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versión impresa ISSN 1807-5932versión On-line ISSN 1980-5322

Clinics vol.73  supl.1 São Paulo  2018  Epub 06-Sep-2018 


Metformin and blood cancers

Ademar Dantas Cunha Júnior1 

Fernando Vieira Pericole1 

Jose Barreto Campello Carvalheira1  * 

1Departamento de Medicina Interna, Universidade Estadual de Campinas, Sao Paulo, SP, BR.


Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer.

Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.

Key words: Metformin; Diabetes; Blood Cancers; myeloma; leukemia; lymphoma


Based on the increasing incidence of cancer along with increasing rates of obesity and type 2 diabetes mellitus (DM2), much effort has been made to identify the epidemiological and biological connections between these conditions. In the clinic, oncologists are gradually being required to tailor cancer treatments for patients with pre-existing diabetes or obesity, and endocrinologists often need to control diabetes in patients who are undergoing treatments for cancer (1).

Despite contradictory reports in the early literature (2-4), many meta-analyses have consistently shown a moderate but direct effect of body mass index (BMI) on the incidence of lymphoma and multiple myeloma (MM) and the elevated risk of leukemia in adults (5-8). Similarly, patients with DM2 frequently develop hematological malignancies (9-11). Notably, the incidence of tumors in patients with DM2 is profoundly affected by the treatment—long-term metformin use has been found to be connected with a reduced incidence of cancer and cancer-related mortality (2).

In this review, the association between hematological cancers and diabetes and the epidemiological, clinical, and preclinical data that establish the value of metformin as a potential treatment for hematologic malignancies are summarized.

Diabetes and cancer

Although the link between DM2 and carcinogenesis was first reported in 1910 by Maynard and Pearson (1910 apud Wojciechowska, 2016) (10), it was over 100 years later that the American Diabetes Association (ADA) and American Society of Clinical Oncology (ASCO) presented their consensus on the factors that link diabetes and cancer (10,12). Notably, DM2 and cancer share many risk factors, especially obesity (12), and DM2 and malignancies are correlated through several conditions, such as hyperinsulinemia (due to resistance to endogenous or exogenous insulin), hyperglycemia, and chronic inflammation due to overweight and body fat mass (10,12).

Adiposity has been correlated with an increased risk of several cancers, including breast, endometrial, pancreatic, and colon cancer. In addition, obese men and women with esophageal, gallbladder, colorectal, pancreatic, liver, and kidney cancer have an elevated risk of cancer-related deaths (Table 1) (13). Notably, BMI consistently has a moderate but direct effect on the rates and risk of death due to lymphoma and MM and is associate with an increased risk of leukemia in adults (Table 2) and of monoclonal gammopathy of uncertain significance (MGUS) transforming into MM (3,6-8,3-26).

Table 1 Relative risks associated with overweight and obesity and percentage of cases attributable to overweight and obesity in the United States, the European Union, and Brazil. 

Type of cancer RR* BMI 25-30 kg/m2 RR* BMI>30 kg/m2 FAP* (%) for the US (30, 31) FAP (%) for the EU (22, 32-34) FAP (%) for BR (35)
Colon cancer (men) 1.5 2.0 35.4 27.5 43.8
Colon cancer (women) 1.2 1.5 20.8 14.2 25.3
Breast cancer (postmenopausal women) 1.3 1.5 22.6 16.7 17.3
Endometrial cancer 2.0 3.5 56.8 45.2 44.8
Kidney (kidney cells) cancer 1.5 2.5 42.5 31.1 31.3(W)/35.6(M)
Adenocarcinoma of the esophagus 2.0 3.0 53.4 42.7 60.2(W)/72.8(M)
Pancreatic cancer 1.3 1.7 26.9 19.3 24.7(W)/33.9(M)
Hepatocellular carcinoma ND* 1.5-4 ND* ND* 23.9(W)/25.9(M)
Gall bladder 1.5 2.0 35.5 27.1 18.2(W)/6.6(M)
Cardiac adenocarcinoma 1.5 2.0 35.5 27.1 62.2(W)/65.5(M)

*RR: relative risk, FAP: fraction attributable to population, BMI: body mass index, ND: not determined, W: women, M: men. USA: United States of America, EU: Europe; BR: Brazil.

Table 2 Incidence of hematological malignancies in obese patients. 

Hematologic malignancy Patient cohort and study
Lymphoma Meta-analysis: RRs for a 5 kg/m(2) increase in BMI were 1.07 (95% confidence interval [CI], 1.04-1.10) for NHL incidence (16 studies, n=17,291 cases) and 1.14 (95% CI, 1.04-1.26) for NHL mortality (five studies, n=3407 cases) (7).
MM Meta-analysis: RRs were 1.12 (95% CI, 1.07-1.18) for overweight individuals and 1.21 (95% CI, 1.08-1.35) for obese individuals; a total of 15 cohort studies on MM incidence and five studies on MM mortality were included (8).
Leukemia Meta-analysis: RRs of leukemia were 1.14 [95% CI, 1.03-1.25] for overweight individuals (BMI 25-30 kg/m(2)) and 1.39 (95% CI, 1.25-1.54) for obese individuals (BMI >or= 30 kg/m(2)); a total of 9 cohort studies with data on BMI or obesity in relation to the incidence of leukemia were included (6).
Subtypes of leukemia Meta-analysis: RRs associated with obesity were 1.25 (95% CI, 1.11-1.41) for CLL, 1.65 (95% CI, 1.16-2.35) for ALL, 1.52 (95% CI, 1.19-1.95) for AML and 1.26 (95% CI, 1.09-1.46) for CML; a total of 4 studies reporting results on subtypes of leukemia were included (6).

ALL: acute lymphocytic leukemia, AML: acute myeloid leukemia, BMI: body mass index, CLL: chronic lymphocytic leukemia, CML: chronic myeloid leukemia, MM: multiple myeloma NHL: Non-Hodgkin Lymphoma, RR: relative risk.

Mechanistically, obesity—a state of excess nutrient levels—chronically activates signaling pathways that upregulate insulin, insulin-like growth factor (IGF), leptin, and inflammatory cytokines (e.g., IL-6) and increases the risk of neoplastic transformation. Consistent with this model, elevated levels of adiponectin, a marker of reduction in adipose tissue, were recently found to be associated with a lower risk of MM (27,28). These factors stimulate cell surface receptors and signaling through Janus kinase (JAK)/signal transducers and activators of transcription (STATs), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K), and all of these molecules are commonly dysregulated in neoplastic cells (29).

Conversely, studies worldwide have shown that DM2 is associated with increased rates of many cancers and cancer-related mortality (Table 3) (36-47). Notably, DM2 is linked with the incidence of solid tumors and an increased risk of lymphoma, leukemia, and MM. A meta-analysis of 26 studies observed an increased risk of non-Hodgkin lymphoma (NHL) and peripheral T cell lymphoma (PTCL), unlike other subtypes of NHL, among patients with DM2. DM2 patients have a risk of 1.22 of developing leukemia (95% confidence interval (CI), 1.03-1.44; P=0.02) and a nonsignificant high risk for developing myeloma (1.22, 95% CI, 0.98-1.53; P=0.08) (48). Further, peak postload glucose levels were correlated with an increased risk of mortality from MM, NHL, and leukemia in the study by Chiu et al. (49). A recent review concluded that the association between DM2 and various cancers is supported by strong evidence in only 14% (breast cancer, intrahepatic cholangiocarcinoma, colorectal cancer (CRC), and endometrial cancer) of the 27 correlations investigated, with no bias (50).

Table 3 Meta-analysis on the relative risk (RR) of cancer in different organs in patients with diabetes. 

Type of cancer (author and year) Number of evaluated studies RR (95% CI*)
Colon (Luo et al. 2012) (36) 24 1.27 (1.14-1.42)
Breast (Boyle et al. 2012) (37) 40 1.27 (1.16-1.39)
Pancreatic (Ben et al. 2011) (38) 35 1.94 (1.66-2.27)
Prostate (Long et al. 2012) (42) 7 2.82 (1.73-4.58)
Prostate (Hwang et al. 2015) (56) 8 1.20 (1.00-1.44)
Liver (Chen et al. 2015) (43) 21 1.86 (1.49-2.31)
Lung (Zhu et al. 2016) (57) 20 1.28 (1.10-1.49)
Bladder (Fang et al. 2013) (44) 24 1.30 (1.18-1.43)
Ovarian (Lee et al. 2013) (58) 18 1.16 (1.01-1.33)

*CI: confidence interval, RR: relative risk.

As the incidence of DM2 is increasing worldwide, MM, leukemia, and NHL are being diagnosed more frequently with concomitant diabetes mellitus (9,48,51-53). Therefore, physicians who treat patients with these comorbidities must consider the possible effects of the treatments for MM and leukemia on glucose metabolism (54,55).

