 1.44, 95% CI 1.09-1.91) [75]. A double blind, placebo controlled RCT demonstrated
that metformin was distributed in the prostate tissue suggesting localized action but did not show a
difference between serum and tissue biomarkers in patients with prostate cancer who received
extended release metformin prior to prostatectomy [76].

Whilst some observational studies and meta-analyses have shown an association of metformin use with
reduced cancer risk, others have not shown such an association. One systematic review showed no
reduced risk of cancer of the prostate, breast, kidney, uterus, ovary, bladder or melanoma, but did show
a protective effect for metformin with CRC, liver, pancreas, oesophagus and stomach [77]. A large
cohort study designed to emulate an intention to treat trial involving 95,820 patients, did not show a
difference in risk of cancer between metformin and sulfonylurea users [78].

A systematic review and meta-analysis showed that metformin as an adjuvant agent in cancer was
particularly beneficial in prostate and CRC [67]. There was significant improvement in the OS (HR 0.82, CI
0.73–0.93) and CSS with metformin use with borderline improvement in recurrence-free survival (RFS)
(HR 0.83, CI 0.69–1.00).

The REDUCE trial, a randomized control trial of patients with a single negative prostate biopsy largely
independent of PSA levels, showed that metformin use was not associated with a decreased risk of
prostate cancer [79]. METAL, a randomized control trial comparing metformin 1gram twice daily to
placebo in patients newly diagnosed with localized prostate cancer due for radical prostatectomy to
understand the mechanism of action, is currently recruiting [80].

Breast Cancer
In vitro studies have demonstrated decreased growth in breast cancer cells by targeting the AMPK
signaling pathway. The role of micro-RNAs is being evaluated and a recent study has shown that

12
metformin inhibits the tumour growth and invasiveness of breast cancer cells by up-regulation of miR-
200c expression [81]. Another study showed that phenformin inhibits growth in breast cancer cells of
transgenic mice overexpressing ErbB2 by targeting IGF/IGF1 pathway possibly hinting at a class effect
[82].

A large retrospective population based study failed to show an association between metformin, stage of
breast cancer or type of tumour [83]. The same authors had also previously not shown an association
with metformin and mortality in breast cancer patients but type of cancer was not known. A meta-
analysis published in 2015 revealed that the all-cause mortality in patients with breast cancer appeared
to be significantly reduced in participants on metformin therapy (HR 0.652; 95% CI 0.488-
0.873; p=0.004). There was, however, no reduction in the incidence of breast cancer in metformin
treated subjects [84]. In a study of 1,983 patients with HER2+ breast cancer, thiazolidinediones and
metformin use was associated with better outcomes [85]. More aggressive forms of breast cancer, such
as triple negative breast cancer have shown more mixed results. It has, however, been suggested that
metformin could potentially reverse doxorubicin multidrug resistance and hence be used as an adjuvant
in chemotherapy [86].

Pancreatic cancer
Pancreatic ductal adenocarcinoma is associated with a high mortality. Metformin treatment has been
associated with reduced acinar-to-ductal metaplasia and intra-epithelial neoplasia in a mouse model
[87]. A meta-analyses of 11 observational studies had shown a lower risk of developing pancreatic
cancer in metformin users (RR 0.63, 95% CI 0.46-0.86, p=0.003) [88]. A phase 2 RCT in metastatic
pancreatic cancer showed addition of metformin 2000 mg per day to standard therapy did not improve
DFS, OS or PFS [89]. To evaluate the survival of pancreatic cancer patients of all stages, a meta-analysis
included nine retrospective cohort studies and two RCTs, and showed a significant improvement in the
metformin group (HR = 0.86, 95% CI 0.76–0.97; P < 0.05) with better outcomes in patients with resection
and localized tumours [90].

Other cancers
Metformin has been associated with improved outcomes in other cancers. A meta-analysis of
endometrial cancer studies showed metformin users had a higher OS compared to non-users and non-
diabetic patients (HR=0.82; CI: 0.70-0.95; p=0.09, I2=40%) [91]. Similarly, a meta-analysis of

13
hepatocellular cancer studies showed metformin use reduced the risk of liver cancer by 48% (OR = 0.52;
95% CI, 0.40–0.68) [92]. In a meta-analysis of renal cell cancer showed metformin use improved OS (HR
0.643, 95% CI 0.520-0.795, P < 0.001) and CSS (HR 0.618, 95% CI 0.446-0.858, P = 0.004) [93]. A
retrospective study of ovarian cancer showed a lower risk for disease relapse (HR = 0.34; 95% CI: 0.27–
0.67; P < 0.01) and disease-related death (HR = 0.29; 95% CI: 0.13–0.58, P = .03) [94]. A retrospective
thyroid cancer cohort study showed metformin use reduced HR to 0.683 (CI: 0.598–0.780) [95].

ONGOING STUDIES

According to ClinicalTrials.gov, there are currently 22 trials of metformin and cancer which are active but
not recruiting, listed in Table 1. Metformin is being investigated in various types of cancers mainly as an
adjuvant therapy.

CONCLUSIONS AND FUTURE DIRECTIONS

Metformin is a drug that generally does more good than harm, and has been proposed as a useful agent
in a wide variety of metabolic conditions. Older epidemiological studies suggested a strong protective
effect of metformin against a number of cancers, mainly in populations with diabetes. More recent data
and meta-analyses have tempered this protective effect, although most studies suggest a degree of
protection against important cancers such as breast, colorectal and prostate cancer. Ongoing clinical and
experimental studies are increasing our knowledge of the potential mechanisms by which metformin
may inhibit cancer. There is strong biological plausibility, but as of the way of many biological
hypotheses supported by observational studies, associations do not always translate into cause and
effect. It remains to be seen whether metformin can evolve into a useful adjunct with other anti-cancer
therapies, particularly in breast and colorectal cancer, both of which exert a significant toll of morbidity
and mortality in diabetic and non-diabetic populations.

