Metformin-induced anticancer activities: recent insights
-
Stephen Safe
,
Vijayalekshmi Nair
Abstract
Metformin is a widely used antidiabetic drug, and there is evidence among diabetic patients that metformin is a chemopreventive agent against multiple cancers. There is also evidence in human studies that metformin is a cancer chemotherapeutic agent, and several clinical trials that use metformin alone or in combination with other drugs are ongoing. In vivo and in vitro cancer cell culture studies demonstrate that metformin induces both AMPK-dependent and AMPK-independent genes/pathways that result in inhibition of cancer cell growth and migration and induction of apoptosis. The effects of metformin in cancer cells resemble the patterns observed after treatment with drugs that downregulate specificity protein 1 (Sp1), Sp3 and Sp4 or by knockdown of Sp1, Sp3 and Sp4 by RNA interference. Studies in pancreatic cancer cells clearly demonstrate that metformin decreases expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes, demonstrating that one of the underlying mechanisms of action of metformin as an anticancer agent involves targeting of Sp transcription factors. These observations are consistent with metformin-mediated effects on genes/pathways in many other tumor types.
Introduction
Metformin or N,N-dimethylbiguanide is a low molecular weight (MW: 129) compound that has been used extensively as a constituent of herbal medicines for treatment of multiple ailments (Witters, 2001; Romero et al., 2017). Professor Jean Sterne in France recognized the importance of metformin (or Glugophage) as an antidiabetic agent and championed its clinical applications for decreasing insulin resistance in diabetics in the mid-1970s in Europe (Sterne, 1959). In 1995, metformin was subsequently approved by the US Food and Drug Administration, and metformin is now widely used as a relatively safe, low-cost drug for treating diabetes (Bailey and Turner, 1996; Nathan et al., 2009; Inzucchi et al., 2015). A recent review of metformin by Romero and coworkers (Romero et al., 2017) pointed out that metformin is rapidly gaining status as ‘the aspirin of the 21st century’, and its use has been associated with improvements in or prevention of many diseases. Figure 1 illustrates some of the health promoting, chemopreventive and chemotherapeutic effects of metformin, which include diabetes, preeclampsia, liver and kidney diseases, cardiovascular diseases, mortality and aging, multiple sclerosis, polycystic ovary disease, modulation of gut microorganisms and metabolites, erectile function and cognitive function (Haffner et al., 2005; Goldberg et al., 2013; Bannister et al., 2014; Cheng et al., 2014; Guo et al., 2014; Bhat et al., 2015; Feng et al., 2015; Goldberg et al., 2015; Victor et al., 2015; Barzilai et al., 2016; Brownfoot et al., 2016; Negrotto et al., 2016; Crowley et al., 2017; Patel et al., 2017; Pollak, 2017; Wu et al., 2017). These impacts on multiple human diseases are also supported by extensive studies on metformin in several model organisms including laboratory animals and suggest that metformin may even surpass aspirin in terms of its broad impact on multiple diseases. There are literally thousands of publications on the mechanisms of action of metformin and the effects of this compound on different pathways. Some of these responses may be due to mitochondrial effects leading to decreased metabolic activity and activation of AMPK and subsequent inhibition of mTOR (Barzilai et al., 2016; Hart et al., 2016; Romero et al., 2017). In this review, we will examine the impacts of metformin on both cancer chemoprevention and chemotherapy and also identify some important underlying pathways associated with these effects.
Metformin and diseases.
The antidiabetic drug metformin plays a role in protecting against several adverse health effects in humans (Haffner et al., 2005; Goldberg et al., 2013, 2015; Bannister et al., 2014; Cheng et al., 2014; Guo et al., 2014; Bhat et al., 2015; Feng et al., 2015; Victor et al., 2015; Barzilai et al., 2016; Brownfoot et al., 2016; Negrotto et al., 2016; Crowley et al., 2017; Patel et al., 2017).
Metformin and cancer – human studies
Introduction
Examination of PubMed showed that under the keywords ‘Metformin’ or ‘Metformin and Cancer’, there were listings for 15 303 and 3493 publications, respectively. Most of the early indications that metformin plays a role in modulating cancer development were observed in papers reporting the incidence of various cancers in diabetics vs. non-diabetics or diabetics treated with other pharmaceuticals. Analysis of individual studies for the chemopreventive effects of metformin demonstrates consistent results for some cancers but highly variable results for patients with other cancers. Several studies have investigated cancer mortalities and sometimes risks in several populations (Gandini et al., 2014; Lega et al., 2014; Wu et al., 2015; Gong et al., 2016; Haukka et al., 2017; Hicks et al., 2017), and this included one report which was a meta-analysis of 265 studies (Wu et al., 2015). The results demonstrate that metformin decreases the overall risk and mortality from cancer, but effects with individual cancers are variable and in some cases there may be an increased benefit for increased use of metformin.
Chemoprevention
The cancer chemopreventive effects of metformin have been extensively investigated (Figure 2) in many types of cancer, including pancreatic cancer patients, in which diabetes is also a risk factor for this cancer (reviewed in Li and Abbruzzese, 2010; Pollak, 2012; De Souza et al., 2016). Early studies in patients from the MD Anderson Cancer Center showed that metformin use in diabetic patients was associated with a decreased risk and decreased mortality from pancreatic cancer (Li et al., 2009; Sadeghi et al., 2012). These results were confirmed in several subsequent studies worldwide showing that in pancreatic patients, metformin use was associated with increased survival, and these observations were strong in patients with resectable pancreatic tumors (Jo et al., 2015; Ambe et al., 2016; Kozak et al., 2016; Lee et al., 2016; Jang et al., 2017). By contrast, it was also reported that there was no association between metformin use and pancreatic cancer survival (Walker et al., 2015; Frouws et al., 2017), suggesting that the benefits of metformin use for pancreatic cancer patients may be only for subsets of patients (e.g. with resectable tumors).
Metformin as a cancer chemopreventive agent.
Metformin inhibits development of several cancers: p, protective; np, not protective (references in brackets).