Antihyperglycemic agents and the risk of cancer

Early studies have observed that compared to no therapy, metformin monotherapy is correlated with a reduced risk of developing cancer, whereas sulfonylurea therapy is correlated with an increased risk (59). These observations led to the hypothesis that hypoglycemic agents differentially influence the risk of cancer, depending on the concentrations of insulin that they induce (60).

Although an initial meta-analysis failed to detect an elevated cancer risk in association with the use of insulin, the meta-analysis had small sample sizes and short durations of study (61,62). Consistent with the above hypothesis, a subsequent meta-analysis in larger populations demonstrated an increase in the overall cancer risk (relative risk [RR] 1.39; 95% CI: 1.14-1.70) correlated with insulin therapy (63-65).

In contrast, a recent meta-analysis reported mixed results concerning insulin secretagogues and the risk of cancer, demonstrating a correlation between the administration of sulfonylureas and an increased risk of some cancers but not others (66,67). In addition, a recent randomized controlled study of over 12,000 patients (average follow-up over six years) failed to demonstrate an increase in the rates of cancer or cancer-specific mortality in insulin users versus controls (68). However, a large meta-analysis of 182 randomized controlled trials including 135,540 patients with diabetes linked the use of metformin and thiazolidinediones (TZDs) with a reduced risk of cancer (69). These reviews suggest that the insulin level is not a surrogate marker of cancer development, thereby indicating a unique mechanism of metformin activity in cancer.

Metformin, cancer, and onco-hematological diseases

History of metformin

Metformin is a derivative of biguanide that has been used for nearly one century to treat DM2. Biguanides initially derived from Galega officinalis (Leguminosae) (or goat’s rue), French lilac, Spanish sainfoin, and false indigo have been recognized for their medicinal value since medieval times in Europe (Figure 1) (70). G. officinalis—arruda-caprária in Brazil—is a medicinal plant that originated in Europe and Asia (62-64), and its medicinal properties have been recognized since medieval times, during which G. officinalis was prescribed in folk medicine to relieve polyuria accompanying DM2 (71).

Figure 1 Galega officinalis (goat’s rue).  

Although G. officinalis reduces glucose concentration in blood of patients with diabetes, the search for its active compound has been slow, primarily due to the effects of light on this plant and the introduction of insulin. Studies at the end of the 19th century indicated that G. officinalis was rich in guanidine, and in 1918, guanidine was shown to have hypoglycemic activity in animals. Nonetheless, guanidine was incredibly toxic for clinical use, prompting interest in galegine (isoamylene guanidine) (71).

In 1929, several biguanides that reduced serum glucose levels, including dimethyl biguanide (1,1-dimethyl biguanide hydrochloride or metformin), were synthesized. Jean Sterne (1909-1997) was the first to perform studies with galegine. Sterne selected dimethyl biguanide (metformin) for clinical development and proposed the name Glucophage. In contrast to sulfonylureas, metformin fails to induce insulin secretion but impedes the release of glucose by the liver and increases muscle glucose uptake (71).

Interestingly, the benefits of metformin in the treatment of diabetes have gained prominence only since 1995. The United Kingdom Prospective Diabetes Study (UKPDS) was a milestone project showing that regardless of glycemic control, metformin reduced the risk of myocardial infarction and all-cause mortality. Consequently, diabetes experts around the world indicated metformin as the first-choice drug for DM2 (70), and metformin has become the most frequently administered agent to treat DM2 (72,73).

In 1995, the benefits of metformin in people with diabetes were found to not only be limited to glycemic control, and metformin was shown to reduce the risk of malignancy in patients with diabetes. Evans et al. (2) were the first group to note an inverse correlation between cancer and metformin use, wherein patients who were exposed to metformin had a low risk of developing cancer. Since then, various studies in DM2 patients have shown that metformin use is associated with a reduced risk of several cancers (2,11,74-79), including prostate cancer (80,81), lung cancer (45,82,83), head and neck cancer (HNC) (84,85), breast cancer (86-88), pancreatic cancer (89), CRC (90-92), endometrial cancer (93), ovarian cancer (94-96) and hepatocellular carcinoma (HCC) (97,98) (Table 4).

Table 4 Meta-analyses and observational and case-control studies on the risk of cancer in organs of patients with diabetes treated with metformin. 

Type of cancer (author and year) Type of study and patient cohort RR, HR or OR (95% CI)*
Several (Evans et al. 2005) (2) Case-Control/2829 OR 0.86 (0.73-1.02)
Several (Zhang et al. 2014) (11) Meta-analysis of 28 studies/NR RR combined 0.70 (0.55-0.88)
Several (Gandini et al. 2014) (78) Meta-analysis of 47 studies/65.540 RR incidence 0.69 (0.52-0.90) RR mortality 0.66 (0.54-0.81)
Several (Yin et al. 2013) (79) Meta-analysis of 20 studies/13.008 HR OS* 0.66 (0.55-0.79) HR OS* 0.62 (0.46-0.84)
Several (Noto et al. 2012) (76) Meta-analysis of 24 studies/21.195 RR mortality 0.66 (0.49-0.88) RR incidence 0.67 (0.53-0.85)
Prostrate (Deng et al. 2015) (80) Meta-analysis of 13 studies/334.532 RR incidence 0.88 (0.78-0.99) RR mortality 1.07 (0.86-1.32)
Prostrate (Raval et al. 2015) (81) Meta-analysis of 9 studies/8284 HR cancer-specific mortality 1.22 (0.58-2.56)
Lung (Sakoda et al. 2015) (82) Retrospective observational/47.351 HR adenocarcinoma 0.69 (0.40-1.17) HR small cell carcinoma 1.82 (0.85-3.91)
Lung (Lin et al. 2015) (83) Retrospective observational/750 HR in favor of metformin use EC IV 0.80 (0.71-0.89)
Lung (Zhu et al. 2015) (45) Meta-analysis of 8 studies/17.997 RR 0.84 (0.73-0.97)
HNC* (Sandulache et al. 2014) (84) Retrospective observational/162 OR OS DM vs. non-DM 2.23 (0.9-5.6; P=0.04) Lower locoregional recurrence (P=0.04)
HNC* (Yen et al., 2014) (85) Retrospective observational/290 The incidence of CCP was 0.64x lower in the metformin group (pcts>65a had lower risk reduction of CCP)
Breast (Col et al. 2012) (86) Meta-analysis of 7 studies/17.997 OR 0.83 (0.71-0.97)
Breast (Jiralerspong et al. 2012) (87) Retrospective/2.529 OR pCR* 2.95 (P=0.04) pCR 24% (met*) x 8% (non-met*)
Breast (Xu et al. 2015) (88) Meta-analysis of 11 studies/5.464 HR OS* 0.53 (0.39-0.71)
Pancreatic (Wang et al. 2014) (89) Meta-analysis of 11 studies/764.195 RR 0.63 (0.46-0.86)
Colon (Lee et al. 2012) (90) Case-Control EC IV/106 HR SLD 0.024 (0.001-0.435) HR OS 0.809 (0.094-6.959)
Colon (Fransgaard et al. 2016) (91) Retrospective observational/30,493 HR DM vs. non-DM 1.12 (1.06-1.18) HR met vs. insulin 0.85 (0.73-0.93)
Colon (Mei et al. 2014) (92) Meta-analysis of 6 studies/2.461 HR OS 0.56 (0.41- 0.77) HR OS-specific 0.66 (0.50-0.87)
Endometrial (Nevadunsky et al. 2014) (93) Retrospective observational/985 HR OS met vs. non-met 0.54 (0.30-0.97)
Ovarian (Dilokthornsakul et al. 2013) (94) Systematic review of 4 studies/ OR 0.57 (0.16-1.99).
Ovarian (Romero et al. 2012) (95) Retrospective observational/341 HR disease recurrence met vs. non-met 0.38 (0.16. 0.90)
Ovarian (Kumar et al. 2013) (96) Retrospective case-control/72 cases and 143 controls HR OS non-met vs. met 2.2 (1.2-3.8)
Liver (Zhang et al. 2012) (97) Meta-analysis of 5 studies/105.495 OR prevention 0.38 (0.24-0.59)
Liver (Ma et al. 2012) (98) Meta-analysis of 11 studies/3452 OR prevention 0.38 (0.24-0.59)

*DM: diabetes mellitus, HNC: head and neck cancer, met: metformin, pCR: pathologic complete response, HR: hazard ratio, OR: odds ratio, OS: Overall survival, RR: relative risk.

