The influence of metformin in the etiology of selected cancers

Article (PDF Available)inContemporary Oncology / Wspólczesna Onkologia 16(3):223-229 · July 2012with17 Reads
DOI: 10.5114/wo.2012.29289 · Source: PubMed
Abstract
Obesity, hypertension and glucose tolerance disorders have become a growing concern in recent years. It is estimated that over 220 million people suffer from diabetes. It is a condition conducive to cardiovascular diseases, nephropathy, retinopathy and neuropathy but also to the development of many types of cancer. Insulin resistance and hyperinsulinemia lead to increased concentration of insulin-like growth factors, activation of IGF-R receptors, activation of PI3K and Ras-Raf pathways and result in increased cell division. The greatest risk is associated with developing stomach, pancreatic, colorectal, esophageal and lung cancer as well as breast and cervical cancer. Numerous cohort studies have confirmed that diabetic patients treated with metformin show a lower cancer morbidity and mortality rate. The dominant mechanism of action is activation of the AMP-activated protein kinase (AMPK) pathway and inhibition of mTOR protein, the key protein to regulate cell growth, apoptosis, proliferation and protein synthesis. Many clinical trials are currently under way to investigate the effectiveness of metformin in the prevention and treatment of neoplasms.
Obesity, hypertension and glucose tol-
erance disorders have become a grow-
ing concern in recent years. It is esti-
mated that over 220 million people
suffer from diabetes. It is a condition con-
ducive to cardiovascular diseases, ne -
phropathy, retinopathy and neuropathy
but also to the development of many
types of cancer. Insulin resistance and
hyperinsulinemia lead to increased con-
centration of insulin-like growth factors,
activation of IGF-R receptors, activa-
tion of PI3K and Ras-Raf pathways and
result in increased cell division. The
greatest risk is associated with devel-
oping stomach, pancreatic, colorectal,
esophageal and lung cancer as well as
breast and cervical cancer. Numerous
cohort studies have confirmed that dia-
betic patients treated with metformin
show a lower cancer morbidity and
mortality rate. The dominant mechanism
of action is activation of the AMP-acti-
vated protein kinase (AMPK) pathway
and inhibition of mTOR protein, the
key protein to regulate cell growth,
apoptosis, proliferation and protein syn-
thesis. Many clinical trials are currently
under way to investigate the effective-
ness of metformin in the prevention and
treatment of neoplasms.
Key words: metformin, oncological treat-
ment, diabetes, AMPK, mTOR.
The influence of metformin in the
etiology of selected cancers
Monika Pawałowska
1
, Anna Markowska
2
1
Department of Oncology, Poznan University of Medical Sciences, Poznan, Poland
2
Department of Perinatology and Gynecology, Poland University of Medical
Sciences, Poznan, Poland
Introduction
According to data gathered by World Health Organization (WHO) from 2008,
approximately 1.5 billion people aged 20 and older were overweight [BMI (body
mass index) 25–29.9 kg/m
2
]; more than 200 million men and almost 300 mil-
lion women were classified as obese (BMI > 30 kg/m
2
). Between 1980 and
2008 the number of obese people doubled. It is widely known that factors
such as obesity, lack of physical activity, and high-carbohydrate diet are con-
ducive to glucose tolerance disorder. According to WHO figures from 2011,
over 220 million people are suffering from diabetes in the world. The Inter-
national Diabetes Federation (IDF) estimates that by 2025 the number of peo-
ple with impaired glucose tolerance will increase to 472 million (9% of the
adult population), of whom around 40–50% will develop type 2 diabetes. Recent
studies show that diabetes is conducive not only to cardiovascular diseases,
nephropathy, retinopathy and neuropathy, but also to the development of
many types of cancers [1–4]. Recent data have shown that metformin, a drug
commonly used in diabetic patients, can significantly decrease the incident
rate and death risk associated with malignant cancers. In this paper we would
like to present the mechanism of metformin’s anticancer action and its role
in selected malignancies.
Diabetes and cancer
Despite a tremendous body of research conducted in this field, there are
still many aspects of the pathomechanism associating diabetes with can-
cer development that remain unclear.