A review summarized several retrospective and case-control studies on metformin and colon cancer, which suggest that metformin decreases the risk and mortality from colon cancer, and improved overall survival was also observed in a meta-analysis of studies (Lee and Kim, 2014; Meng et al., 2017). Moreover, one study also reported that metformin decreased formation of adenomas and polyps in patients after polysectomy, demonstrating the effectiveness of this drug as a chemopreventic agent that decreases formation of precancerous lesions (Higurashi et al., 2016). Most studies show that metformin decreases the risk or mortality of colon cancer patients with diabetes (Garrett et al., 2012; Lee et al., 2012; Spillane et al., 2013; Fransgaard et al., 2016; He et al., 2016; Paulus et al., 2016; Ramjeesingh et al., 2016; Park et al., 2017), although one report observed protection in female but not male patients (Park et al., 2017). By contrast, a population-based study in Great Britain (Mc Menamin et al., 2016) did not observe a protective effect of metformin and the reason for this outlier report is unclear. A number of studies in diabetics with prostate cancer also showed that metformin decreased the incidence and/or mortality from prostate cancer (Yu et al., 2014; Deng et al., 2015; Hwang et al., 2015; Raval et al., 2015; Stopsack et al., 2016; Wang et al., 2016), whereas prostate cancer chemoprevention was not observed in a patient group from the United Kingdom (Azoulay et al., 2011). Metformin decreased liver cancer risk or mortality in several studies in diabetic patients (Lai et al., 2012; Chen et al., 2013; Singh et al., 2013; Zheng et al., 2013), and similar results were observed for lung cancer patients (Tsai et al., 2014; Kong et al., 2015; Lin et al., 2015; Tian et al., 2016; Wan et al., 2016; Lin et al., 2017).
Metformin also influenced outcomes of diabetic patients with hormone-dependent breast and endometrial cancers. Meta-analysis of several studies showed that metformin decreased mortality but not incidence of breast cancer in diabetics (Yang et al., 2015), and several other studies also reported decreased mortality. However, there were some differences in the chemopreventive effects of metformin that were dependent on tumor classification (El-Benhawy and El-Sheredy, 2014; Xiao et al., 2014; Kim et al., 2015; Vissers et al., 2015). For example, among the Luminal A, Luminal B (high Ki67) and Luminal B (ErbB2+) subtypes of breast cancer, metformin significantly decreased the mortality from breast cancer (Xiao et al., 2014). By contrast, one study showed that metformin did not affect survival of triple negative breast cancer patients (Bayraktar et al., 2012), and another report showed no survival benefits for breast cancer patients using metformin (Oppong et al., 2014). Meta-analysis of endometrial cancer studies reported that metformin decreased mortality (Perez-Lopez et al., 2017), and this was confirmed in other studies (Ko et al., 2014; Nevadunsky et al., 2014; Ezewuiro et al., 2016), including one indicating that diabetic patients only with non-endometrioid endometrial cancer benefitted from metformin (Nevadunsky et al., 2014). Diabetics using metformin compared to other antidiabetic drugs exhibit decreased mortality and/or incidence of multiple myeloma (Wu et al., 2014), glioblastoma (Adeberg et al., 2015) and gastric cancer (Kim et al., 2014), but no significant differences were observed for esophageal cancer (Agrawal et al., 2014), renal (Hakimi et al., 2013; Psutka et al., 2015) and head and neck cancers (Becker et al., 2014). Thus, it is apparent that metformin is a chemopreventive agent for many but not all cancers, and like many other anticancer agents, metformin is likely to target specific tumor subtypes which, with the exception of breast cancer, have yet to be identified.
Chemotherapy
The chemopreventive effects of metformin have been determined in diabetic patients with cancer, and this may not necessarily be representative of the effects of this compound in non-diabetics. Nevertheless, the exciting effects of metformin as a cancer chemopreventive agent coupled with its effects on cancer cells in culture and animal models have led to the initiation of over 100 clinical trials that are investigating metformin as a chemotherapeutic agent (Romero et al., 2017). Results of some studies evaluating the cancer chemotherapeutic efficacy of metformin are summarized in Table 1, and this includes some diabetic patient groups but focuses on responses after diagnosis (Bensimon et al., 2014; Bhat et al., 2014; Mitsuhashi et al., 2014; Kordes et al., 2015; Sayed et al., 2015; Chae et al., 2016; Chaiteerakij et al., 2016; Han et al., 2016; Reni et al., 2016; Sivalingam et al., 2016). Most studies had some limitations with respect to duration, number of patients and other variabilities (e.g. diabetic vs. non-diabetic); however, studies with metformin alone or in combination with other drugs exhibited minimal benefits of metformin use. There were some positive results observed for cervical and endometrial cancers; however, a more definitive evaluation of metformin use in cancer chemotherapy is premature pending results of the large number of ongoing clinical trials.
Metformin as a cancer chemotherapeutic agent.