Mechanisms of action of metformin and preclinical and ongoing studies in hematologic malignancies

Two potential accepted antineoplastic mechanisms of metformin have been proposed (Figure 2). First, metformin inhibits mitochondrial complex 1, resulting in low ATP production and an increase in the concentration of ADP; ADP is transformed to AMP by the catalytic effect of the enzyme adenylate kinase. Under low ATP concentrations, AMP binds to the γ subunit of AMPK leading to some conformational changes in the α subunit, and this favors the phosphorylation of AMPK (72). Moreover, the inhibition of complex 1 produces reactive nitrogen species. These radicals stimulate protein kinase C ζ (PKCζ), which successively phosphorylates LKB1L and LKB1S, thereby leading to the activation of LKB1. Activated LKB1 phosphorylates and activates AMPK (90), resulting in the inhibition of downstream AKT/mTOR signaling and consequent suppression of cell proliferation (100,101). Second, metformin induces reductions in circulating insulin concentrations and IGF, preventing the activation of the insulin and IGF receptor signaling pathways and resulting in decreased growth promotion and mutagenesis (102,103). Notably, IGF-1 and insulin receptors interact to implement antiapoptotic signaling that increases AKT/mTOR kinase activity (104,105).

Figure 2 The insulin-dependent (indirect effects) and AMPK-dependent molecular mechanisms (direct effects) underlying the anticancer effects of metformin. AMPK activation in the liver results in decreased insulin and IGF-1 levels and consequent attenuated downstream signaling. In cancer cells, AMPK inhibits PI3K/AKT/mTORC1 signaling directly through the phosphorylation of the Raptor subunit and indirectly through the phosphorylation of the TSC1/2 complex and insulin receptor substrate 1 (IRS1) and the activation of regulated in development and DNA damage response 1 (REDD1). In addition, metformin-induced activation of AMPK leads to the phosphorylation of p53, inducing cycle arrest, apoptosis and autophagy. Inhibition of mTORC1 results in a decrease in global protein synthesis and lipogenesis. Metabolic alterations are also achieved by the inhibition of acetyl-CoA carboxylase (ACC) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. 

Despite the importance of LKB1 in the AMPK-dependent antineoplastic effects of metformin, this drug abolishes the increase in tumor growth linked with high-fat diet and hyperinsulinemia, irrespective of LKB1 expression by the tumor. This antineoplastic activity is connected with decreased circulating insulin levels and insulin receptor activation in tumoral tissues, similar to the mechanisms underlying tumor growth repression by dietary control (106-109).

Many studies have shown that metformin synergizes with chemotherapeutic drugs at low doses, minimizing the side effects of high doses (99,110,111). More than 40 phase I/II clinical cancer trials ( on metformin in combination with chemotherapeutics are underway worldwide. These studies are examining the antineoplastic effects of metformin. This drug is used jointly with chemotherapeutic agents in cancers of the digestive (hepatic, gastric, pancreatic, and colorectal) and reproductive systems (ovarian and endometrial) and lung, prostate, and breast cancer, and the clinical limitations of metformin in cancer treatment are being determined. Several trials have reported synergistic or additive effects of such combinations (87,111-131). In contrast, observational retrospective studies have observed that these combinations are antagonistic in certain cancers (132-136). Therefore, metformin synergizes with standard chemotherapy drugs to increase chemosensitivity in specific cancers.

Cell metabolism is epigenetically regulated (137,138). Cells control their metabolism in response to extracellular signals and the availability of nutrients by altering their epigenetic and transcriptional programs. Notably, metformin is also involved in this cooperation between epigenetic and metabolic mechanisms. Du et al. (139) found that metformin decreases histone H2B (H2BK120) and monoubiquitination levels and inhibits the transcription of target genes, such as cyclin D1 and p21. Metformin-activated AMPK increases the histone deacetylase activity of SIRT1 to downregulate acetylated p53 and p21 levels (140). Further, the loss of the MM SET domain (MMSET) in MM cells (141) is regulated by metformin in prostate cancer cells (142). Finally, metformin decreases the levels of a histone demethylase coactivator (143) and a metabolic enzyme in the TCA cycle (144,145).

Myeloma and metformin

AKT mediates the pathogenesis and progression of MM and resistance to standard treatments. Many upstream signaling pathways converge on AKT to govern survival and proliferative signals and apoptosis suppression. Early data have revealed high expression of AKT in myeloma cell lines and bone marrow aspirates from patients, especially in the advanced stages (105). In accordance, in vitro and in vivo, the combination of metformin and dexamethasone synergizes to eliminate MM cells, inhibiting cell proliferation through reduced AKT/mTOR signaling (146). This phenomenon is mediated by the phosphorylation of TSC2 (147), which negatively regulates cell growth by acting upstream of mTOR (148).

Notably, metformin inhibits glucose regulatory protein 78 (GRP78), an essential factor in bortezomib-induced autophagy and pharmacologically increases the anti-myeloma effects of bortezomib. Concomitant treatment with metformin and bortezomib inhibits the effects of the unfolded protein response (UPR) on GRO78, thus impairing autophagosome formation and increasing apoptosis and confirming the impeded growth of xenotransplanted myeloma cells in vivo (149).

The low toxicity and potent in vitro and in vivo effects of metformin, in combination with the findings of retrospective epidemiological studies in various cancer models, have prompted nearly 200 trials ( examining metformin alone or in combination with other antitumoral agents in patients without diabetes. However, few studies are determining the effects of metformin in MM (Table 5).

Table 5 Ongoing clinical studies with metformin in MM. 

Type of disease Disease status Type of study Associated drugs Country of study identifier
MM* or CLL* Recurrent/refractory Pilot Ritonavir USA* NCT02948283
MM* Recurrent/refractory Phase II High doses of dexamethasone BR* NCT02967276

*MM: multiple myeloma, CLL: chronic lymphocytic leukemia, USA: United States of America, BR: Brazil.

Leukemias and metformin

The LKB1/AMPK/mTOR axis functions in hematopoietic cancers, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL); consequently, metformin represents a new perspective in hematological cancer therapy. Nevertheless, metformin does not appear to alter the growth, differentiation, or survival of normal CD34+ stem cells (150-152).

Mutations/deletions in PTEN or post-translational inhibition of its lipid phosphatase activity is responsible for much of the chronic stimulation of PI3K/AKT/mTOR signaling in T-ALL (153). In accordance, deletion of LKB1 in mice on a PTEN+/- background increases the incidence of various tumors, including lymphomas, the development of which is significantly delayed by metformin (154). Thus, metformin might increase the chemosensitivity of ALL through its inhibitory effects on the AKT/mTOR pathway via AMPK activation (155,156).

Insulin might contribute to the chemoresistance of ALL cells by activating PI3K/AKT/mTOR signaling. IGF-1 signaling increases the proliferation of cell lines (157,158) and inhibits dexamethasone-induced apoptosis (158), promoting the growth of malignant cells. Thus, elevated levels of exogenous insulin might activate insulin and IGF-1 receptor (IGF-1R) on ALL blasts (157), a phenomenon that can be blocked through a metformin-mediated reduction in insulin levels.

The PI3K/AKT/mTOR pathway is also stimulated by upstream oncogenes, such as the protein kinase BCR-ABL, a t(9,22) translocation product in chronic and acute Ph1+ leukemias, and the Tax oncoprotein, which is central in the pathogenesis of HTLV human retrovirus infection and adult T cell leukemia. Through the activation of AMPK, metformin suppresses the proliferation and clonogenic activity of several chronic myeloid leukemia (CML) lines, such as those that are imatinib-resistant and T315I BCR-ABL mutants (152).

In leukemic stem cells and stem cells of solid tumors, metformin is selective toward inducing death in vitro and tumor xenografts (159). These findings are notable because the leukemic stem cells that persist despite antineoplastic treatment are one of the causes of neoplasia relapse (160).

When combined with chemotherapy or other drugs, metformin might have additive effects on reducing cell growth and drug efflux through its activity on AMPK or P-glycoprotein (161,162). In acute promyelocytic leukemia (APL), metformin synergizes with trans-retinoic acid, inducing the differentiation and apoptosis in leukemic blasts (163). An examination of glucose dependence in chronic lymphocytic leukemia (CLL) cells demonstrated differential sensitivity to glucose deprivation; thus, the administration of the HIV protease inhibitor ritonavir and metformin to CLL cells has provided a strong rationale to target glucose metabolism and the ensuing metabolic plasticity in CLL (164).

Based on these findings, future studies should examine the role of metformin in improving chemotherapy outcomes in ALL patients with or without diabetes. Many trials are testing metformin in patients without diabetes who have solid tumors. Four recent clinical trials ( are measuring the clinical and biological outcomes of metformin combined with standard systemic chemotherapy in relapsed ALL (Table 6), and their findings will be reported soon.