Intense protein synthesis and rapid cell division within cancerous tissue
demand high energy consumption. Therefore the proliferating cells need to
ensure themselves a constant delivery of the basic energy source that is glu-
cose. In the case of hypoglycemia cancer cells rely on glycosylation to pro-
duce ATP (the Warburg effect) [5]. Some authors have shown that hyper-
glycemia is connected with increased risk of cancer. Park et al. [4] compared
populations of patients with a fasting serum glucose level under 109 mg/dl
and above 126 mg/dl and showed that the cancer-related mortality rate was
38% higher in the latter group. The highest mortality in that group was asso-
ciated with gastric cancer (HR: 1.52; 95% CI: 1.25–1.84) and lung cancer
(HR: 1.48; 95% CI: 1.18–1.87). Jee et al. came to similar conclusions [6]. In this
Korean study a significant increase in mortality rate was found among peo-
ple with the fasting serum glucose level over 140 mg/dl when compared with
a group with the level under 90 mg/dl (HR: 1.29; 95% CI: 1.22–1.37 among men
and HR: 1.23; 95% CI: 1.09–1.39 among women). In the male population the
highest death rate was associated with esophageal (HR: 1.44; 95% CI:
1.08–1.93), liver (HR: 1.57; 95% CI: 1.40–1.76), pancreatic (HR: 1.91; 95% CI: 1.52–
2.41) and colorectal (HR: 1.31; 95% CI: 1.03–1.67) cancer. The highest death
Wspolczesna Onkol 2012; 16 (3): 223–229
DOI: 10.5114/wo.2012.29289
Review
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współczesna onkologia/contemporary oncology
rate among women suffering from diabetes with fasting
blood glucose level in the morning over 140 mg/dl was asso-
ciated with liver (HR: 1.33; CI: 1.01–1.81), lung (HR: 1.50; CI:
0.94–1.78), breast (HR: 1.24; CI: 0.65–1.92) and cervical (HR:
1.81; CI: 1.03–3.15) cancer; however, no such association was
found for gastric and colorectal cancer.
On the other hand, in most cases normoglycemia allows
for a concentration of glucose appropriate to meet the needs
of cancerous cells [7]. A meta-analysis by Johnson and Bowk-
er [8] assessed the benefits of an intensified glycemic con-
trol in patients with type 2 diabetes in the context of de -
velopment of neoplasms. In the conclusion of the large
randomized study which included populations of many thou-
sands of patients, the authors did not find any decrease in
the risk of cancer mortality rates among patients with type
2 diabetes with normal blood glucose level and HbA
1c
. These
results do not support the thesis that hyperglycemia is linked
to increased carcinogenesis.
In an experimental model for the study of the influence
of glucose concentration on tumor growth, Tannock and
Kopelyan [9] found that higher glucose concentration
increased the rate of cell division. However, at a glucose lev-
el of 5 mmol/L the intensity of cell division plateaus and any
further increase in concentration does not lead to an
increased rate of cell division. This suggests that hyper-
glycemia has no effect on cell proliferation.
Therefore, hyperinsulinemia rather than hyperglycemia
seems to be the factor inducing intense cell proliferation.
Activation of insulin receptors and insulin-like growth fac-
tor receptors (IGF-R) localized on the surface of cancer cells
leads to cell proliferation [10]. Insulin resistance and hyper-
insulinemia lead to increased concentration of insulin-like
growth factors, activation of IGF-R receptors and activation
of PI3K and Ras-Raf pathways, and result in increased cell
division.
Metformin – anticancer drug?
Metformin has been successfully used for many years to
treat patients with type 2 diabetes. A multicentre, random-
ized study conducted by UKPDS (United Kingdom Prospec-
tive Diabetes Study) [11] in patients with type 2 diabetes
showed that treatment with metformin reduced the risk of
myocardial infarction and diabetes-related death by 30% as
compared with treatment with insulin and sulphonylurea
derivatives. Numerous cohort studies have confirmed the the-
sis that patients with diabetes treated with metformin also
have a lower risk of cancer incidence and mortality [12, 13].
