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Anti-Cancer Agents in Medicinal Chemistry, 2012, 12, 000-000
1
Metformin: A Rising Star to Fight the Epithelial Mesenchymal Transition in
Oncology
Guislaine Barrière*, Michel Tartary and Michel Rigaud *
Clinical Laboratory, Astralab Department of Specialized Analyses, 7-11 Avenue de Lattre de Tassigny, 87000 Limoges, France
Abstract: Metformin is a biguanide derivative which is widely prescribed as an oral drug for diabetes mellitus type 2. This old molecule
has recently received a new attention because of its therapeutic properties in oncology, that seem to be independent of its action on
glycemia homeostasis. The reappraisal of its pharmacological effects was supported by delineation of signaling pathways and more
recently clinical trials. Numerous epidemiological studies showed that diabetics have an increased risk of several types of cancer and
cancer mortality. Complex relationship between cancer and type 2 diabetes is going to be unraveled and recent observations revealed a
significant action of metformin, but not other anti-diabetic agents, on cancer cells. As metformin may act as an anticancer drug through
inhibition of mTOR, it might have greater benefice than suggested by insulin lowering alone. This review summarizes major publications
on the link between cancer and metformin underscoring new implications of this chemical drug in oncology field. New perspectives
about utilization of this molecule in clinical oncological routine, are described, particularly for patients without disturbance of glucose
homeostasis. As the epithelial mesenchymal transition (EMT) seems implicated into invasive process and metastasis in cancer, and as
metformin is able to inhibit EMT pathways, it is important to highlight cellular mechanisms of metformin.
Keywords: AKT, AMPK, cancer, clinical trials, dedifferentiated circulating tumor cells, diabetes, EMT, epidemiology, insulin, LKB1,
metformin, mTOR, neoadjuvant therapy, S6KB, Stemness.
INTRODUCTION
Metformin (N,N-dimethylimidodicarbonimidic diamide IUPAC) is a N’,N’-dimethylbiguanide, which belongs to the class
of nitreones. It was extracted from Galega officinalis (goat’s-rue or
French lilac). As infusion, this plant was used in Middle Age to
fight polyuria. Metformin is widely prescribed for type 2 diabetic
patients and was approved in 1970’s in Europe and in 1995 in the
United States. It has a wide variety of indications like: polycystic
ovarian syndrome, metabolic syndrome management and diabetes
prevention in high risk populations. The molecule was described as
a product of N’, N’-dimethylguanidine synthesis by Werner and
Bell [1]. Metformin is a safety drug. The most common described
side effects are diarrhea and dyspepsia. Renal function must be
controlled before starting metformin as it can lead to lactic acidosis
for patient with kidney deficiency. Phenformin and buformin were
withdrawn from clinical use as they are less suitable for routine
treatment due to the higher rates of lactic acidosis. Two galenic
metformin formulations are available, immediate release, slow or
extended release, the latter avoiding the most common
gastrointestinal side effects. Metformin primary actions are
neoglucogenesis inhibition, reduction of insulin resistance in
peripheral tissues and then increased glucose uptake in skeletal
muscle. It may exert its effects by activation of AMP-activated
protein kinase (AMPK) able to inhibit neoglucogenesis during
cellular stress. This old molecule received particular attention for its
potential beneficial effects on fighting cancer cells independently
from its role in diabetes [2-7]. This review depicts reasons for
which metformin emerges today in oncology, the signaling
pathways by which it acts, its potential mechanisms on cancer cells
and its impact on epithelial mesenchymal transition (EMT).
METFORMIN AND CANCER
For more than 10 years medical literature has indicated 1) a
relation between diabetes and cancer 2) a worse prognosis for
*Address correspondence to these authors at the Clinical laboratory,
Astralab department of specialized Analyses, 7-11 Avenue de Lattre de
Tassigny, 87000 Limoges, France; Tel: 33.5.55.48.85.01;
E-mail: [email protected] and Tel: 33.5.55.48.85.01;
E-mail: [email protected]
1871-5206/12 $58.00+.00
diabetic patients with cancer than for non diabetic patients. Type 2
diabetes and development of cancers, particularly epithelial tumors
localized to breast, pancreatic, colorectal, urinary and genital
tractus, are linked [8-13]. To the opposite, studies reported a
reduced risk for cancer prostate [14]. In breast cancer,
epidemiological landmark studies noted prevalence of type 2
diabetes in newly diagnosed cancer patients (estimated from 8 to
18%) [15]. Moreover, compared with their nondiabetic
counterparts, patients with breast cancer and pre-existing diabetes
have a greater risk of death [16,17]. Clinical and epidemiological
incidences have underlined hyperinsulinemia, and insulin resistance
as factors connected to poor cancer outcomes [18].