Table 6 Ongoing clinical studies with metformin in leukemias and lymphomas. 

Type of disease Disease status Type of study Associated drugs Country of study identifier
CLL* Relapsed and untreated disease Pilot None USA* NCT01750567
CLL* or MM* Recurrent/refractory Pilot Ritonavir USA* NCT02948283
ALL Relapsed Phase I Vincristine, dexamethasone, doxorubicin, and PEG-asparaginase USA* NCT01324180
AML* Relapsed and refractory Phase I Cytarabine USA* NCT01849276
NHL* other solid tumors Relapsed and refractory to other treatments Phase I Sirolimus USA* NCT02145559
NHL* other solid tumors Relapsed and refractory to other treatments Phase I Temsirolimus Canada NCT00659568
DLBCL* Previously, untreated Phase II R-CHOP USA* NCT02531308
DLBCL* Double-hit lymphoma Phase II DA-EPOCH-R USA* NCT02815397

*ALL: acute lymphocytic leukemia, AML: acute myeloid leukemia, CLL: chronic lymphocytic leukemia, DA-EPOCHR: dose-adjusted etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin + rituximab, MM: multiple myeloma, NHL: non-Hodgkin lymphoma, DLBCL: diffuse large B cell lymphoma, R-CHOP: rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone, USA: United States of America.

Lymphoma and metformin

Shi et al. (165) have provided the first evidence of the in vitro and in vivo activity of metformin in human lymphoma cells, demonstrating that the activity of drug on AMPK inhibits the growth of B and T cell lymphomas by inhibiting mTOR signaling without the involvement of AKT. Moreover, the response of lymphoma to drugs such as doxorubicin and temsirolimus, a mTOR inhibitor, is significantly improves upon coadministration with metformin. In addition to inhibiting the mTOR pathway, metformin activates p53 by suppressing murine double minute X (MDMX), thereby causing apoptosis (166).

Rosilio et al. (167) demonstrated that metformin, phenformin, and AICAR, an AMPK activator, have robust antitumor activities against human T-LEN and human T-ALL lines. The mechanism of action of these agents is to suppress tumor metabolism and proliferation by inducing apoptosis, activating AMPK, and constitutively inhibiting mTOR. Further, several signal transduction pathways [mTOR, AKT, NF-kappaB (NF-κB), Fatty acid synthase (FASN), and insulin-like growth factor-1 receptor (IGF-1R)] are overexpressed in Peripheral T-cell lymphomas (PTCL), supporting the use of metformin as an inhibitor of mTORC2 and NF-κB in PTCL (168).

In diffuse large B cell lymphoma (DLBCL) patients with diabetes, metformin, as a first-line chemoimmunotherapeutic agent with rituximab, improved progression-free survival (PFS; 94 months vs. 55.4 months, P=0.007) and overall survival (OS; 100 months vs. 70.5 months, P=0.031) compared with other antidiabetogenic agents (169). Despite the impressive results of this retrospective trial, only four ongoing clinical trials ( are evaluating the effects of metformin with standard systemic chemotherapy in the settings of relapsed and refractory NHL (Table 6).

The combined increase in the occurrence of diabetes, obesity, and cancer has created a significant problem in which complex disease pathophysiologies are intertwined. Dissection of the epidemiological and molecular links between these diseases has revealed novel target molecules and new treatment opportunities. In conjunction with interdisciplinary research, epidemiological and preclinical data support that metformin benefits select patients with solid tumors and hematological tumors; however, strict clinical trials are required to pinpoint patients who might benefit from metformin combinations. Thus, we need to assess whether the anticancer effects of metformin depend on metabolic variables, such as diabetes, BMI, insulin resistance, and obesity-related inflammation.


1. Klil-Drori AJ, Azoulay L, Pollak MN. Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? Nat Rev Clin Oncol. 2017;14(2):85-99, 10.1038/nrclinonc.2016.120. [ Links ]

2. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304-5, 10.1136/bmj.38415.708634.F7. [ Links ]

3. Shlomai G, Neel B, LeRoith D, Gallagher EJ. Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy. J Clin Oncol. 2016;34(35):4261-9, 10.1200/JCO.2016.67.4044. [ Links ]

4. Colhoun HM; SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009;52(9):1755-65, 10.1007/s00125-009-1453-1. [ Links ]

5. Renehan AG, Roberts DL, Dive C. Obesity and cancer: pathophysiological and biological mechanisms. Arch Physiol Biochem. 2008;114(1):71-83, 10.1080/13813450801954303. [ Links ]

6. Larsson SC, Wolk A. Overweight and obesity and incidence of leukemia: a meta-analysis of cohort studies. Int J Cancer. 2008;122(6):1418-21, 10.1002/ijc.23176. [ Links ]

7. Larsson SC, Wolk A. Body mass index and risk of non-Hodgkin's and Hodgkin's lymphoma: a meta-analysis of prospective studies. Eur J Cancer. 2011;47(16):2422-30, 10.1016/j.ejca.2011.06.029. [ Links ]

8. Wallin A, Larsson SC. Body mass index and risk of multiple myeloma: a meta-analysis of prospective studies. Eur J Cancer. 2011;47(11):1606-15, 10.1016/j.ejca.2011.01.020. [ Links ]

9. Khan AE, Gallo V, Linseisen J, Kaaks R, Rohrmann S, Raaschou-Nielsen O, et al. EPIC Group. Diabetes and the risk of non-Hodgkin's lymphoma and multiple myeloma in the European Prospective Investigation into Cancer and Nutrition. Haematologica. 2008;93(6):842-50, 10.3324/haematol.12297. [ Links ]

10. Wojciechowska J, Krajewski W, Bolanowski M, Kręcicki T, Zatoński T. Diabetes and Cancer: a Review of Current Knowledge. Exp Clin Endocrinol Diabetes. 2016;124(5):263-75, 10.1055/s-0042-100910. [ Links ]

11. Zhang ZJ, Li S. The prognostic value of metformin for cancer patients with concurrent diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16(8):707-10, 10.1111/dom.12267. [ Links ]

12. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. CA Cancer J Clin. 2010;60(4):207-21, 10.3322/caac.20078. [ Links ]

13. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625-38, 10.1056/NEJMoa021423. [ Links ]

14. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569-78, 10.1016/S0140-6736(08)60269-X. [ Links ]

15. Landgren O, Rajkumar SV, Pfeiffer RM, Kyle RA, Katzmann JA, Dispenzieri A, et al. Obesity is associated with an increased risk of monoclonal gammopathy of undetermined significance among black and white women. Blood. 2010;116(7):1056-9, 10.1182/blood-2010-01-262394. [ Links ]

16. Fernberg P, Odenbro A, Bellocco R, Boffetta P, Pawitan Y, Zendehdel K, et al. Tobacco use, body mass index, and the risk of leukemia and multiple myeloma: a nationwide cohort study in Sweden. Cancer Res. 2007;67(12):5983-6, 10.1158/0008-5472.CAN-07-0274. [ Links ]

17. Larsson SC, Wolk A. Body mass index and risk of multiple myeloma: a meta-analysis. Int J Cancer. 2007;121(11):2512-6, 10.1002/ijc.22968. [ Links ]

18. Castillo JJ, Mulkey F, Geyer S, Kolitz JE, Blum W, Powell BL, et al. Relationship between obesity and clinical outcome in adults with acute myeloid leukemia: A pooled analysis from four CALGB (alliance) clinical trials. Am J Hematol. 2016;91(2):199-204, 10.1002/ajh.24230. [ Links ]

19. Chang SH, Luo S, Thomas TS, O'Brian KK, Colditz GA, Carlsson NP, et al. Obesity and the Transformation of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: A Population-Based Cohort Study. J Natl Cancer Inst. 2016;109(5):djw264, 10.1093/jnci/djw264. [ Links ]

20. Leo QJ, Ollberding NJ, Wilkens LR, Kolonel LN, Henderson BE, Le Marchand L, et al. Obesity and non-Hodgkin lymphoma survival in an ethnically diverse population: the Multiethnic Cohort study. Cancer Causes Control. 2014;25(11):1449-59, 10.1007/s10552-014-0447-6. [ Links ]

21. Lichtman MA. Obesity and the risk for a hematological malignancy: leukemia, lymphoma, or myeloma. Oncologist. 2010;15(10):1083-101, 10.1634/theoncologist.2010-0206. [ Links ]

22. Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K; International Agency for Research on Cancer Handbook Working Group. Body Fatness and Cancer-Viewpoint of the IARC Working Group. N Engl J Med. 2016;375(8):794-8, 10.1056/NEJMsr1606602. [ Links ]