Evans et al. [12] found a 23% reduction in cancer incidence
among patients treated with metformin as compared with
sulphonylurea derivatives. Another Canadian study [14]
during a five-year follow-up of 10 309 people with diagnosed
type 2 diabetes showed a significant cancer-related mortality
reduction among patients receiving metformin in compar-
ison to patients treated with oral sulphonylurea derivatives
or insulin (3.5% vs. 4.9% vs. 5.8%). A Scottish cohort study
[13] conducted among 12 255 people suffering from type 2
diabetes showed a 7.3% rate of newly diagnosed cancer
among patients treated with metformin as compared with
11.6% of patients treated with other drugs. The median time
between the diagnoses of diabetes and cancer was 3.5 and
2.6 years respectively (p = 0.001). Decensi et al. [15] found
in turn in their meta-analysis a 31% reduction of cancer inci-
dence and mortality in diabetic patients taking metformin.
Metformin belongs to the biguanide class derived from
goat’s rue (Galega officinalis), a herbaceous plant used in
Ancient Egypt and medieval Europe [16–18]. It was first syn-
thesized in 1922 by two scientists, Werner and Bellow from
Trinity College, Dublin. The first biguanides (metformin and
phenformin) were introduced in France in the 1950s after
numerous publications by Jeane Sterne. They were withdrawn
from the market after several years due to their severe
adverse effects (phenformin) with particular focus on an
increased risk of lactic acidosis. Having scored highly in many
drug safety clinical trials, metformin (1,1-dimethylbiguanide)
was introduced to the U.S. market in 1995 and gained more
popularity with every year. The most common adverse effects
after regular use of this drug are associated with the gas-
trointestinal tract, e.g. nausea, flatulence, vomiting, diarrhea.
A small percentage of patients experience hives or other skin
lesions. Lactic acidosis is very uncommon and affects
mostly elderly people who suffer from circulation, liver or
kidney failure. Apart from diabetics, metformin has also been
successfully used in women with polycystic ovary syndrome,
increasing the ovulation rate, and improving glucose tol-
erance and disordered lipid balance [19–21].
The hypoglycemic effect of metformin relies on the direct
inhibition of gluconeogenesis and glycogenolysis in the liv-
er. Metformin increases anaerobic glycolysis of peripheral
tissue, particularly in skeletal muscles. Furthermore, it
has an ability to enhance the number of GLUT4 glucose trans-
porters and insulin receptors.
Metformin’s mechanism of action is complex and may
involve several pathways. The processes influenced by this
drug include the following:
activation of LKB1 (liver kinase B1)/AMPK (AMP-activated
protein kinase) pathway,
• inhibition of cell division and/or promotion of apoptosis,
• promotion of autophagy,
• down-regulation of circulating insulin,
• activation of the immune system.
It is recognized that the basic mechanism of metformin
action involves AMP-activated serine/threonine kinase,
a type of protein that plays a key role in the regulation of
cellular metabolism of both normal and cancer cells. AMP-
activated protein kinase becomes activated under conditions
of cellular energy deficit and a low AMP:ATP ratio. This resets
the metabolic pathways from anabolic toward catabolic
processes [22] and to promotion of e.g. glycolysis and oxi-
dation of fatty acids; at the same time pathways of gluco-
neogenesis, protein, cholesterol and fatty acid synthesis are
stopped [23]. AMP-activated protein kinase activation by met-
formin is mediated by LKB1 [24]. Liver kinase B1 is a sup-
pressor protein. Its mutation is found in the hereditary Peutz-
Jeghers syndrome characterized by the development of many
hamartomatous polyps, skin lesions in the form of lentig-
ines and a tendency to develop multiple carcinomas, par-
ticularly of the small intestine, stomach, pancreas and colon.
225
The influence of metformin in the etiology of selected cancers
The activation of AMPK by LKB1 leads to phosphoryla-
tion of tuberous sclerosis complex 2 (TSC-2), which in turn
inhibits the mTOR protein (mammalian target of rapamycin),
a key protein which regulates processes of cell growth and
angiogenesis, and promotes cell division and protein syn-
thesis. The inhibiting effect of AMPK on mTOR results in
blocking of the PI3K/PKB/Akt pathway, thus downregulat-
ing the synthesis of many proteins, e.g. eukaryotic initia-
tion factor 4e-binding protein-4E-SPs, ribosomal protein S6
kinase, responsible for mitotic promotion [25, 26] (Fig. 1). Met-
formin may also inhibit mTOR dependent pathways in the
absence of AMPK, LKB1 and TSC2 in a Rag GTPase depen-
dent manner [27]. AMP-activated protein kinase also pro-
motes cellular autophagy through the phosphorylation of
cyclin-dependent kinase inhibitor protein, p27 [28].