| Tumor site (reference) | Patients | Biomarker/response |
|---|---|---|
| Multiple (Chae et al., 2016) | Different patient groups (review) | Multiple |
| Pancreatic (Kordes et al., 2015) | Double-blind randomized; 6–8 months; gemicitabine/erlotinib±metformin | No increase in survival |
| Pancreatic (Chaiteerakij et al., 2016) | Survival of patients (diabetic) after diagnosis±metformin | Some survival benefit (not significant) |
| Pancreatic (Reni et al., 2016) | Randomized Phase II trial PEXG (4 drugs)±metformin | No significant survival benefit |
| Prostate (Bensimon et al., 2014) | Multiple cohorts (diabetic) followed after diagnosis±metformin (3.7 year) | No effects on mortality |
| Liver (Bhat et al., 2014) | Retrospective (diabetic) study with liver cancer followed after diagnosis | No survival advantage |
| Lung (Sayed et al., 2015) | Stage 4 NSCLC treated with drug cocktail±metformin | No survival advantage |
| Cervical (Han et al., 2016) | Diabetic patients±metformin; monitored after diagnosis | Significant decrease in mortality |
| Endometrial (Sivalingam et al., 2016) | Studies including women with endometrial cancer and atypical hyperplasia; short duration±metformin | Decreased Ki-67 |
| Endometrial (Mitsuhashi et al., 2014) | Preoperative prospective trial (4–6 week) | Decreased Ki-67 |
Metformin mechanisms of action as an anticancer agent
Introduction
The antidiabetic activities of metformin have been extensively investigated and this involves interactions of this drug with multiple pathways in tissues that contribute to insulin resistance (reviewed in Pernicova and Korbonits, 2014). The positively charged metformin molecule targets the mitochondria and inhibits complex 1 and ATP formation and this can affect many downstream pathways in multiple tissues and organs (Pernicova and Korbonits, 2014; Romero et al., 2017). It was suggested that the loss of ATP contributes to the inhibition of hepatic gluconeogenesis, and this response is AMPK and LKB1 independent (Foretz et al., 2010). Another study showed that metformin non-competitively inhibits the redox shuttle enzyme glycerophosphate dehydrogenase, and this also results in decreased hepatic gluconeogenesis, which contributes to the antidiabetic activity of metformin (Madiraju et al., 2014). Glucagon-induced gluconeogenesis can also be inhibited by metformin through inhibiting production of cAMP and PKA activity. These and many other mechanisms have been proposed to explain the mechanism of action of metformin as an antidiabetic drug, and it is likely that some of these pathways may contribute to the cancer chemopreventive effects of metformin. However, the mechanisms of the chemotherapeutic effects of metformin may be different, and it is evident from a large number of studies that the effects of metformin are diverse and are tumor and cell type dependent. The future use of metformin alone or in combined therapies requires insight into the various pathways and/or genes affected by metformin in order to design drug combinations that facilitate and optimize drug-drug interactions.
Metformin subcellular targets
The biological effects of drugs depend on drug interactions with intracellular targets, which subsequently lead to a cascade of downstream events that alters a response. Table 2 summarizes several studies that show direct metformin interactions with intracellular targets that subsequently can contribute to the reported antidiabetic and anticancer activities of this drug, and some of these interactions may be directly associated with the anticancer activities of this drug. For example, metformin activates AMPK in rat hepatoma H4IIE cells, resulting in decreased pS6 phosphorylation, and these responses are abrogated after cotreatment with triethylene tetramine (trien), a copper chelating agent (Logie et al., 2012). This paper does not identify the direct protein(s) target(s) of metformin but indicates that metformin’s copper binding properties may contribute to AMPK activation. In vitro studies showed that metformin directly inhibited AMP deaminase, resulting in increased AMP levels and activation of AMPK (Ouyang et al., 2011). There is also evidence that inhibitors of mitochondrial complex 1 of the respiratory change can enhance AMP levels and activation of AMPK (Buzzai et al., 2007; Hawley et al., 2016), resulting in inhibition of mTOR and downstream pro-survival signaling pathways. The importance of mitochondrial targeting of metformin was confirmed in studies with metformin coupled with triphenylphosphonium (MitoMet), which enhanced mitochondrial targeting. These mitochondrial-targeted metformin analogs were orders of magnitude more potent than metformin as complex 1 inhibitors, inhibitors of pancreatic cancer cell growth and activators of AMPK and inhibition of mTOR (Boukalova et al., 2016). These results strongly implicate that the anticarcinogenic activity of metformin, is due, in part to inhibition of complex 1. An example of an extramitochondrial activation of AMPK by metformin involves mislocation of mutation K-ras to the cytosol in cancer cell (Iglesias et al., 2013). Metformin displaces active K-ras from the cell membrane via a PKC-dependent pathway; however, evidence for direct metformin-K-ras interactions was not determined. Finally, there is also evidence in neuronal cells that metformin associates with and disrupts the PP2A complex (Kickstein et al., 2010), and it is possible that inhibition of PP2A-dependent phosphatase activity could contribute to the anticancer activity of metformin.
Direct intracellular targets of metformin.
| Target | Implications | Reference |
|---|---|---|
| High mobility group box 1 (HMGB1) | Binds to metformin and inhibits its pro-inflammatory activity | (Horiuchi et al., 2017) |
| Copper interactions | Extensive π-bond interaction with copper; copper competitor blocks metformin-induced pAMPK (activation) and other responses in liver cancer cells | (Logie et al., 2012) |
| Inhibits PP2A signaling | Inhibits interactions of PP2A subunits and PP2A activity and thereby blocks downstream signaling (murine neurons) | (Kickstein et al., 2010) |
| Interacts with organic ion transporters | Binds Oct1 and other ion transporters to facilitate uptake and secretion of metformin | (Becker et al., 2009; Tzvetkov et al., 2009; Chen et al., 2010; Segal et al., 2011; Nakamichi et al., 2013; Liang et al., 2015; Yee et al., 2015) |
| Inhibition of glycerophosphate dehydrogenase | Inhibit mitochondrial GPD (in vivo) and thereby blocks gluconeogenesis | (Madiraju et al., 2014) |
| Inhibition of AMP deaminase activity | This inhibitory effect stimulates glucose transport in L6 cells | (Ouyang et al., 2011) |
| Decrease K-ras activity | Displaces constitutively active K-ras from cell membrane and inhibits Ras signaling | (Iglesias et al., 2013) |
| Inhibition of mitochondrial complex 1 | Inhibition of complex 1 can lead to multiple effects including AMPK activation | (El-Mir et al., 2000; Owen et al., 2000; Brunmair et al., 2004; Hinke et al., 2007; Wheaton et al., 2014; Boukalova et al., 2016; Hawley et al., 2016) |
Metformin-mediated anticancer pathways and/or genes in cancer cells