23. Kyrgiou M, Kalliala I, Markozannes G, Gunter MJ, Paraskevaidis E, Gabra H, et al. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ. 2017;356:j477, 10.1136/bmj.j477. [ Links ]

24. Gallagher EJ, LeRoith D. Diabetes, antihyperglycemic medications and cancer risk: smoke or fire? Curr Opin Endocrinol Diabetes Obes. 2013;20(5):485-94, 10.1097/ [ Links ]

25. Larsson SC, Wolk A. Obesity and risk of non-Hodgkin's lymphoma: a meta-analysis. Int J Cancer. 2007;121(7):1564-70, 10.1002/ijc.22762. [ Links ]

26. Nagel G, Stocks T, Späth D, Hjartåker A, Lindkvist B, Hallmans G, et al. Metabolic factors and blood cancers among 578,000 adults in the metabolic syndrome and cancer project (Me-Can). Ann Hematol. 2012;91(10):1519-31, 10.1007/s00277-012-1489-z. [ Links ]

27. Hofmann JN, Birmann BM, Teras LR, Pfeiffer RM, Wang Y, Albanes D, et al. Low Levels of Circulating Adiponectin Are Associated with Multiple Myeloma Risk in Overweight and Obese Individuals. Cancer Res. 2016;76(7):1935-41, 10.1158/0008-5472.CAN-15-2406. [ Links ]

28. Hofmann JN, Mailankody S, Korde N, Wang Y, Tageja N, Costello R, et al. Circulating Adiponectin Levels Differ Between Patients with Multiple Myeloma and its Precursor Disease. Obesity (Silver Spring). 2017;25(8):1317-20, 10.1002/oby.21894. [ Links ]

29. Hopkins BD, Goncalves MD, Cantley LC. Obesity and Cancer Mechanisms: Cancer Metabolism. J Clin Oncol. 2016;34(35):4277-83, 10.1200/JCO.2016.67.9712. [ Links ]

30. Marmot M, Atinmo T, Byers T, Chen J, Hirohata T, Jackson A, et al. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington DC: World Cancer Research Fund/American Institute for Cancer Research; 2007. [ Links ]

31. Calle EE, Thun MJ. Obesity and cancer. Oncogene. 2004;23(38):6365-78, 10.1038/sj.onc.1207751. [ Links ]

32. Arnold M, Pandeya N, Byrnes G, Renehan PA, Stevens GA, Ezzati PM, et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. 2015;16(1):36-46, 10.1016/S1470-2045(14)71123-4. [ Links ]

33. Bergström A, Pisani P, Tenet V, Wolk A, Adami HO. Overweight as an avoidable cause of cancer in Europe. Int J Cancer. 2001;91(3):421-30. Erratum in: Int J Cancer 2001;92(6):927, doi: 10.1002/1097-0215(200002)9999:9999<::AID-IJC1053>3.0.CO;2-T. [ Links ]

34. Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults. Lancet. 2014;384(9945):755-65, 10.1016/S0140-6736(14)60892-8. [ Links ]

35. Azevedo e, Silva G, de Moura L, Curado MP, Gomes FS, Otero U, Rezende LF, et al. The Fraction of Cancer Attributable to Ways of Life, Infections, Occupation, and Environmental Agents in Brazil in 2020. PLoS One. 2016;11(2):e0148761, 10.1371/journal.pone.0148761. [ Links ]

36. Luo W, Cao Y, Liao C, Gao F. Diabetes mellitus and the incidence and mortality of colorectal cancer: a meta-analysis of 24 cohort studies. Colorectal Dis. 2012;14(11):1307-12, 10.1111/j.1463-1318.2012.02875.x. [ Links ]

37. Boyle P, Boniol M, Koechlin A, Robertson C, Valentini F, Coppens K, et al. Diabetes and breast cancer risk: a meta-analysis. Br J Cancer. 2012;107(9):1608-17, 10.1038/bjc.2012.414. [ Links ]

38. Ben Q, Xu M, Ning X, Liu J, Hong S, Huang W, et al. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. Eur J Cancer. 2011;47(13):1928-37, 10.1016/j.ejca.2011.03.003. [ Links ]

39. Bonovas S, Filioussi K, Tsantes A. Diabetes mellitus and risk of prostate cancer: a meta-analysis. Diabetologia. 2004;47(6):1071-8, 10.1007/s00125-004-1415-6. [ Links ]

40. Yang WS, Va P, Bray F, Gao S, Gao J, Li HL, et al. The role of pre-existing diabetes mellitus on hepatocellular carcinoma occurrence and prognosis: a meta-analysis of prospective cohort studies. PLoS One. 2011;6(12):e27326, 10.1371/journal.pone.0027326. [ Links ]

41. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol. 2004;159(12):1160-7, 10.1093/aje/kwh161. [ Links ]

42. Long XJ, Lin S, Sun YN, Zheng ZF. Diabetes mellitus and prostate cancer risk in Asian countries: a meta-analysis. Asian Pac J Cancer Prev. 2012;13(8):4097-100, 10.7314/APJCP.2012.13.8.4097. [ Links ]

43. Chen J, Han Y, Xu C, Xiao T, Wang B. Effect of type 2 diabetes mellitus on the risk for hepatocellular carcinoma in chronic liver diseases: a meta-analysis of cohort studies. Eur J Cancer Prev. 2015;24(2):89-99, 10.1097/CEJ.0000000000000038. [ Links ]

44. Fang H, Yao B, Yan Y, Xu H, Liu Y, Tang H, et al. Diabetes mellitus increases the risk of bladder cancer: an updated meta-analysis of observational studies. Diabetes Technol Ther. 2013;15(11):914-22, 10.1089/dia.2013.0131. [ Links ]

45. Zhu N, Zhang Y, Gong YI, He J, Chen X. Metformin and lung cancer risk of patients with type 2 diabetes mellitus: A meta-analysis. Biomed Rep. 2015;3(2):235-41, 10.3892/br.2015.417. [ Links ]

46. Tseng CH, Tseng FH. Diabetes and gastric cancer: the potential links. World J Gastroenterol. 2014;20(7):1701-11, 10.3748/wjg.v20.i7.1701. [ Links ]

47. Chen Y, Wu F, Saito E, Lin Y, Song M, Luu HN, et al. Association between type 2 diabetes and risk of cancer mortality: a pooled analysis of over 771,000 individuals in the Asia Cohort Consortium. Diabetologia. 2017;60(6):1022-32, 10.1007/s00125-017-4229-z. [ Links ]

48. Castillo JJ, Mull N, Reagan JL, Nemr S, Mitri J. Increased incidence of non-Hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: a meta-analysis of observational studies. Blood. 2012;119(21):4845-50, 10.1182/blood-2011-06-362830. [ Links ]

49. Chiu BC, Gapstur SM, Greenland P, Wang R, Dyer A. Body mass index, abnormal glucose metabolism, and mortality from hematopoietic cancer. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2348-54, 10.1158/1055-9965.EPI-06-0007. [ Links ]

50. Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis JP. Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ. 2015;350:g7607, 10.1136/bmj.g7607. [ Links ]

51. Richardson PG, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, et al. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol. 2009;144(6):895-903, 10.1111/j.1365-2141.2008.07573.x. [ Links ]

52. Richardson PG, Briemberg H, Jagannath S, Wen PY, Barlogie B, Berenson J, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24(19):3113-20, 10.1200/JCO.2005.04.7779. [ Links ]

53. Badros A, Goloubeva O, Dalal JS, Can I, Thompson J, Rapoport AP, et al. Neurotoxicity of bortezomib therapy in multiple myeloma: a single-center experience and review of the literature. Cancer. 2007;110(5):1042-9, 10.1002/cncr.22921. [ Links ]

54. Jagannath S. Treatment of patients with myeloma with comorbid conditions: considerations for the clinician. Clin Lymphoma Myeloma. 2008;8Suppl 4:S149-56, 10.3816/CLM.2008.s.011. [ Links ]

55. Koltin D, Sung L, Naqvi A, Urbach SL. Medication induced diabetes during induction in pediatric acute lymphoblastic leukemia: prevalence, risk factors and characteristics. Support Care Cancer. 2012;20(9):2009-15, 10.1007/s00520-011-1307-5. [ Links ]

56. Hwang IC, Park SM, Shin D, Ahn HY, Rieken M, Shariat SF. Metformin association with lower prostate cancer recurrence in type 2 diabetes: a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2015;16(2):595-600, 10.7314/APJCP.2015.16.2.595. [ Links ]

57. Zhu L, Cao H, Zhang T, Shen H, Dong W, Wang L, et al. The Effect of Diabetes Mellitus on Lung Cancer Prognosis: A PRISMA-compliant Meta-analysis of Cohort Studies. Medicine (Baltimore). 2016;95(17):e3528, 10.1097/MD.0000000000003528. [ Links ]