The role of metformin in oncology
As mentioned, metformin significantly lowers the death
risk associated with malignant cancers. If we look closer
at the figures from the numerous studies [15, 29, 30] we
will see that this phenomenon applies only to some types
of cancer, e.g. esophageal, liver, colorectal, pancreas, breast
and lung. In a Taiwanese study, Lee et al. [29] found a sub-
stantial reduction in liver and colorectal cancer morbidity
among patients taking metformin (HR: 0.58 and 0.38,
respectively).
Breast cancer
Obesity and diabetes are acknowledged risk factors of
breast cancer for peri- and postmenopausal women.
According to Thor and Anderson [31] the risk increases by
20% and the cancers very often are estrogen receptor pos-
itive.
Many studies conducted on breast cancer lines have
shown positive action of metformin on these malignant cells.
Alimova et al. [33] studied in diverse subtypes of breast can-
cer cell lines the effect of metformin on receptor expression
and molecular pathways that participate in cell prolifera-
tion and apoptosis. Metformin inhibited cell proliferation by
blocking the cell cycle at the G1 checkpoint, and downreg-
ulated cyclin D1 and transcription factor E2F1 expression, with
no impact on other cell cycle regulators, such as p27kip1 or
p21WAF1. It has been proven that metformin inhibits the
MAPK (mitogen activated protein kinase) signaling pathway
as well as Act activity [34]. Another mode of metformin activ-
ity is suppressing the phosphorylation of signal transduc-
er and activator of transcription Stat3, also responsible for
cellular proliferation and apoptosis, angiogenesis and acti-
vation of expression of genes related to breast cancer sur-
vival [31]. The cytotoxic effect of metformin on breast can-
cer cells may also take place via damage to the
poly(ADP-ribose) polymerases (PARPs) – enzymes respon-
sible for genome integrity – and via activation of caspase
associated with cell apoptosis [31, 35]. High and low-con-
centration metformin in in vitro studies inhibited erbB2
expression and showed biological activity against estrogen
receptors (ER) [30]. According to Liu et al. [36] metformin in
vitro and in vivo (nude mice strain) exerts an inhibiting effect
in cell culture conditions and reduces tumor mass in ani-
mal models. Bernstein et al. [37] tested receptor status in
carcinoma cells after previous surgery in 90 female patients
with diabetes, treated with metformin and other antidia-
betic medication. In their work they noted that the frequency
of progesterone-positive receptors in women treated with
metformin was significantly higher in comparison to the
group treated with other medication and these results may
be used in breast cancer therapy.
Scientists from Texas [32] analyzed responses to neoad-
juvant chemotherapy for early-stage breast cancer in 2529
women over a 17-year period – 2374 women were nondia-
betic, 68 diabetic using metformin and 87 diabetic using oth-
er treatment – and reported a complete pathological
remission in 24% of women taking metformin versus 8%
of women taking other antidiabetic medication and 16% of
nondiabetic patients (p = 0.02). More randomized studies
are necessary to ascertain whether metformin improves
responses to chemotherapy in women suffering from
breast cancer and whether there is a benefit of adding this
drug to conventional treatment [38, 39].
receptor
protein synthesis
cell proliferation
and growth
Fig. 1. The role of metformin in the etiology of cancer. Adapted
from: Cancer Res 2007; 67: 10804-10812 [25] – reprinted with
permission
PTEN – phosphatase and tensin homologue deleted on chromosome 10;
PI3K – phosphatidylinositol-3-kinase; PKB/AKT – protein kinase B/Akt; mTOR
– mammalian target of rapamycin; TSC-2 – tuberous sclerosis complex 2;
LKB1 – liver kinase B1; AMPK – AMP-activated protein kinase; 4E-BP1 –
eukaryotic initiation factor 4E-binding protein; S6K – protein S6 kinases
LKB1
AMPK
insulin
PI3K
PKB/AKT
TSC2
mTOR
4E-BP1 S6K
PTEN
metformin
226
współczesna onkologia/contemporary oncology
Ongoing phase II and III clinical trials evaluate its role in
breast cancer, where mTOR is suggested to be the shield
[40].