There is strong evidence that metformin inhibits cancer cell proliferation, migration and invasion and induces apoptosis; however, the genes and/or pathways involved are highly variable and differ between cells derived from the same tumor and different tumor type. It is likely that some of this variability between studies may not be due to major mechanistic differences but to the focus of various laboratories on different genes and pathways that may be complementary. As indicated in Table 2, metformin activates AMPK to inhibit mTOR and downstream signaling, and metformin-induced activation of this pathway has been reported in many different cancer cell lines (Buzzai et al., 2007; Zakikhani et al., 2008; Vazquez-Martin et al., 2009; Algire et al., 2010; Ben Sahra et al., 2010, 2011; Kim et al., 2011; Blandino et al., 2012; Cerezo et al., 2013; Storozhuk et al., 2013; Zheng et al., 2013; Takayama et al., 2014; Gollavilli et al., 2015; Yi et al., 2017; Zhang et al., 2017). These represent only a small number of the studies showing that metformin activates AMPK in cancer cell lines; however, due to the tumor-type, genotypic variability and different experimental approaches, the effects of metformin appear highly variable. For example, in breast cancer cell lines in which the effects of metformin are, in part, AMPK dependent, the pathways that are described are highly variable. In one study in SUM159PT breast cancer cells, metformin-induced AMPK-dependent downregulation of Myc, and this was accompanied by the upregulation of microRNA-33a (miR-33a) and Dicer, a key enzyme in formation of miRs (Blandino et al., 2012). It was also reported that metformin inhibited breast tumor and cancer cell growth via upregulating tumor suppressor-like miR-200c and downregulating Myc and Akt2 expression, and this was probably due to AMPK activation but was not determined (Zhang et al., 2017). Another study in ER-negative MDA-MB-231 and BT-549 breast cancer cells showed that metformin activation of AMPK resulted in growth arrest and inhibition of migration and invasion which was linked to induction of G3K3β and SIRT1 and downregulation of Myc and the Myc-regulated oncogenic protein metadherin (Gollavilli et al., 2015). By contrast, several studies show that the anticancer activities of metformin in breast and other cancer cell lines are AMPK independent. For example, metformin directly suppressed expression of the ErbB2/HER2 oncogene in ErbB2-breast cancer cells, and this effect was AMPK independent but dependent on inhibition of the p70S6K1 kinase (mTOR downstream kinase) (Vazquez-Martin et al., 2009). Metformin also increases REDD1 expression (p53 dependent) in prostate, breast and lung cancer (Ben Sahra et al., 2011), and under glucose-deprived conditions, metformin downregulated p63 in head and neck cancer cells (Yi et al., 2017) and all of these responses were AMPK independent. Thus, the effects of metformin in cancer cells appear to be highly variable.
Mechanisms of action of metformin: are Sp transcription factors a target?
The actions of metformin in cancer cell lines derived from multiple tumors show that this compound decreases cancer cell proliferation, migration and survival, and activation of AMPK is a trigger for inducing many of these responses. Pancreatic cancer was one of the first cancers where it was shown that metformin exhibited chemopreventive activity among diabetics; however, continuing studies gave mixed results (Table 1). Metformin and related biquanides are highly effective anticancer agents in pancreatic cancer cells (Kisfalvi et al., 2009; Rozengurt et al., 2010; Kim et al., 2011; Bao et al., 2012; Gou et al., 2013; Karnevi et al., 2013; Lonardo et al., 2013; Sinnett-Smith et al., 2013; Soares et al., 2013; Li et al., 2017; Rajeshkumar et al., 2017). A recent study showed that metformin suppressed cancer initiation and progression in the LS-KrasG12D/+; Trp53f1/+; Pdx-Cre(KPC) mouse that expresses an active Ras (KrasG12D/+) and mutated p53 in the pancreas and spontaneously develops pancreatic tumors similar to the pancreatic ductal adenocarcinomas (PDACs) observed in humans (Chen et al., 2017). Most in vitro studies on metformin in pancreatic cancer cells showed the importance of AMPK activation, the insulin growth factor receptor 1 (IGF-R1), modulation of microRNA (miR) expression and inhibitory effects on pancreatic cancer stem cells.
Studies in this laboratory have focused on the pro-oncogenic activity of specificity protein 1 (Sp1), Sp3 and Sp4 transcription factors (TFs), which are highly expressed in pancreatic and other cancer cell lines, and there are a number of anticancer drugs that act, in part, by targeting Sp transcription factors (TFs) (Wei et al., 2004; Safe and Abdelrahim, 2005; Abdelrahim et al., 2006; Chintharlapalli et al., 2007; Chadalapaka et al., 2008, 2012; Jutooru et al., 2010a,b,c, 2014; Basha et al., 2011; Chintharlapalli et al., 2011; Pathi et al., 2011a,b, 2012, 2014; Chadalapaka et al., 2012; Gandhy et al., 2012; Liu et al., 2012; Sreevalsan and Safe, 2013; Hedrick et al., 2015, 2017; Kasiappan et al., 2016; Safe and Kasiappan, 2016; Jin et al., 2017; Karki et al., 2017; Taoka et al., 2017). Compounds that induce downregulation of Sp1, Sp3 and Sp4 include NSAIDs such as tolfenamic acid, diclofenac, aspirin and GT-094, a nitroaspirin analog and arsenic trioxide; and natural product-derived anticancer agents such as betulinic acid, curcumin, piperlongumine, cannabinoids, celastrol, phenethylisothiocyanate (PEITC), benzylisothiocyanate (BITC) and the synthetic triterpenoids methyl 2-cyano-3,12-dioxo-oleana-1,9-dien-28-oate (CDDO-Me, bardoxolone) and methyl 2-cyano-3,11-dioxo-18β-olean-1,13-dien30-oate (CDODA-Me) (Wei et al., 2004; Safe and Abdelrahim, 2005; Abdelrahim et al., 2006; Chintharlapalli et al., 2007, 2011; Chadalapaka et al., 2008, 2012, 2013; Jutooru et al., 2010a,b,c, 2014; Basha et al., 2011; Gandhy et al., 2012; Liu et al., 2012; Pathi et al., 2012, 2014, 2011a,b; Sreevalsan and Safe, 2013; Hedrick et al., 2015, 2017; Kasiappan et al., 2016; Safe and Kasiappan, 2016; Jin et al., 2017; Karki et al., 2017; Taoka et al., 2017). The potent anticancer activity of drugs that target downregulation of Sp TFs is due to the subsequent downregulation of pro-oncogenic Sp-regulated genes that contribute to cancer cell growth, survival and migration/invasion. Based on RNA interference (RNAi) experiments, Sp TFs regulate bcl-2, survivin, cyclin D1, vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2, hepatocyte growth factor receptor (c-MET), platelet-derived growth factor receptor 1 (PDGFR), epidermal growth factor receptor (EGFR), ErbB2 (via YY1), insulin-like growth factor receptor (IGFR-1), p65 (NF-κB), cMyc, EZH2, MDR1 and multiple integrins (Wei et al., 2004; Safe and Abdelrahim, 2005; Abdelrahim et al., 2006; Chintharlapalli et al., 2007, 2011; Chadalapaka et al., 2008, 2012, 2013; Jutooru et al., 2010a,b,c, 2014; Basha et al., 2011; Pathi et al., 2011a,b, 2012, 2014; Gandhy et al., 2012; Liu et al., 2012; Sreevalsan and Safe, 2013; Hedrick et al., 2015, 2016, 2017; Kasiappan et al., 2016; Safe and Kasiappan, 2016; Jin et al., 2017; Karki et al., 2017; Taoka et al., 2017). Sp-regulation of some of these genes is cell context dependent, and many are coregulated by Sp and other TFs. Interestingly, inspection of published results for metformin shows that like metformin, knockdown of Sp1, Sp3 and Sp4 also inhibits cancer cell growth and migration and induces apoptosis. In addition, metformin also decreases expression of several Sp-regulated genes, including VEGF (Li et al., 2017), ErbB2 (Soares et al., 2013) and EZH2 (Bao et al., 2012) in pancreatic cancer cells; MDR1, c-Myc, p65 and bcl2 in breast cancer cells (Kim et al., 2011; Zhang et al., 2017); MMP9 in melanoma cells (Cerezo et al., 2013); and also ErbB2 in breast cancer cells (Vazquez-Martin et al., 2009).