Hyperinsulinemia (exogenous insulin or secondary blood increased
insulin) can directly promote tumorigenesis through the insulin
receptor in epithelial tissues or indirectly acting on other
modulators: insulin like growth factors, sex hormones [19, 20].
All these studies led to examine effect of treatment with oral
drugs and or insulin on the development of cancer. Then,
metformin seemed to be a new anticancer agent. Evans et al
showed a lower risk for several cancers in type 2 diabetes patients
treated with metformin rather than other diabetes medications [21].
Apart from previous epidemiological studies about cancer incidence
and diabetes, new results have established that metformin may
reduce cancer risks in metformin treated patients and enhance
efficacy of chemotherapy. This new paradigm is based on
numerous publications. In such a way, Bodmer et al demonstrated
that long term metformin use is associated with decreased risk of
breast cancer [22]. They identified case patients with a recorded
incident diagnosis of breast cancer and they found decreased risk of
breast cancer in women under metformin for several years. No such
effect was seen for short-term metformin or sulfonylureas or other
antidiabetes drugs utilization. These results were confirmed by the
work of Libby et al who described that users of metformin are at
low risk of incident cancer [23]. Many authors implemented this
new aspect of metformin prescription [24-28]. When early-stage
breast cancer patients received neoadjuvant chemotherapy and
metformin, Jiralerspong et al showed a higher pathologic complete
response rate. Upon 2529 patients with breast cancer who received
neoadjuvant chemotherapy, the rate of pathologic complete
responses was 24% in the metformin group, 8% in non metformin
group and 16% in the non diabetic group. Even if comparison of
© 2012 Bentham Science Publishers
2 Anti-Cancer Agents in Medicinal Chemistry, 2012, Vol. 12, No. 0
pathologic complete response rates between metformin and non
diabetic groups did not meet significance, it trended toward [29].
All these data strongly support the clinical development of
metformin as an anticancer agent. Currently there are numerous
ongoing clinical trials. Results in neoadjuvant breast cancer therapy
indicated that metformin may potentiate classic chemotherapy [30].
It remains to be proved the relevance of metformin therapy to non
diabetic patients [31]. Hadad et al proposed to test metformin in a
preoperative window of oppotunity [32]. Yurekli et al suggested to
introduce metformin in adjuvant treatment of Her-2 positive breast
cancer [33].
MODULATION OF AMPK ENERGY CELL SENSOR BY
METFORMIN
AMP-activated protein kinase (AMPK) is an energy sensor
involved in the regulation of cell metabolism. Its activation is
depending on the cellular AMP/ATP ratio. AMPK signal acts on its
downstream regulators mTOR/S6K1. This pathway is a central one
for the regulation of cellular energy. Its activation leads to switch
on catabolic pathways (fatty acid beta oxidation, glycolysis) and
inhibits ATP consumption (gluconeogenesis, protein and fatty acid
synthesis and cholesterol biosynthesis) [34].
When AMP increases, AMPK is allosterically activated by
phosphorylation of its catalytic α subunit by the upstream kinase
LKB1. Secondary, AMP prevents dephosphorylation of AMPK by
phosphatases [35].
Metformin leads to increased cellular AMP/ATP ratio, by
disrupting mitochondrial complex I [36]. Thus, nitrogen species are
generated, activating PKC which phosphorylates LKB1 leading to
its nucleocytoplasmic translocation and activation of AMPK [37].
Metformin activates AMPK by at least two LKB1 dependent
mechanisms [38]. Uptake of glucose and its utilization by skeletal
muscle inhibits hepatic gluconeogenesis and decreases insulin
resistance. Type 2 diabetes is characterized by relative insulin
deficiency due to reduced tissue responsiveness to insulin, this is
known as insulin resistance. Metformin lowers insulin level in the
blood. These metabolic actions are mediated by activated AMPK
on the mammalian target of rapamycine (mTOR). Activated AMPK
induces phosphorylation of TSC2 (part of the heterodimeric
tuberous sclerosis complex TSC including TSC1 and TSC2) [39].