58. Lee JY, Jeon I, Kim JW, Song YS, Yoon JM, Park SM. Diabetes mellitus and ovarian cancer risk: a systematic review and meta-analysis of observational studies. Int J Gynecol Cancer. 2013;23(3):402-12, 10.1097/IGC.0b013e31828189b2. [ Links ]

59. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52(9):1766-77, 10.1007/s00125-009-1440-6. [ Links ]

60. Onitilo AA, Engel JM, Glurich I, Stankowski RV, Williams GM, Doi SA. Diabetes and cancer II: role of diabetes medications and influence of shared risk factors. Cancer Causes Control. 2012;23(7):991-1008, 10.1007/s10552-012-9971-4. [ Links ]

61. Home PD, Lagarenne P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia. 2009;52(12):2499-506, 10.1007/s00125-009-1530-5. [ Links ]

62. Dejgaard A, Lynggaard H, Råstam J, Krogsgaard Thomsen M. No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis. Diabetologia. 2009;52(12):2507-12, 10.1007/s00125-009-1568-4. [ Links ]

63. Janghorbani M, Dehghani M, Salehi-Marzijarani M. Systematic review and meta-analysis of insulin therapy and risk of cancer. Horm Cancer. 2012;3(4):137-46, 10.1007/s12672-012-0112-z. [ Links ]

64. Karlstad O, Starup-Linde J, Vestergaard P, Hjellvik V, Bazelier MT, Schmidt MK, et al. Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies. Curr Drug Saf. 2013;8(5):333-48, 10.2174/15680266113136660067. [ Links ]

65. Colmers IN, Bowker SL, Tjosvold LA, Johnson JA. Insulin use and cancer risk in patients with type 2 diabetes: a systematic review and meta-analysis of observational studies. Diabetes Metab. 2012;38(6):485-506, 10.1016/j.diabet.2012.08.011. [ Links ]

66. Soranna D, Scotti L, Zambon A, Bosetti C, Grassi G, Catapano A, et al. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist. 2012;17(6):813-22, 10.1634/theoncologist.2011-0462. [ Links ]

67. Thakkar B, Aronis KN, Vamvini MT, Shields K, Mantzoros CS. Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies. Metabolism. 2013;62(7):922-34, 10.1016/j.metabol.2013.01.014. [ Links ]

68. Bordeleau L, Yakubovich N, Dagenais GR, Rosenstock J, Probstfield J, Chang Yu P, et al. The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care. 2014;37(5):1360-6, 10.2337/dc13-1468. [ Links ]

69. Wu L, Zhu J, Prokop LJ, Murad MH. Pharmacologic Therapy of Diabetes and Overall Cancer Risk and Mortality: A Meta-Analysis of 265 Studies. Sci Rep. 2015;5:10147, 10.1038/srep10147. [ Links ]

70. Witters LA. The blooming of the French lilac. J Clin Invest. 2001;108(8):1105-7, 10.1172/JCI14178. [ Links ]

71. Bailey CJ. Metformin: its botanical background. Pract Diab Int. 2004;21(3):115-7, 10.1002/pdi.606. [ Links ]

72. Gong J, Kelekar G, Shen J, Shen J, Kaur S, Mita M. The expanding role of metformin in cancer: an update on antitumor mechanisms and clinical development. Target Oncol. 2016;11(4):447-67, 10.1007/s11523-016-0423-z. [ Links ]

73. Papanagnou P, Stivarou T, Tsironi M. Unexploited Antineoplastic Effects of Commercially Available Anti-Diabetic Drugs. Pharmaceuticals (Basel). 2016;9(2):E24. [ Links ]

74. Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol. 2013;37(3):207-18, 10.1016/j.canep.2012.12.009. [ Links ]

75. Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2010;3(11):1451-61. [ Links ]

76. Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One. 2012;7(3):e33411, 10.1371/journal.pone.0033411. [ Links ]

77. Franciosi M, Lucisano G, Lapice E, Strippoli GF, Pellegrini F, Nicolucci A. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One. 2013;8(8):e71583, 10.1371/journal.pone.0071583. [ Links ]

78. Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, et al. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res (Phila). 2014;7(9):867-85. [ Links ]

79. Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist. 2013;18(12):1248-55, 10.1634/theoncologist.2013-0111. [ Links ]

80. Deng D, Yang Y, Tang X, Skrip L, Qiu J, Wang Y, et al. Association between metformin therapy and incidence, recurrence and mortality of prostate cancer: evidence from a meta-analysis. Diabetes Metab Res Rev. 2015;31(6):595-602, 10.1002/dmrr.2645. [ Links ]

81. Raval AD, Thakker D, Vyas A, Salkini M, Madhavan S, Sambamoorthi U. Impact of metformin on clinical outcomes among men with prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2015;18(2):110-21, 10.1038/pcan.2014.52. [ Links ]

82. Sakoda LC, Ferrara A, Achacoso NS, Peng T, Ehrlich SF, Quesenberry CP Jr, et al. Metformin use and lung cancer risk in patients with diabetes. Cancer Prev Res (Phila). 2015;8(2):174-9. [ Links ]

83. Lin JJ, Gallagher EJ, Sigel K, Mhango G, Galsky MD, Smith CB, et al. Survival of patients with stage IV lung cancer with diabetes treated with metformin. Am J Respir Crit Care Med. 2015;191(4):448-54, 10.1164/rccm.201407-1395OC. [ Links ]

84. Sandulache VC, Hamblin JS, Skinner HD, Kubik MW, Myers JN, Zevallos JP. Association between metformin use and improved survival in patients with laryngeal squamous cell carcinoma. Head Neck. 2014;36(7):1039-43, 10.1002/hed.23409. [ Links ]

85. Yen YC, Lin C, Lin SW, Lin YS, Weng SF. Effect of metformin on the incidence of head and neck cancer in diabetics. Head Neck. 2015;37(9):1268-73, 10.1002/hed.23743. [ Links ]

86. Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT. Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat. 2012;135(3):639-46, 10.1007/s10549-012-2170-x. [ Links ]

87. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27(20):3297-302, 10.1200/JCO.2009.19.6410. [ Links ]

88. Xu H, Chen K, Jia X, Tian Y, Dai Y, Li D, et al. Metformin Use Is Associated With Better Survival of Breast Cancer Patients With Diabetes: A Meta-Analysis. Oncologist. 2015;20(11):1236-44, 10.1634/theoncologist.2015-0096. [ Links ]

89. Wang Z, Lai ST, Xie L, Zhao JD, Ma NY, Zhu J, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2014;106(1):19-26, 10.1016/j.diabres.2014.04.007. [ Links ]

90. Lee DJ, Kim B, Lee JH, Park SJ, Hong SP, Cheon JH, et al. The effect of metformin on responses to chemotherapy and survival in stage IV colorectal cancer with diabetes. Korean J Gastroenterol. 2012;60(6):355-61, 10.4166/kjg.2012.60.6.355. [ Links ]

91. Fransgaard T, Thygesen LC, Gögenur I. Metformin Increases Overall Survival in Patients with Diabetes Undergoing Surgery for Colorectal Cancer. Ann Surg Oncol. 2016;23(5):1569-75, 10.1245/s10434-015-5028-8. [ Links ]

92. Mei ZB, Zhang ZJ, Liu CY, Liu Y, Cui A, Liang ZL, et al. Survival benefits of metformin for colorectal cancer patients with diabetes: a systematic review and meta-analysis. PLoS One. 2014;9(3):e91818, 10.1371/journal.pone.0091818. [ Links ]

93. Nevadunsky NS, Van Arsdale A, Strickler HD, Moadel A, Kaur G, Frimer M, et al. Metformin use and endometrial cancer survival. Gynecol Oncol. 2014;132(1):236-40, 10.1016/j.ygyno.2013.10.026. [ Links ]

94. Dilokthornsakul P, Chaiyakunapruk N, Termrungruanglert W, Pratoomsoot C, Saokaew S, Sruamsiri R. The effects of metformin on ovarian cancer: a systematic review. Int J Gynecol Cancer. 2013;23(9):1544-51, 10.1097/IGC.0b013e3182a80a21. [ Links ]

95. Romero IL, McCormick A, McEwen KA, Park S, Karrison T, Yamada SD, et al. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol. 2012;119(1):61-7, 10.1097/AOG.0b013e3182393ab3. [ Links ]

96. Kumar S, Meuter A, Thapa P, Langstraat C, Giri S, Chien J, et al. Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer. 2013;119(3):555-62, 10.1002/cncr.27706. [ Links ]

97. Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(7):2347-53, 10.1210/jc.2012-1267. [ Links ]