The effects of metformin on expression of several putative Sp-regulated genes suggest that Sp1, Sp3 and Sp4 may be targets of metformin, and this was further investigated in Panc1, Panc28 and L3.6pL pancreatic cancer cells. Metformin (0–20 μm) inhibited growth, induced apoptosis and decreased expression of Sp1, Sp3 and Sp4 in all three cell lines, and these effects suggest that Sp downregulation contributes to the anticancer activity of metformin because Sp knockdown (individually and combined) also inhibits growth and induces apoptosis in pancreatic cancer cells (Nair et al., 2013, 2014).
A major mechanism of action of metformin in both non-cancer and cancer cells is linked to activation of AMPK, which in turn can affect multiple downstream pathways including inhibition of mTOR and induction of autophagy. Interestingly, the induction of autophagy by 2-deoxyglucose, which inhibits glucose metabolism, is significantly attenuated by cotreatment with metformin, and this is accompanied by enhanced p53-dependent apoptosis in prostate cancer cells (Ben Sahra et al., 2010). In addition, the inhibition of mTOR in pancreatic cancer was also linked to the downregulation of Sp1, Sp3 and Sp4 in pancreatic cancer cells (Nair et al., 2014). In these cells, metformin downregulated insulin-like growth factor receptor and decreased Akt phosphorylation in pancreatic cancer cells, and this resulted in decreased mTOR phosphorylation. Knockdown of Sp1, Sp3 and Sp4 by RNAi gave similar results, thus linking metformin-mediated inhibition of mTOR to Sp downregulation by this drug. The effects of metformin as an activator of AMPK were not determined in this study (Nair et al., 2014), but it is possible that activation of AMPK by metformin was also a contributing pathway.
Although a role for AMPK activation by metformin was not determined, we observed that metformin inhibited activation of pmTOR, and mTOR activation was also inhibited after knockdown of Sp1, Sp3 and Sp4 by RNAi (Nair et al., 2014). In addition, metformin also decreased expression of several Sp-regulated genes, including bcl-2, survivin, cyclin D1, VEGF, VEGFR1, fatty acid synthase (FAS), activation of sterol regulatory element binding protein 1 (SREBP) and EGFR (Nair et al., 2013, 2014). Metformin also modulated expression of genes directly linked to mechanistic pathways, and these include decreased Ras activity, repression of miR-27a and induction of miR-regulated ZBTB10 (a transcriptional repressor) and the dual phosphatases mitogen-activated protein kinase phosphatase 1 (MKP1 and MKP5) (Nair et al., 2013, 2014) (Figure 3).
Metformin and Sp transcription factors – a possible underlying mechanism of action.
Metformin downregulates Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes in pancreatic cancer cells (Nair et al., 2013, 2014).
The mechanisms of drug-induced downregulation of Sp TFs are both drug and cell context dependent, and for Panc28 and L3.6pL cells, metformin-mediated Sp downregulation could be blocked by the proteasome inhibitor gliotoxin (Nair et al., 2013). A previous study showed that the NSAID tolfenamic acid also induced proteasome-dependent degradation of Sp1, Sp3 and Sp4 in pancreatic cancer cells (Abdelrahim et al., 2006). The mechanism associated with proteasome activation by metformin in pancreatic cancer cells was not determined; however, a recent study reported that metformin-induced proteasome-dependent degradation of the Sp-regulated gene cyclin D1 in ovarian cancer cells, and this was linked to activation of AMPK and GSK3β (Gwak et al., 2017). Thus, the metformin-AMPK- GSKβ pathway may also be responsible for Sp downregulation in pancreatic cancer cells, and there are other reports showing that GSK3β plays a role in proteasome activation (Ichikawa et al., 2015; Wakatsuki et al., 2017). Metformin also downregulated Sp1, Sp3, Sp4 and Sp-regulated genes in the highly invasive Panc1 pancreatic cancer cell line (Nair et al., 2014); however, this response was independent of proteasome activation or induction of ROS, which is a major pathway for degradation of Sp TFs (Safe and Kasiappan, 2016). Metformin-induced Sp downregulation was accompanied by downregulation of miR-27a and induction of the miR-regulated transcriptional repressor ZBTB10, which competitively binds GC-rich Sp binding sites to displace Sp TFs. Metformin-mediated downregulation of miR-27a and induction of ZBTB10 is sufficient to decrease expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes (Mertens-Talcott et al., 2007), and we observed that this pathway was inhibited after cotreatment with the phosphatase inhibitor sodium orthovanadate (SOV) (Nair et al., 2013). There was previous evidence that both mitogen-activated protein kinase phosphatase 1 (MPK1) and MKP5 are induced by compounds (e.g. curcumin and rosiglitazone) (Nonn et al., 2007; Jan et al., 2009; Chen et al., 2011) that also decrease Sp TFs (Jutooru et al., 2010a; Gandhy et al., 2012), and we observed that metformin also induced MKP1 and MKP5 (Nair et al., 2013). Moreover, MKP1/MKP5 overexpression also downregulated miR-27a, induced ZBTB10 and decreased expression of Sp1, Sp3 and Sp4, demonstrating that induction of these phosphatases by metformin was critical for Sp downregulation in Panc28 and L3.6pL cells (Nair et al., 2013). There is also evidence that AMPK activates phosphatases (Berasi et al., 2006; Kim et al., 2010); however, the metformin-AMPK-MKP1/MKP5 pathway was not further investigated in pancreatic cancer cells, and the precise role of AMPK (upstream or downstream) in Sp downregulation has not been determined.