Then TSC2 stimulates its GTPase activity toward Rheb [40]. Then
the signaling pathway Rheb/mTOR is blocked, acting on mTORC1
(rapamycin-sensitive mTOR complex formed by the associated
proteins : raptor, mLST8, PRAS40, and deptor) [41]. Thus, S6K1 as
well as 4E-BP1 (transcription factors), the down-stream effectors of
mTORC1, are inefficient. By lowering insulin levels (as an indirect
effect) metformin reduces the PI3K/AKT signaling pathway
involved in cell survival [42, 43]. Metformin can also directly target
mTOR independently of AMPK and TSC2 [44]. Mechanisms and
pathways are summarized in Fig. (1a).
POTENTIAL MECHANISMS OF METFORMIN ON
CANCER CELLS
Reported mechanisms include effects of the drug on cell
growth, cell cycle, mTOR pathway, blood insulin level and finally
on epithelial mesenchymal transition (EMT), a major key for cancer
cell survival.
Effect on Cell Cycle
Metformin was able to inhibit breast cancer cells in vitro, in an
AMPK-dependent manner, this action being associated with mTOR
activation decrease. Many studies provided informations on the
mechanisms by which metformin acts along with the arrest of cell
cycle ( G0/G1 or S phase arrest) and particularly leads to decrease
cyclin D1. [45-48]. Cell division can be inhibited by tumor
suppressor p53 when phosphorylated by AMPK leading cells, under
bad nutrition conditions, to apoptosis [49-51].
Barrière et al.
Buzzai et al showed that p53 deficient cells and not p53 wild
type are sensitive to metformin [52]. Others have shown that cell
lines with or without functional p53 displayed similar sensitivity to
metformin [45]. Moreover Ben Sahra et al indicated that the
combined use of metformin and 2 desoxy glucose leads to p53 and
AMPK mediated apoptosis [53] and that metformin acts
independently of the p53 status on cell proliferation [54].
Effect on Tyrosine Kinases
Simultaneously to the suppression of mTOR activity, several
protein kinases at once are inhibited. This is particularly true for the
oncoprotein HER2. Vazquez-Martin et al demonstrated that HER2
oncoprotein itself may represent a key cellular target involved in
the anti breast cancer action of metformin. They demonstrated that
suppression of HER2 overexpression, under metformin, appears to
occur via direct inhibition (AMPK independent) of S6K1 activity
[55]. In the same manner, EGFR is inhibited in pancreatic cancer
cells [56]. It becomes obvious that PI3K/mTOR/S6K1 axis is
central to the occurence of lapatinib (tyrosine kinase inhibitor)
resistance in HER2 overexpressing breast cancer cells. Induced
activation of AMPK has been described to suppress mTOR
enzymatic activity and survivin protein synthesis involved in
apoptosis [57-59]. By these effects metformin can reverse resitance
to lapatinib.
Effect via Insulin
Beside the direct action (insulin independent) of metformin on
AMPK/mTOR/S6K1 axis, other effects are indirect (insulin
dependent) [60]. Effectively the reversal of hyperglycemia, the
decrease of both insulin resistance and hyperinsulinemia may play a
major role in anticancer activity of metformin. Insulin, a growth
promoting hormone, has mitogenic, antiapoptotic and proinvasive
activities on tumor cells. Insulin may bind and activate IGF1
receptors ((IGF-1R), which have much more potent mitogenic and
transforming activity than the insulin receptors (IR). Furthermore,
cancer cells often express high level IGF-1R and IR, underlining
potential sensitivity to the growth promoting effects of insulin [61,
62]. Thus metformin by this indirect way may decrease the negative
impact of the hormone on tumor development, as the flux through
IRS-1/AKT/mTOR/S6K1 axis is slowed down.
Aging, Cancer and Metformin
Metformin appears to have potent cancer chemopreventive
properties by triggering DNA damage response signaling [63,64].
Metformin would be able to induce specific senescence like growth
inhibition of premalignant cells or malignant cells. Cellular
senescence would be a restricting cancer progression mechanism.
Avoiding these safeguards, tumors can become immortal and
proliferate. Early studies by Warburg demonstrated that cancer cells
preferentially metabolize glucose by glycolysis although this
pathway generates less ATP than the process of mitochondrial
respiration [65]. Metformin able to inhibit the glucose flux, while
stimulating lactate/pyruvate flux and mitochondrial biogenesis,
causes ATP depletion and drastic increase of cellular AMP [66].