98. Ma SJ, Zheng YX, Zhou PC, Xiao YN, Tan HZ. Metformin use improves survival of diabetic liver cancer patients: systematic review and meta-analysis. Oncotarget. 2016;7(40):66202-211. [ Links ]

99. Rocha GZ, Dias MM, Ropelle ER, Osório-Costa F, Rossato FA, Vercesi AE, et al. Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res. 2011;17(12):3993-4005, 10.1158/1078-0432.CCR-10-2243. [ Links ]

100. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167-74, 10.1172/JCI13505. [ Links ]

101. Hawley SA, Gadalla AE, Olsen GS, Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adeninenucleotide-independent mechanism. Diabetes. 2002;51(8):2420-5, 10.2337/diabetes.51.8.2420. [ Links ]

102. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12(3):159-69, 10.1038/nrc3215. [ Links ]

103. Martin M, Marais R. Metformin: a diabetes drug for cancer, or a cancer drug for diabetics? J Clin Oncol. 2012;30(21):2698-700, 10.1200/JCO.2012.42.1677. [ Links ]

104. Abroun S, Ishikawa H, Tsuyama N, Liu S, Li FJ, Otsuyama K, et al. Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I in myeloma cells that highly express IL-6 receptor alpha [corrected]. Blood. 2004;103(6):2291-8, 10.1182/blood-2003-07-2187. [ Links ]

105. Keane NA, Glavey SV, Krawczyk J, O'Dwyer M. AKT as a therapeutic target in multiple myeloma. Expert Opin Ther Targets. 2014;18(8):897-915, 10.1517/14728222.2014.924507. [ Links ]

106. Hadad SM, Baker L, Quinlan PR, Robertson KE, Bray SE, Thomson G, et al. Histological evaluation of AMPK signalling in primary breast cancer. BMC Cancer. 2009;9:307, 10.1186/1471-2407-9-307. [ Links ]

107. Wingo SN, Gallardo TD, Akbay EA, Liang MC, Contreras CM, Boren T, et al. Somatic LKB1 mutations promote cervical cancer progression. PLoS One. 2009;4(4):e5137, 10.1371/journal.pone.0005137. [ Links ]

108. Algire C, Amrein L, Bazile M, David S, Zakikhani M, Pollak M. Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene. 2011;30(10):1174-82, 10.1038/onc.2010.483. [ Links ]

109. Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17(4):351-9, 10.1038/ncb3124. [ Links ]

110. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 2011;71(9):3196-201, 10.1158/0008-5472.CAN-10-3471. [ Links ]

111. Hanna RK, Zhou C, Malloy KM, Sun L, Zhong Y, Gehrig PA, et al. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecol Oncol. 2012;125(2):458-69, 10.1016/j.ygyno.2012.01.009. [ Links ]

112. Kim HJ, Kwon H, Lee JW, Kim HJ, Lee SB, Park HS, et al. Metformin increases survival in hormone receptor-positive,HER2-positive breast cancer patients with diabetes. Breast Cancer Res. 2015;17:64, 10.1186/s13058-015-0574-3. [ Links ]

113. Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, et al. Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget. 2015;6(14):12748-62, 10.18632/oncotarget.3327. [ Links ]

114. Hsieh SC, Tsai JP, Yang SF, Tang MJ, Hsieh YH. Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the ERK/JNK-mediated NF-κB-dependent pathway that reduces uPA and MMP-9 expression. Amino Acids. 2014;46(12):2809-22, 10.1007/s00726-014-1838-4. [ Links ]

115. Yamazaki K, Yasuda N, Inoue T, Nagakura T, Kira K, Saeki T, et al. The combination of metformin and a dipeptidyl peptidase IV inhibitor prevents 5-fluorouracil-induced reduction of small intestine weight. Eur J Pharmacol. 2004;488(1-3):213-8, 10.1016/j.ejphar.2004.02.019. [ Links ]

116. Li W, Wang QL, Liu X, Dong SH, Li HX, Li CY, et al. Combined use of vitamin D3 and metformin exhibits synergistic chemopreventive effects on colorectal neoplasia in rats and mice. Cancer Prev Res(Phila). 2015;8(2):139-48. [ Links ]

117. Chai X, Chu H, Yang X, Meng Y, Shi P, Gou S. Metformin Increases Sensitivity of Pancreatic Cancer Cells to Gemcitabine by Reducing CD133+ Cell Populations and Suppressing ERK/P70S6K Signaling. Sci Rep. 2015;5:14404, 10.1038/srep14404. [ Links ]

118. Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia. 2011;13(5):483-91, 10.1593/neo.11148. [ Links ]

119. Xie Y, Wang YL, Yu L, Hu Q, Ji L, Zhang Y, et al. Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. J Steroid Biochem Mol Biol. 2011;126(3-5):113-20, 10.1016/j.jsbmb.2010.12.006. [ Links ]

120. Rothermundt C, Hayoz S, Templeton AJ, Winterhalder R, Strebel RT, Bärtschi D, et al. Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur Urol. 2014;66(3):468-74, 10.1016/j.eururo.2013.12.057. [ Links ]

121. Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, et al. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 2010;70(6):2465-75, 10.1158/0008-5472.CAN-09-2782. [ Links ]

122. Babcook MA, Shukla S, Fu P, Vazquez EJ, Puchowicz MA, Molter JP, et al. Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer. Mol Cancer Ther. 2014;13(10):2288-302, 10.1158/1535-7163.MCT-14-0451. [ Links ]

123. Liu H, Scholz C, Zang C, Schefe JH, Habbel P, Regierer AC, et al. Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Res. 2012;32(5):1627-37. [ Links ]

124. Soo JS, Ng CH, Tan SH, Malik RA, Teh YC, Tan BS, et al. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells. Apoptosis. 2015;20(10):1373-87, 10.1007/s10495-015-1158-5. [ Links ]

125. Chen H, Yao W, Chu Q, Han R, Wang Y, Sun J, et al. Synergistic effects of metformin in combination with EGFR-TKI in the treatment of patients with advanced non-small cell lung cancer and type 2 diabetes. Cancer Lett. 2015;369(1):97-102, 10.1016/j.canlet.2015.08.024. [ Links ]

126. Li L, Han R, Xiao H, Lin C, Wang Y, Liu H, et al. Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res. 2014;20(10):2714-26, 10.1158/1078-0432.CCR-13-2613. [ Links ]

127. Lin CC, Yeh HH, Huang WL, Yan JJ, Lai WW, Su WP, et al. Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol. 2013;49(2):241-50, 10.1165/rcmb.2012-0244OC. [ Links ]

128. Honjo S, Ajani JA, Scott AW, Chen Q, Skinner HD, Stroehlein J, et al. Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer. Int J Oncol. 2014;45(2):567-74, 10.3892/ijo.2014.2450. [ Links ]

129. Hadad SM, Coates P, Jordan LB, Dowling RJ, Chang MC, Done SJ, et al. Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial. Breast Cancer Res Treat. 2015;150(1):149-55, 10.1007/s10549-015-3307-5. [ Links ]

130. Mitsuhashi A, Kiyokawa T, Sato Y, Shozu M. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. Cancer. 2014;120(19):2986-95, 10.1002/cncr.28853. [ Links ]

131. Miranda VC, Braghiroli MI, Faria LD, Bariani G, Alex A, Bezerra Neto JE, et al. Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients With Refractory Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2016;15(4):321-8.e1, 10.1016/j.clcc.2016.04.011. [ Links ]

132. Reni M, Dugnani E, Cereda S, Belli C, Balzano G, Nicoletti R, et al. (Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial. Clin Cancer Res. 2016;22(5):1076-85, 10.1158/1078-0432.CCR-15-1722. [ Links ]

133. Sui X, Xu Y, Yang J, Fang Y, Lou H, Han W, et al. Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation. PLoS One. 2014;9(5):e97781, 10.1371/journal.pone.0097781. [ Links ]

134. Lesan V, Ghaffari SH, Salaramoli J, Heidari M, Rostami M, Alimoghaddam K, et al. Evaluation of antagonistic effects of metformin with Cisplatin in gastric cancer cells. Int J Hematol Oncol Stem Cell Res. 2014;8(3):12-9. [ Links ]

135. Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015;16(7):839-47, 10.1016/S1470-2045(15)00027-3. [ Links ]

136. Sayed R, Saad AS, El Wakeel L, Elkholy E, Badary O. Metformin Addition to Chemotherapy in Stage IV Non-Small Cell Lung Cancer: an Open Label Randomized Controlled Study. Asian Pac J Cancer Prev. 2015;16(15):6621-6, 10.7314/APJCP.2015.16.15.6621. [ Links ]

137. Yu X, Li S. Non-metabolic functions of glycolytic enzymes in tumorigenesis. Oncogene. 2017;36(19):2629-36, 10.1038/onc.2016.410. [ Links ]