During the recent ASCO (American Society of Clinical
Oncology) meeting (2011) it was reported that the Clinical
Trials Group from the National Cancer Institute of Canada
has initiated enrollment of over 3500 women with node-
positive and node-negative breast cancer who will receive
metformin compared with placebo for 5 years [41].
Colorectal cancer
Colorectal cancer risk is higher in obese patients with type
2 diabetes. Patients treated with insulin are twice as like-
ly to develop this type of cancer as compared to patients
taking metformin [42]. It has been supported that aberrant
crypt foci (crypts of Lieberkuhn) may play a role in colon can-
cer pathogenesis [43].
The inhibiting effect of metformin on intestinal epithe-
lial cell proliferation and the development of aberrant
crypt foci and polyps has been shown in an animal model.
The mechanism of metformin-mediated suppression of the
abovementioned precancerous states occurred via the
most common way – through AMPK activation and mTOR
inhibition [43].
Studies of colon cancer cell lines prove that AMPK acti-
vation is accompanied by lower expression of VEGF as well
as GLUT1 and COX-2 glucose transporter, which may addi-
tionally result in cell apoptosis [46]. Other studies have shown
that metformin also induces apoptosis in suppressor
p53-deficient colon cancer cells [47].
The findings of these studies show that type 2 diabetic
patients constitute a high risk group for colon cancer and
suggest a preventive effect of metformin.
Pancreatic cancer
Jee et al. [6] estimated whether the increase in risk
of death from pancreatic cancer depended on duration of
diabetes. The scientists found that the mortality risk
increased according to diabetes duration with a twofold rise
in mortality for diabetes duration of less than 5 years and
a threefold rise for diabetes duration of more than 10 years.
The evidence provided by an American study [48] explor-
ing the relationship between metformin and pancreatic can-
cer risk proved the protective effect of the drug. According
to the authors it reduces the risk of pancreatic cancer by over
a half (HR: 0.38, 95% CI: 0.22–0.69; p = 0.001).
Other cancers
In breast and endometrial cancer alike, the presence
of progesterone receptors (PR) plays a vital role. A study by
Cui et al. [49] established a significant IGF1-induced reduc-
tion in the number of PR in breast cancer cells. This phe-
nomenon has been linked with the activity of the
PI3K/Akt/mTOR pathway and inhibition of PR gene tran-
scription. Similar results were obtained by Xiu et al. [50] in
an examination of endometrial cancer cell lines. The
results of their study show that IGF2 mediates activation
of the PI3K/Akt/mTOR pathway, 4E-BP and p70S6K phos-
phorylation and a significant increase in cell proliferation,
while both IGF1 and IGF2 inhibit expression of the PR A/B
gene (Fig. 2). The authors also demonstrated that metformin
exerts a counteracting effect on the abovementioned
processes and this may imply that introduction of this drug
combined with progesterone supplementation would result
in a better response to treatment.
Ongoing clinical trials
The promising results of many cohort and experimen-
tal studies triggered further clinical trials which aim to deter-
mine whether this inexpensive, generally available and safe
medication can reduce cancer incidence or improve cancer
prognosis. Another interesting issue demanding further stud-
ies is the aspect of metformin use in nondiabetic patients.
Could this group also benefit from metformin treatment?
Currently many phase I, II and III trials are under way to study
metformin’s effect on breast, prostate, endometrial and pan-
creatic cancer (Table 1). Perhaps in the near future met-
formin’s antineoplastic activity will be generally recognized
and eventually it will be applied in oncotherapy.