The field of oncology is one of the most rigorous in terms of its use of the gold standard of evidence in
randomised controlled trials. It is therefore encouraging to note that oncologists have taken up the
mantle, and initiated a number of large randomised controlled trials of metformin as adjunctive therapy
in patients with a variety of cancers, many of which have been successfully recruited into. We await the

14
results of these studies over the coming years, in the hope that metformin may offer fresh hope for an
improved outlook in patients with cancer, with and without diabetes.

WORD COUNT: 4407

CONLFICTS OF INTEREST: NONE

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Table 1 - Depicting the current trials involving metformin and cancer which are active but not recruiting

Study Phase Estimated

Completion
1 A Trial of Standard Chemotherapy With Metformin (vs Placebo) in Women Phase 2 September
With Metastatic Breast Cancer 2017

2 Combination of Metformin to Neoadjuvant Radiochemotherapy in the Phase 2 May 2017

Treatment of Locally Advanced Rectal Cancer (METCAP)

3 Metformin Hydrochloride as First-Line Therapy in Treating Patients With Phase 2 September

Locally Advanced or Metastatic Prostate Cancer 2017
4 A Phase III Randomized Trial of Metformin vs Placebo in Early Stage Breast Phase 3 July 2020
Cancer
5 Exercise and Metformin in Colorectal and Breast Cancer Survivors Phase 2 December 2017
6 Evaluation of Metformin, Targeting Cancer Stem Cells for Prevention of Phase 2 February 2018

Relapse in Gynecologic Patients

7 Metformin as a Chemoprevention Agent in Non-small Cell Lung Cancer Phase 2 January 2019
8 Metformin-Docetaxel Association in Metastatic Hormone-refractory Phase 2 December 2017
Prostate Cancer
9 Exemestane-RAD001-Metformin Phase 2 September
2019
10 Metformin Hydrochloride vs. Placebo in Overweight or Obese Patients at Not December 2018
Elevated Risk for Breast Cancer provided
11 Metformin and Omega-3 Fatty Acids in Woman With a History of Early Phase 1 October 2018
Stage Early Stage Breast Cancer
12 An Endometrial Cancer Chemoprevention Study of Metformin Phase 3 May 2019
13 Phase I Factorial Trial of Temozolomide, Memantine, Mefloquine, and Phase 1 September
Metformin for Post-Radiation Therapy (RT) Glioblastoma Multiforme (GBM) 2018
14 A Phase II, Single-Arm Study of RAD001 (Everolimus), Letrozole, and Phase 2 October 2018
Metformin in Patients With Advanced or Recurrent Endometrial Carcinoma
15 A Pharmacodynamic Study of Sirolimus and Metformin in Patients With Phase 1 July 2018
Advanced Solid Tumors
16 Metformin Hydrochloride in Preventing Oral Cancer in Patients With an Phase 2 October 2017
Oral Premalignant Lesion
17 Chemotherapy and Radiation Therapy With or Without Metformin Phase 2 March 2018
Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer
18 Combination of Metformin With Gefitinib to Treat NSCLC Phase 2 July 2017
19 Survivorship Promotion In Reducing IGF-1 Trial Phase 2 June 2018
20 A Randomized Phase II Study of Metformin Plus Phase 2 November 2019
Paclitaxel/Carboplatin/Bevacizumab in Patients With Adenocarcinoma.
21 Reach for Health Study: Obesity-related Mechanisms and Mortality in Not December 2016
Breast Cancer Survivors provided
22 Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML Phase 1 July 2018

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Figure 1

Proposed mechanisms of metformin action in T2D

Metformin enters the hepatocyte through OCT1 and accumulates in the mitochondria where it inhibits
complex I. This leads to a reduction in ATP and concomitant rise in AMP. Elevated AMP levels lead to
activation of AMPK, although metformin may also promote AMPK activation in a direct manner. AMPK
inhibits gluconeogenic gene transcription by preventing formation of the CREB–CBP–CRTC2 complex,
both directly and via SIRT1. Furthermore, AMPK inhibits lipogenesis through ACC, ChREBP and SREBP
phosphorylation, which helps to improve insulin sensitivity. Several AMPK-independent mechanisms of
metformin action also exist. The reduction in cellular energy status can directly inhibit gluconeogenic
flux. Additionally, increased AMP has an inhibitory effect on adenylate cyclase leading to decreased
cAMP production. This in turn reduces the activity of PKA and its downstream targets, which include
CREB. Metformin also inhibits mGPD. This prevents glycerol from contributing to gluconeogenesis and
increases the cytosolic redox state, which in turn makes the conversion of lactate to pyruvate
unfavourable thus limiting the use of lactate as a gluconeogenic substrate.

Reproduced from Pryor R, Cabreiro F. Repurposing metformin: an old drug with new tricks in its binding
pockets. Biochem J 2015;471(3):307-22

26
Figure 2: Putative mechanisms of action of metformin in cancer

Reproduced with permission from Daugan M, Wojcicki AD, d’Hayer B, Boudy V. Metformin: an anti-
diabetic drug to fight cancer. Pharmacological Research 2016;113:675-85.

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