138. Li S, Swanson SK, Gogol M, Florens L, Washburn MP, Workman JL, et al. Serine and SAM Responsive Complex SESAME Regulates Histone Modification Crosstalk by Sensing Cellular Metabolism. Mol Cell. 2015;60(3):408-21, 10.1016/j.molcel.2015.09.024. [ Links ]

139. DU Y, Zheng H, Wang J, Ren Y, Li M, Gong C, et al. Metformin inhibits histone H2B monoubiquitination and downstream gene transcription in human breast cancer cells. Oncol Lett. 2014;8(2):809-12, 10.3892/ol.2014.2158. [ Links ]

140. Zhang E, Guo Q, Gao H, Xu R, Teng S, Wu Y. Metformin and Resveratrol Inhibited High Glucose-Induced Metabolic Memory of Endothelial Senescence through SIRT1/p300/p53/p21 Pathway. PLoS One. 2015;10(12):e0143814, 10.1371/journal.pone.0143814. [ Links ]

141. Martinez-Garcia E, Popovic R, Min DJ, Sweet SM, Thomas PM, Zamdborg L, et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood. 2011;117(1):211-20, 10.1182/blood-2010-07-298349. [ Links ]

142. White-Al Habeeb NM, Garcia J, Fleshner N, Bapat B. Metformin Elicits Antitumor Effects and Downregulates the Histone Methyltransferase Multiple Myeloma SET Domain (MMSET) in Prostate Cancer Cells. Prostate. 2016;76(16):1507-18, 10.1002/pros.23235. [ Links ]

143. Amelio I, Cutruzzolá F, Antonov A, Agostini M, Melino G. Serine and glycine metabolism in cancer. Trends Biochem Sci. 2014;39(4):191-8, 10.1016/j.tibs.2014.02.004. [ Links ]

144. Zakikhani M, Bazile M, Hashemi S, Javeshghani S, Avizonis D, St Pierre J, et al. Alterations in cellular energy metabolism associated with the antiproliferative effects of the ATM inhibitor KU-55933 and with metformin. PLoS One. 2012;7(11):e49513, 10.1371/journal.pone.0049513. [ Links ]

145. Boukouris AE, Zervopoulos SD, Michelakis ED. Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription. Trends Biochem Sci. 2016;41(8):712-30, 10.1016/j.tibs.2016.05.013. [ Links ]

146. Zi FM, He JS, Li Y, Wu C, Yang L, Yang Y, et al. Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models. Cancer Lett. 2015;356(2 Pt B):443-53. [ Links ]

147. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115(5):577-90, 10.1016/S0092-8674(03)00929-2. [ Links ]

148. Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol.2002;4(9):699-704, 10.1038/ncb847. [ Links ]

149. Jagannathan S, Abdel-Malek MA, Malek E, Vad N, Latif T, Anderson KC, et al. Pharmacologic screens reveal metformin that suppresses GRP78-dependent autophagy to enhance the anti-myeloma effect of bortezomib. Leukemia. 2015;29(11):2184-91, 10.1038/leu.2015.157. [ Links ]

150. Green AS, Chapuis N, Lacombe C, Mayeux P, Bouscary D, Tamburini J. LKB1/AMPK/mTOR signaling pathway in hematological malignancies: from metabolism to cancer cell biology. Cell Cycle. 2011;10(13):2115-20, 10.4161/cc.10.13.16244. [ Links ]

151. Green AS, Chapuis N, Maciel TT, Willems L, Lambert M, Arnoult C, et al. The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation. Blood. 2010;116(20):4262-73, 10.1182/blood-2010-02-269837. [ Links ]

152. Vakana E, Platanias LC. AMPK in BCR-ABL expressing leukemias. Regulatory effects and therapeutic implications. Oncotarget. 2011;2(12):1322-8. [ Links ]

153. Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M, et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest. 2008;118(11):3762-74, 10.1172/JCI34616. [ Links ]

154. Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL, et al. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008;412(2):211-21, 10.1042/BJ20080557. [ Links ]

155. Grimaldi C, Chiarini F, Tabellini G, Ricci F, Tazzari PL, Battistelli M, et al. AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications. Leukemia. 2012;26(1):91-100, 10.1038/leu.2011.269. [ Links ]

156. Pan J, Chen C, Jin Y, Fuentes-Mattei E, Velazquez-Tores G, Benito JM, et al. Differential impact of structurally different anti-diabetic drugs on proliferation and chemosensitivity of acute lymphoblastic leukemia cells. Cell Cycle. 2012;11(12):2314-26, 10.4161/cc.20770. [ Links ]

157. Zadik Z, Estrov Z, Karov Y, Hahn T, Barak Y. The effect of growth hormone and IGF-I on clonogenic growth of hematopoietic cells in leukemic patients during active disease and during remission-a preliminary report. J Pediatr Endocrinol. 1993;6(1):79-83, 10.1515/JPEM.1993.6.1.79. [ Links ]

158. Yamada H, Iijima K, Tomita O, Taguchi T, Miharu M, Kobayashi K, et al. Effects of insulin-like growth factor-1 on B-cell precursor acute lymphoblastic leukemia. Int J Hematol. 2013;97(1):73-82, 10.1007/s12185-012-1234-3. [ Links ]

159. Huntly BJ, Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer. 2005;5(4):311-21, 10.1038/nrc1592. [ Links ]

160. Lane SW, Scadden DT, Gilliland DG. The leukemic stem cell niche: current concepts and therapeutic opportunities. Blood. 2009;114(6):1150-7, 10.1182/blood-2009-01-202606. [ Links ]

161. Rosilio C, Ben-Sahra I, Bost F, Peyron JF. Metformin: a metabolic disruptor and anti-diabetic drug to target human leukemia. Cancer Lett. 2014;346(2):188-96, 10.1016/j.canlet.2014.01.006. [ Links ]

162. Kim HG, Hien TT, Han EH, Hwang YP, Choi JH, Kang KW, et al. Metformin inhibits P-glycoprotein expression via the NF-κB pathway and CRE transcriptional activity through AMPK activation. Br J Pharmacol. 2011;162(5):1096-108, 10.1111/j.1476-5381.2010.01101.x. [ Links ]

163. Huai L, Wang C, Zhang C, Li Q, Chen Y, Jia Y, et al. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway. Biochem Biophys Res Commun. 2012;422(3):398-404, 10.1016/j.bbrc.2012.05.001. [ Links ]

164. Adekola KU, Dalva Aydemir S, Ma S, Zhou Z, Rosen ST, Shanmugam M. Investigating and targeting chronic lymphocytic leukemia metabolism with the human immunodeficiency virus protease inhibitor ritonavir and metformin. Leuk Lymphoma. 2015;56(2):450-9, 10.3109/10428194.2014.922180. [ Links ]

165. Shi WY, Xiao D, Wang L, Dong LH, Yan ZX, Shen ZX, et al. Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis. 2012;3:e275, 10.1038/cddis.2012.13. [ Links ]

166. Gu JJ, Zhang Q, Mavis C, Czuczman MS, Hernandez-Ilizaliturri FJ. Metformin Induces p53-Dependent Mitochondrial Stress in Therapy-Sensitive and -Resistant Lymphoma Pre-Clinical Model and Primary Patients Sample with B-Cell Non-Hodgkin Lymphoma (NHL). Blood. 2015;12(23):4008. [ Links ]

167. Rosilio C, Lounnas N, Nebout M, Imbert V, Hagenbeek T, Spits H, et al. The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells. Cancer Lett. 2013;336(1):114-26, 10.1016/j.canlet.2013.04.015. [ Links ]

168. Quesada AE, Nguyen ND, Rios A, Brown RE. Morphoproteomics identifies constitutive activation of the mTORC2/Akt and NF-κB pathways and expressions of IGF-1R, Sirt1, COX-2, and FASN in peripheral T-cell lymphomas: pathogenetic implications and therapeutic options. Int J Clin Exp Pathol. 2014;7(12):8732-9. [ Links ]

169. Singh A, Gu J, Yanamadala V, Czuczman M, Hernandez-Ilizaliturri F. Metformin lowers the mitochondrial potential of lymphoma cells and its use during front- line rituximab-based chemo-immunotherapy improves the clinical outcome of diffuse Large B-cell lymphoma. Blood. 2013; 122(21):1825. [ Links ]

Recibido: 22 de Octubre de 2017; Aprobado: 18 de Mayo de 2018

*Corresponding author. E-mail:

No potential conflict of interest was reported.

Cunha Júnior AD and Pericole FV wrote the initial drafts of the manuscript, and Carvalheira JB revised the manuscript.

Commemorative Edition: 10 years of ICESP

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