Fig. 2. The effect of metformin on PR expression. Adapted from:
J Steroid Biochem Mol Biol 2011; 126: 113-120 [50] – reprinted
with permission
IGF-2 – insulin-like growth factor 2; IGR-1R – insulin-like growth factor receptor 1;
PTEN – phosphatase and tensin homologue deleted on chromosome 10;
PI3K/AKT – phosphatidylinositol-3-kinase/Akt; mTOR
– mammalian target of rapamycin; AMPK – AMP-activated protein kinase;
LKB1 – liver kinase B1; 4E-BP1 – eukaryotic initiation factor 4E-binding protein;
p70S6K – 70 protein S6 kinases; mRNA PR – progesterone receptor mRNA
IGF-2
IGF-1R
PI3/AKT
4E-BP1/p70S6K
mRNA PR
Metformin
AMPK
mTOR
LKB1
227
The influence of metformin in the etiology of selected cancers
Table 1. A selection of ongoing clinical trials determining metformin’s effect on oncologic diseases
Type of cancer Official title Trial identifier no Estimated Purpose of the study
enrollment
prostate cancer Metformin in Castration-Resistant Prostate Cancer NCT01215032 106 prospective study
to evaluate metformin’s effect on PSA concentration in prostate cancer
patients receiving androgen deprivation therapy
pancreatic cancer Combination Chemotherapy With or Without NCT01167738 82 randomized phase II trial
Metformin Hydrochloride in Treating Patients With to evaluate the effectiveness of combination chemotherapy with
Metastatic Pancreatic Cancer or without metformin hydrochloride in treating patients with
metastatic pancreatic cancer
endometrial cancer Metformin and Endometrial Cancer NCT01205672 30 non-randomized phase I trial
to evaluate the effect of metformin on s6K expression in endometrial
cancer
colorectal cancer A Trial of Metformin for Colorectal Cancer Risk NCT01312467 39 a phase II study
Reduction Among Patients With a History to evaluate the potential preventive effect of metformin in patients
of Colorectal Adenomas and Elevated Body with history of colorectal adenomas and a BMI > 30
Mass Index
breast cancer A Phase III Randomized Trial of Metformin vs Placebo NCT01101438 3582 a phase III study
in Early Stage Breast Cancer A Phase III Randomized to evaluate the effect of the addition of metformin to standard
Trial of Metformin vs Placebo in Early Stage Breast Cancer chemotherapy in women with early-stage breast cancer.
breast cancer Metformin Hydrochloride in Treating Women With Stage I NCT00984490 30 a phase II study
or Stage II Breast Cancer That Can Be Removed By Surgery to evaluate the effect of metformin on cell proliferation (Ki67)
and apoptosis (kaspaza 3) in women with stage I or stage II cancer
breast cancer Metformin Pre-Surgical Pilot Study NCT00930579 35 a phase II study
to evaluate the effect of metformin on the AMPK/mTOR
pathway in women with newly diagnosed early-stage breast cancer.
breast cancer The Impact of Obesity and Obesity Treatments NCT00933309 24 phase I study
on Breast Cancer to evaluate the effect of aromatase inhibitor treatment in combination with
metformin and rosiglitazone in obese women with estrogen receptor
positive breast cancer
breast cancer Clinical and Biologic Effects of Metformin in Early Stage NCT00897884 40 to evaluate the effect of pre-operative metformin therapy on cell
Breast Cancer proliferation in tumor tissue in women diagnosed with breast cancer
breast cancer A Trial of Standard Chemotherapy With Metformin (vs Placebo) NCT01310231 78 randomized phase II trial
in Women With Metastatic Breast Cancer to evaluate standard chemotherapy with metformin on PFS in women with
metastatic breast cancer.