Summary
Metformin exhibits both cancer chemopreventive and chemotherapeutic activity and clearly warrants thorough evaluation for its potential as a single agent or a component of drug cocktails used for cancer treatment. The design of effective drug combinations requires an in-depth knowledge of the underlying mechanisms of action of metformin, and results from our laboratory suggest that many of the effects observed for metformin in pancreatic cancer and possibly other cancers may be due to targeting downregulation of Sp TFs and pro-oncogenic Sp-regulated genes.
Acknowledgments
The financial assistance of the National Institutes of Health (P30-ES023512, S. Safe), Funder Id: 10.13039/100000066, Texas AgriLife Research (S. Safe) and Sid Kyle Chair endowment (S. Safe) is gratefully acknowledged.
References
Abdelrahim, M., Baker, C.H., Abbruzzese, J.L., and Safe, S. (2006). Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J. Natl. Cancer Inst. 98, 855–868.10.1093/jnci/djj232Search in Google Scholar PubMed
Adeberg, S., Bernhardt, D., Ben Harrabi, S., Bostel, T., Mohr, A., Koelsche, C., Diehl, C., Rieken, S., and Debus, J. (2015). Metformin influences progression in diabetic glioblastoma patients. Strahlenther Onkol. 191, 928–935.10.1007/s00066-015-0884-5Search in Google Scholar PubMed
Agrawal, S., Patel, P., Agrawal, A., Makhijani, N., Markert, R., and Deidrich, W. (2014). Metformin use and the risk of esophageal cancer in Barrett esophagus. South Med. J. 107, 774–779.10.14423/SMJ.0000000000000212Search in Google Scholar PubMed
Algire, C., Amrein, L., Zakikhani, M., Panasci, L., and Pollak, M. (2010). Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr. Relat. Cancer 17, 351–360.10.1677/ERC-09-0252Search in Google Scholar PubMed
Ambe, C.M., Mahipal, A., Fulp, J., Chen, L., and Malafa, M.P. (2016). Effect of metformin use on survival in resectable pancreatic cancer: a single-institution experience and review of the literature. PLoS One 11, e0151632.10.1371/journal.pone.0151632Search in Google Scholar PubMed PubMed Central
Azoulay, L., Dell’Aniello, S., Gagnon, B., Pollak, M., and Suissa, S. (2011). Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol. Biomarkers Prev. 20, 337–344.10.1158/1055-9965.EPI-10-0940Search in Google Scholar PubMed
Bailey, C.J. and Turner, R.C. (1996). Metformin. N. Engl. J. Med. 334, 574–579.10.1056/NEJM199602293340906Search in Google Scholar PubMed
Bannister, C.A., Holden, S.E., Jenkins-Jones, S., Morgan, C.L., Halcox, J.P., Schernthaner, G., Mukherjee, J., and Currie, C.J. (2014). Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes. Metab. 16, 1165–1173.10.1111/dom.12354Search in Google Scholar PubMed
Bao, B., Wang, Z., Ali, S., Ahmad, A., Azmi, A.S., Sarkar, S.H., Banerjee, S., Kong, D., Li, Y., Thakur, S., et al. (2012). Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev. Res. (Phila). 5, 355–364.10.1158/1940-6207.CAPR-11-0299Search in Google Scholar PubMed PubMed Central
Barzilai, N., Crandall, J.P., Kritchevsky, S.B., and Espeland, M.A. (2016). Metformin as a Tool to Target Aging. Cell Metab. 23, 1060–1065.10.1016/j.cmet.2016.05.011Search in Google Scholar PubMed PubMed Central
Basha, R., Baker, C.H., Sankpal, U.T., Ahmad, S., Safe, S., Abbruzzese, J.L., and Abdelrahim, M. (2011). Therapeutic applications of NSAIDS in cancer: special emphasis on tolfenamic acid. Front. Biosci. (Schol Ed). 3, 797–805.Search in Google Scholar
Bayraktar, S., Hernadez-Aya, L.F., Lei, X., Meric-Bernstam, F., Litton, J.K., Hsu, L., Hortobagyi, G.N., and Gonzalez-Angulo, A.M. (2012). Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer. Cancer 118, 1202–1211.10.1002/cncr.26439Search in Google Scholar PubMed PubMed Central
Becker, M.L., Visser, L.E., van Schaik, R.H., Hofman, A., Uitterlinden, A.G., and Stricker, B.H. (2009). Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. Diabetes 58, 745–749.10.2337/db08-1028Search in Google Scholar PubMed PubMed Central
Becker, C., Jick, S.S., Meier, C.R., and Bodmer, M. (2014). Metformin and the risk of head and neck cancer: a case-control analysis. Diabetes Obes. Metab. 16, 1148–1154.10.1111/dom.12351Search in Google Scholar PubMed
Ben Sahra, I., Laurent, K., Giuliano, S., Larbret, F., Ponzio, G., Gounon, P., Le Marchand-Brustel, Y., Giorgetti-Peraldi, S., Cormont, M., Bertolotto, C., et al. (2010). Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 70, 2465–2475.10.1158/0008-5472.CAN-09-2782Search in Google Scholar PubMed
Ben Sahra, I., Regazzetti, C., Robert, G., Laurent, K., Le Marchand-Brustel, Y., Auberger, P., Tanti, J.F., Giorgetti-Peraldi, S., and Bost, F. (2011). Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 71, 4366–4372.10.1158/0008-5472.CAN-10-1769Search in Google Scholar PubMed
Bensimon, L., Yin, H., Suissa, S., Pollak, M.N., and Azoulay, L. (2014). The use of metformin in patients with prostate cancer and the risk of death. Cancer Epidemiol. Biomarkers Prev. 23, 2111–2118.10.1158/1055-9965.EPI-14-0056Search in Google Scholar PubMed