This modification of AMP/ATP ratio might induce an inhibition of
mTOR via AMPK activation. Experimental data supported the fact
that metformin slows aging rate, increases life span, inhibits tumor
development of HER-2/neu transgenic mice [67-70]. Many studies
are warranted to elucidate the relationship between senescence and
cancer. The role of metformin in these pathological status must be
highlighted.
Metformin and Triple Negative Breast Cancer
A distinct group of breast cancers called triple negative cancers
(TN) fails to express HER2 estrogen and progesterone receptors.
They have stem like and or mesenchymal features. They are
frequently chemoresistant. Recent observational studies have shown
that metformin had unique anticancer effects against TN. Thereby,
Metformin and Cancer
Anti-Cancer Agents in Medicinal Chemistry, 2012, Vol. 12, No. 0
3
Fig. (1). Mechanisms of action of metformin. a) Signaling pathways are delineated in left part of the scheme. Metformin seems to exert its effects by at least
two distinct mechanisms: inhibition of mTORC1 (mammalian target of rapamycin complex 1) and an indirect mechanism depending on insulin. AMPK
(AMP-activated protein kinase) is a cellular energy sensor. Its activation inhibits hepato-gluconeogenesis and increases glucose uptake in skeletal muscle
(metabolic effects). 4E-BP1: eucaryotic initiation factor 4E-binding proteins; S6KB: ribosomal protein S6 kinase; TSC1 and TSC2: tumor supressor tuberous
sclerosis complex 1 and 2; Rheb: Ras homologue enriched in brain; PTEN: phosphatase and tensin homologue deleted on chromosome 10; AKT: protein
kinase; PI3K: phosphatidyl inositide 3 kinase; IRS1: insulin receptor substrate1; IGF-1R: insulin growth factor 1 receptor; LKB1: liver kinase B1. Red arrows
and bars are effective when AMPK is activated by AMP/ATP ratio and/or metformin. Black arrows and bars show signaling pathways when AMPK activation
is switched off. b) In the right insert, EMT (epithelial mesenchymal transition) of breast cancer cells is depicted showing cellular targets of metformin. TIC
(tumor initiating cells): are mesenchymal cells characterized by PI3Kα, Twist1 and Akt2 gene expression; Stem cells are cancer stem cells characterized by
ALDH1, BMI1 and CD44; GA733-2, Muc1, Her-2neu are classical markers of epithelial cancer cells; TAC: tumor activated cells; EPC: endothelial progenitor
cell like; MET: mesenchymal epithelial transition.
Liu et al reported that metformin inhibits cell proliferation, colony
formation, and induces apoptosis. Two of the molecular effects in
TN cells : reduction of cyclin D1 and activation of AMPK have
been reported in other breast cancer subtypes. Specific effects in
TN reported by these authors are induction of apoptosis, proteolytic
cleavage of PARP, activation of caspase -3, -8 and 9, reduction of
EGFR, P-Src, P-MAPK and cyclin E in dose and time dependent
manner [46]. These results, arising from experiments on TN cell
lines, seem not to be correlated to clinical trials. Effectively,
Bayraktar et al in a retrospective study showed that metformin use
during adjuvant therapy was not associated with improved survival
outcomes. However they indicated a trend toward a decrease in the
risk of developing distant metastases in diabetic patients receiving
metformin [71]. TN cells are particularly sensitive to metformin.
Deng et al demonstrated that the drug targets Stat3 to inhibit cell
growth and induce apoptosis in TN. Prolonged upregulation of
activation of Stat3 has been associated with TN characteristics. This
activation has diverse procarcinogenic effects and particularly
TGFβ-associated EMT. Thus, metformin down regulates Stat3
expression and or activity in TN [72]. These findings deserve to be
tested with more studies.
EMT and Metformin
During the last ten years a new concept sparkled in cancer
biology : involvement of an epithelial mesenchymal transition
(EMT) in the metastatic dissemination of epithelial cancer cells.