breast cancer Effect of Metformin on Breast Cancer Metabolism NCT01266486 40 to measure metformin induced effects in phosphorylation of S6K, 4E-BP-1
and AMPK
breast cancer The Use of Metformin in Early Breast Cancer Patients NCT01302002 30 to evaluate the effects of metformin on proliferation (Ki67) and apoptosis
Pre-Surgery (TUNEL) in women with stage I or II breast cancer
228
współczesna onkologia/contemporary oncology
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Address for correspondence
Monika Pawałowska
Department of Oncology
Poznan University of Medical Sciences
Szamarzewskiego 82/84
60-569 Poznań, Poland
tel. +48 61 854 90 20
Submitted: 13.08.2011
Accepted: 2.04.2012
    • "Moreover, recent studies show that diabetes is conducive not only to cardiovascular diseases, nephropathy, retinopathy and neuropathy , but also to the development of many types of cancers . Recent data have shown that metformin, a drug commonly used in diabetic patients, can significantly decrease the incidence rate and death risk associated with malignant cancers [24]. However, the evidence of the effects of metformin on ovarian cancer is still limited and inconclusive. "
    [Show abstract] [Hide abstract] ABSTRACT: Ovarian cancer is one of the most difficult problems in gynecologic oncology and the search for new drugs effective in the treatment of this kind of cancer, especially in cases resistant to current forms of therapy, remains a challenging priority. The aim of the study was to analyze the effect of metformin on apoptosis and the BIRC5 gene expression in ovarian cancer cell line SKOV-3. The BIRC5 gene encodes survivin protein. SKOV-3 cells were treated with metformin (10 mM). Apoptotic changes in studied cells were analyzed by double staining using a mixture of fluorochromes - Hoechst 33258/propidium iodide (PI). The expression of the BIRC5 gene at the mRNA level was analyzed using the real-time PCR technique. Treatment of cells with metformin causes changes in the cell shape from oval to spindle and leads to the separation of the cells from the monolayer. Furthermore, metformin induces apoptosis and necrosis of ovarian cancer cells. A statistically significant increase in the number of apoptotic cells after 48 and 72 hours' treatment with metformin relative to a control cells seems to be correlated with a decrease in the expression of the BIRC5 gene at the mRNA level. Metformin seems to be a promising agent, whose use in ovarian cancer patients may contribute to improving the effectiveness of therapy.
    Full-text · Article · Jun 2014
    • "Metformin is an anti-diabetic drug which has been shown to decrease the risk of colon cancer by targeting one of IGF-1s downstream pathways. Its role in inhibiting tumorigenesis is related to increased expression of AMPK that subsequently inhibits the action of mammalian target of rapamycin (mTOR) thereby inhibiting tumor growth and proliferation (Figure 1) [100]. Also, metformin could downregulate the levels of circulating insulin thus decreasing its effect on elevation of IGF-1 levels. "
    [Show abstract] [Hide abstract] ABSTRACT: The step-wise development of colorectal neoplasia from adenoma to carcinoma suggests that specific interventions could delay or prevent the development of invasive cancer. Several key factors involved in colorectal cancer pathogenesis have already been identified including cyclooxygenase 2 (COX-2), nuclear factor kappa B (NF-κB), survivin and insulin-like growth factor-I (IGF-I). Clinical trials of COX-2 inhibitors have provided the "proof of principle" that inhibition of this enzyme can prevent the formation of colonic adenomas and potentially carcinomas, however concerns regarding the potential toxicity of these drugs have limited their use as a chemopreventative strategy. Curcumin, resveratrol and quercetin are chemopreventive agents that are able to suppress multiple signaling pathways involved in carcinogenesis and hence are attractive candidates for further research.
    Full-text · Article · Sep 2013
  • [Show abstract] [Hide abstract] ABSTRACT: This research was carried out to evaluate the chemopreventive effects of different doses of metformin treatment for 6 months on rectal aberrant crypt foci (ACF) in patients with impaired glucose tolerance (IGT). A total of 120 Chinese patients with IGT were enrolled and assigned randomly to a low-dose metformin group (n=30, metformin at 250 mg/day), a middle-dose metformin group (n=30, metformin at 500 mg/day), a high-dose metformin group (n=30, metformin at 1500 mg/day), and a control (untreated with metformin) group (n=30). Each participant was followed for 6 months by protocol, and the number of ACF per patient in the above four groups was examined by magnifying colonoscopy before, and after 3 and 6 months of, treatment. The mean ACF numbers in both the middle-dose and the high-dose metformin groups were significantly decreased at 3 as well as 6 months of treatment, whereas they did not change in the low-dose metformin and the untreated groups. In the high-dose metformin group, BMI, waist circumference, fasting plasma glucose, homeostatic model assessment of insulin resistance index, and 2-h plasma glucose were significantly decreased. However, no such change was observed in the middle-dose metformin group. Changes in the ACF number correlated positively with changes in the homeostatic model assessment of insulin resistance (r=0.273, P=0.013), BMI (r=0.241, P=0.042), and 2-h plasma glucose (r=0.252, P=0.037), respectively, in the high-dose metformin group, but no such correlation was observed in the middle-dose metformin group. Metformin suppressed ACF formation in IGT patients in a dose-dependent manner, possibly through direct and indirect (attenuating insulin resistance) mechanisms.
    Article · Aug 2014
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