Berasi, S.P., Huard, C., Li, D., Shih, H.H., Sun, Y., Zhong, W., Paulsen, J.E., Brown, E.L., Gimeno, R.E., and Martinez, R.V. (2006). Inhibition of gluconeogenesis through transcriptional activation of EGR1 and DUSP4 by AMP-activated kinase. J. Biol. Chem. 281, 27167–27177.10.1074/jbc.M602416200Search in Google Scholar PubMed
Bhat, M., Chaiteerakij, R., Harmsen, W.S., Schleck, C.D., Yang, J.D., Giama, N.H., Therneau, T.M., Gores, G.J., and Roberts, L.R. (2014). Metformin does not improve survival in patients with hepatocellular carcinoma. World J. Gastroenterol. 20, 15750–15755.10.3748/wjg.v20.i42.15750Search in Google Scholar PubMed PubMed Central
Bhat, A., Sebastiani, G., and Bhat, M. (2015). Systematic review: preventive and therapeutic applications of metformin in liver disease. World J. Hepatol. 7, 1652–1659.10.4254/wjh.v7.i12.1652Search in Google Scholar PubMed PubMed Central
Blandino, G., Valerio, M., Cioce, M., Mori, F., Casadei, L., Pulito, C., Sacconi, A., Biagioni, F., Cortese, G., Galanti, S., et al. (2012). Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat. Commun. 3, 865.10.1038/ncomms1859Search in Google Scholar PubMed
Boukalova, S., Stursa, J., Werner, L., Ezrova, Z., Cerny, J., Bezawork-Geleta, A., Pecinova, A., Dong, L., Drahota, Z., and Neuzil, J. (2016). Mitochondrial targeting of metformin enhances its activity against pancreatic cancer. Mol. Cancer Ther. 15, 2875–2886.10.1158/1535-7163.MCT-15-1021Search in Google Scholar PubMed
Brownfoot, F.C., Hastie, R., Hannan, N.J., Cannon, P., Tuohey, L., Parry, L.J., Senadheera, S., Illanes, S.E., Kaitu’u-Lino, T.J., and Tong, S. (2016). Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am. J. Obstet. Gynecol. 214, 356 e351–356 e315.10.1016/j.ajog.2015.12.019Search in Google Scholar PubMed
Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhausl, W., et al. (2004). Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53, 1052–1059.10.2337/diabetes.53.4.1052Search in Google Scholar PubMed
Buzzai, M., Jones, R.G., Amaravadi, R.K., Lum, J.J., DeBerardinis, R.J., Zhao, F., Viollet, B., and Thompson, C.B. (2007). Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67, 6745–6752.10.1158/0008-5472.CAN-06-4447Search in Google Scholar PubMed
Cerezo, M., Tichet, M., Abbe, P., Ohanna, M., Lehraiki, A., Rouaud, F., Allegra, M., Giacchero, D., Bahadoran, P., Bertolotto, C., et al. (2013). Metformin blocks melanoma invasion and metastasis development in AMPK/p53-dependent manner. Mol. Cancer Ther. 12, 1605–1615.10.1158/1535-7163.MCT-12-1226-TSearch in Google Scholar PubMed
Chadalapaka, G., Jutooru, I., Chintharlapalli, S., Papineni, S., Smith, R. 3rd, Li, X., and Safe, S. (2008). Curcumin decreases specificity protein expression in bladder cancer cells. Cancer Res. 68, 5345–5354.10.1158/0008-5472.CAN-07-6805Search in Google Scholar PubMed PubMed Central
Chadalapaka, G., Jutooru, I., and Safe, S. (2012). Celastrol decreases specificity proteins (Sp). and fibroblast growth factor receptor-3 (FGFR3) in bladder cancer cells. Carcinogenesis 33, 886–894.10.1093/carcin/bgs102Search in Google Scholar PubMed PubMed Central
Chadalapaka, G., Jutooru, I., Sreevalsan, S., Pathi, S., Kim, K., Chen, C., Crose, L., Linardic, C., and Safe, S. (2013). Inhibition of rhabdomyosarcoma cell and tumor growth by targeting specificity protein (Sp) transcription factors. Int. J. Cancer 132, 795–806.10.1002/ijc.27730Search in Google Scholar PubMed PubMed Central
Chae, Y.K., Arya, A., Malecek, M.K., Shin, D.S., Carneiro, B., Chandra, S., Kaplan, J., Kalyan, A., Altman, J.K., Platanias, L., et al. (2016). Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 7, 40767–40780.10.18632/oncotarget.8194Search in Google Scholar PubMed PubMed Central
Chaiteerakij, R., Petersen, G.M., Bamlet, W.R., Chaffee, K.G., Zhen, D.B., Burch, P.A., Leof, E.R., Roberts, L.R., and Oberg, A.L. (2016). Metformin use and survival of patients with pancreatic cancer: a cautionary lesson. J. Clin. Oncol. 34, 1898–1904.10.1200/JCO.2015.63.3511Search in Google Scholar PubMed PubMed Central
Chen, L., Pawlikowski, B., Schlessinger, A., More, S.S., Stryke, D., Johns, S.J., Portman, M.A., Chen, E., Ferrin, T.E., Sali, A., et al. (2010). Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenet. Genomics 20, 687–699.10.1097/FPC.0b013e32833fe789Search in Google Scholar PubMed PubMed Central
Chen, C.C., Hardy, D.B., and Mendelson, C.R. (2011). Progesterone receptor inhibits proliferation of human breast cancer cells via induction of MAPK phosphatase 1 (MKP-1/DUSP1). J. Biol. Chem. 286, 43091–43102.10.1074/jbc.M111.295865Search in Google Scholar PubMed PubMed Central
Chen, H.P., Shieh, J.J., Chang, C.C., Chen, T.T., Lin, J.T., Wu, M.S., Lin, J.H., and Wu, C.Y. (2013). Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 62, 606–615.10.1136/gutjnl-2011-301708Search in Google Scholar PubMed