EMT endows cancer cells with stem cell properties. However there
is still a too large gap between the concept and its clinical
development. The EMT is a process in which epithelial cells lose
their polarity and acquire migratory properties [73]. EMT was first
noted during embryogenesis to drive the transformation of
epithelial cells into mobile mesenchymal cells that travel to distant
anatomical sites. This process normaly tightly regulated is
abnormally disrupted and activated during cancer metastasis and
recurrence. It is considered to promote cancer cells progression and
invasion into the surrounding environment [74]. As EMT may be
sufficient to trigger ontogeny of cancer stem cells, Vazquez-Martin
et al studied how metformin can act on the expression of key
drivers of the EMT machinery [75]. Based on the work of Liu et al,
who reported that metformin has unique effect against TN breast
cancer cells [46] they investigated whether the response of basal
like breast cancer cells to metformin might relate to its ability to
suppress cancer stem cell phenotypes by regulating EMT status
[76]. By using CD44+ CD24- enriched MDA-MB-231 and CD44+
CD24+ enriched MDA-MB-468 basal-like cancer cell lines, they
illustrated for the first time that metformin suppresses the EMT
status in CD44+ cells. This was done by transcriptional repression
of key EMT drivers including ZEB1, TWIST1, SLUG [77-86] and
pleiotropic cytokines TGFβ [87, 88] thus eliminating the breast
cancer stem cell phenotypes in cell populations bearing either
4 Anti-Cancer Agents in Medicinal Chemistry, 2012, Vol. 12, No. 0
mesenchymal or epithelial markers. Their findings demonstrated
that metformin down regulates the expression of several EMT
controllers. Among them, they underlined TWIST1 and ZEB1 that
regulate invasion, motility and senescence [89-91]. Metformin
prevented generation of cancer stem cell phenotype by down
regulating some EMT regulators (“EMT status”) independently of
changes in EMT fonctioning (“EMT phenotype”). Moreover,
Brown et al showed that a switch in CD44 alternative splicing
is required for EMT. Additionally the CD44s isoform activated
AKT signaling providing a mechanistic link to a key pathway that
drive EMT [92]. All these data provide arguments to clinical
development of metformin as a therapy able to forbid ontogenesis
of cancer stem cells. The molecular action of metformin can also be
explained by up regulation of tumor suppressive miRNA let-7a and
miRNA-96 and down regulation of oncogenic miRNA181a. This
can be the key preventing self-renewal of cancer-initiating cells
arising from EMT [93]. EMT in human epithelial cancers was
evidenced by detection of dedifferentiated circulating tumor cells
showing mesenchymal and or stem characters [94-95]. Fig. (1b)
indicated how metformin could act in breast cancer and target
mesenchymal cells.
METFORMIN DOSING
Recommendations of prescription in type 2 diabetes are the
following: the starting dosage of metformin is 500 mg twice daily.
The maximum dosage for children age 10 to 16 is 2000 mg, and for
adults age 17 and older is 2550 mg. The dose should be only
increased when necessary and slowly in such a way to avoid side
effects. The dose is increased by up 500 mg every week to reach
the 2.50 g maximum. Extended-release metformin (long-acting)
improves gastrointestinal tolerability and allows once-daily dosing.
Total daily doses of metformin have been largely described for type
2 diabetes. Generally, dosing is choosed to decrease glycemia and
blood HbA1c levels. However these prescriptions were established
for diabetic patients but not for people safe of disrupted glycemia
regulation. When looking at concentrations of metformin reported
in oncology experiences, as well in vitro on cancer cell lines as in
vivo in animal experiments, a wide concentration range was used.
Based on these data, it seems us necessary to determine metformin
Table 1.
Barrière et al.
dosing in cancer patients. Clinical trials could highlight the problem
of metformin dosing in oncology.
METFORMIN SIDE EFFECTS
Toxicity
Metformin has been used for over 50 years and seems to be a
safety drug. The most frequent adverse events are gastrointestinal
symptoms [96, 97]. Digestive disorders (diarrhea, vomiting)
represent the most common metformin side effects (around 30%)
which are usually minor and transient and can be avoided by
utilization of sustained release galenic formulations. In healthy
individual metformin affects glucose, vitamin B12 and the digestive
uptake of bile salts [98]. Long term metformin prescription has
been shown to lead vitamin B12 malabsorption [99]. It has been
suggested that this side effect may increase cancer tissue toxicity of
adjuvant chemotherapy [100]. The only toxicity which has been
described is lactic acidosis. The presence of clinical conditions,
such as renal failure, increases the risk of metformin-associated
lactic acidosis. This metabolic event is really very rare
(4.3/100000/year) [101]. Although very unusual, one must be aware
that carboplatin can cause mitochondrial toxicity and trigger lactic
acidosis. Its occurence can be promoted by metformin associated
therapy [102]. Some biguanide analogs like phenformin were
withdrawn from clinical use in the 1970s, because of their
association with lactic acidosis.
Angiogenese
Phoenix et al reported in xenograph model of breast cancer that
metformin appears to increase the production of VEGF wich is a
neoangiogenic signal [103]. Stambolic et al noted two concerns
about this result. The first one is related to the used dose and the
other criticism is that of the model system [104]. The prospect that
metformin administration could result in neoangiogenic cancer
phenotype deserves further attention.
Resistance to Metformin
As many other anticancer drugs used on a daily chronic basis
metformin might generate refractory cancer cells. This concept has
Summary of Metformin Key Studies, Clinical and Experimental Reports
Clinical reports
Evans et al [21]
Metformin lowers risk of cancer in type II diabetes patients
Bodmer et al [22]
Long term metformin and decreased risk of breast cancer
Libby et al [23]
Low risk of incident cancer for metformin users
Landman et al [24]
Lower cancer mortality in type II diabetes patients using metformin
Hosono et al [26]
Action of metformin on colorectal aberrant crypt foci
Jiralerspong et al [29]
Metformin and pathologic complete responses in breast cancer
Pollak et al [31]
Metformin and other biguanides in oncology
Hadad et al [32]
Biological effects of metformin in operable breast cancer
Experimental reports
Zhuang et al [45]
Cell cycle arrest in metformin treated breast cancer cells
Alimova et al [47]
Metformin inhibits breast cancer cell growth
Vazquez-Martin et al [55]
Metformin suppresses erbB-2 oncoprotein overexpression
Vazquez-Martin et al [59]
Metformin overcomes breast cancer resistance to Her2 inhibitors
Anisimov et al [68]
Metformin increases life span in femal SHR mice
Vazquez-Martin et al [75]
Metformin regulates breast cancer stem cell ontogeny
Oliveras-Ferraros et al [93]
Micro(mi)RNA expression profile of breast cancer epithelial cells treated with metformin
Martin-Castillo et al [105]
Metformin and cancer: doses and mechanisms
Metformin and Cancer
been particularly described in the work of Martin-Castillo et al
[105]. They demonstrated that disruption of AMPK/mTOR/ S6K1
axis on chronic exposure to metformin efficiently relieves negative
feedback suppression on the IGF-1R/IRS-1 axis [106]. This
complex phosphorylates and activates PI3K and then AKT.
Abolition of the negative feedback loop leads to increase of cell
survival signals due to PI3K/AKT activation axis and thus
counteracts the antitumor activity of metformin.
CLINICAL TRIALS
All the data reported in the literature strongly support the
clinical development of metformin as an anticancer agent. Thus
several clinical trials are ongoing to test metformin drug as an
adjuvant treatment as well as combined with other oncotherapies.
The largest trial (NCT01101438) will recruit more than 3000
patients with breast cancer (T1-3, N0-3, M0) and without diabetes
to compare metformin and placebo. The primary outcome is disease
free survival (DFS) and secondary are overall survival (OS), and
relevant medical endpoints. Two phase II trials involving pancreatic
cancer are underway (NCT01167738 and NCT 01210911). A
phase II trial involving prostate cancer patients (NCT01215032)
will test metformin to androgen derivation therapy. Other numerous
trials are on the way, list and description can be find at
http://clinicaltrials.gov. The future role of metformin in neoadjuvant
treatement, its side effects, its synergy with conventional
chemotherapies need to be defined. Results will have great interest
as in some studies metformin will be given for the first time in non
diabetic patients and moreover practically all types of cancer are
included. This is important as clinical results with metformin in
patients with insulin resitance do not take into account the problem
of this drug prescription to insulin sensitive patients. In vitro studies
have indicated that metformin is a strong mTOR inhibitor as other
drugs do. Combined therapies with rapalogues could be interesting
since metformin can counteract increased glucose levels resulting
from mTOR inhibition. The major advantage of metformin can be,
in combination with HER2 inhibitors, to overcome traztuzumab
resitance and protection of cardiac cells from HER2-inhibition–
related cardiotoxicity. Metformin exerts cardioprotective actions via
AMPK and increases the expression of adiponectin and its receptors
adipoR1 and adipo R2 in cardiomyocytes [107]. Key studies are
summarized in Table 1.
Anti-Cancer Agents in Medicinal Chemistry, 2012, Vol. 12, No. 0
CONFLICT OF INTEREST
The author(s) confirm that this article content has no conflicts
of interest.
ACKNOWLEDGEMENTS
Our work was financially supported by URCAM- Limousin
(Union Régionale des Caisses d’Assurance Maladie).
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CONCLUSION
The link between cancer and type 2 diabetes has been suggested
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Revised: April 19, 2012
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