Chen, K., Qian, W., Jiang, Z., Cheng, L., Li, J., Sun, L., Zhou, C., Gao, L., Lei, M., Yan, B., et al. (2017). Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer. Mol. Cancer 16, 131.10.1186/s12943-017-0701-0Search in Google Scholar PubMed PubMed Central
Cheng, C., Lin, C.H., Tsai, Y.W., Tsai, C.J., Chou, P.H., and Lan, T.H. (2014). Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J. Gerontol. A Biol. Sci. Med. Sci. 69, 1299–1305.10.1093/gerona/glu073Search in Google Scholar PubMed
Chintharlapalli, S., Papineni, S., Ramaiah, S.K., and Safe, S. (2007). Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res. 67, 2816–2823.10.1158/0008-5472.CAN-06-3735Search in Google Scholar PubMed
Chintharlapalli, S., Papineni, S., Lei, P., Pathi, S., and Safe, S. (2011). Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC Cancer 11, 371.10.1186/1471-2407-11-371Search in Google Scholar PubMed PubMed Central
Crowley, M.J., Diamantidis, C.J., McDuffie, J.R., Cameron, C.B., Stanifer, J.W., Mock, C.K., Wang, X., Tang, S., Nagi, A., Kosinski, A.S., et al. (2017). Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review. Ann. Intern. Med. 166, 191–200.10.7326/M16-1901Search in Google Scholar PubMed PubMed Central
De Souza, A., Khawaja, K.I., Masud, F., and Saif, M.W. (2016). Metformin and pancreatic cancer: Is there a role? Cancer Chemother. Pharmacol. 77, 235–242.10.1007/s00280-015-2948-8Search in Google Scholar PubMed
Deng, D., Yang, Y., Tang, X., Skrip, L., Qiu, J., Wang, Y., and Zhang, F. (2015). Association between metformin therapy and incidence, recurrence and mortality of prostate cancer: evidence from a meta-analysis. Diabetes Metab. Res. Rev. 31, 595–602.10.1002/dmrr.2645Search in Google Scholar PubMed
El-Benhawy, S.A. and El-Sheredy, H.G. (2014). Metformin and survival in diabetic patients with breast cancer. J. Egypt Public Health Assoc. 89, 148–153.10.1097/01.EPX.0000456620.00173.c0Search in Google Scholar PubMed
El-Mir, M.Y., Nogueira, V., Fontaine, E., Averet, N., Rigoulet, M., and Leverve, X. (2000). Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275, 223–228.10.1074/jbc.275.1.223Search in Google Scholar PubMed
Ezewuiro, O., Grushko, T.A., Kocherginsky, M., Habis, M., Hurteau, J.A., Mills, K.A., Hunn, J., Olopade, O.I., Fleming, G.F., and Romero, I.L. (2016). Association of metformin use with outcomes in advanced endometrial cancer treated with chemotherapy. PLoS One 11, e0147145.10.1371/journal.pone.0147145Search in Google Scholar PubMed PubMed Central
Feng, L., Lin, X.F., Wan, Z.H., Hu, D., and Du, Y.K. (2015). Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis. Gynecol. Endocrinol. 31, 833–839.10.3109/09513590.2015.1041906Search in Google Scholar PubMed
Foretz, M., Hebrard, S., Leclerc, J., Zarrinpashneh, E., Soty, M., Mithieux, G., Sakamoto, K., Andreelli, F., and Viollet, B. (2010). Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355–2369.10.1172/JCI40671Search in Google Scholar PubMed PubMed Central
Fransgaard, T., Thygesen, L.C., and Gogenur, I. (2016). Metformin increases overall survival in patients with diabetes undergoing surgery for colorectal cancer. Ann. Surg. Oncol. 23, 1569–1575.10.1245/s10434-015-5028-8Search in Google Scholar PubMed
Frouws, M.A., Sibinga Mulder, B.G., Bastiaannet, E., Zanders, M.M., van Herk-Sukel, M.P., de Leede, E.M., Bonsing, B.A., Mieog, J.S., Van de Velde, C.J., and Liefers, G.J. (2017). No association between metformin use and survival in patients with pancreatic cancer: an observational cohort study. Medicine (Baltimore). 96, e6229.10.1097/MD.0000000000006229Search in Google Scholar PubMed PubMed Central
Gandhy, S.U., Kim, K., Larsen, L., Rosengren, R.J., and Safe, S. (2012). Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp). transcription factors by targeting microRNAs. BMC Cancer 12, 564.10.1186/1471-2407-12-564Search in Google Scholar PubMed PubMed Central
Gandini, S., Puntoni, M., Heckman-Stoddard, B.M., Dunn, B.K., Ford, L., DeCensi, A., and Szabo, E. (2014). Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev. Res. (Phila). 7, 867–885.10.1158/1940-6207.CAPR-13-0424Search in Google Scholar PubMed PubMed Central
Garrett, C.R., Hassabo, H.M., Bhadkamkar, N.A., Wen, S., Baladandayuthapani, V., Kee, B.K., Eng, C., and Hassan, M.M. (2012). Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. Br. J. Cancer 106, 1374–1378.10.1038/bjc.2012.71Search in Google Scholar PubMed PubMed Central
Goldberg, R., Temprosa, M., Otvos, J., Brunzell, J., Marcovina, S., Mather, K., Arakaki, R., Watson, K., Horton, E., and Barrett-Connor, E. (2013). Lifestyle and metformin treatment favorably influence lipoprotein subfraction distribution in the Diabetes Prevention Program. J. Clin. Endocrinol. Metab. 98, 3989–3998.10.1210/jc.2013-1452Search in Google Scholar PubMed PubMed Central
Goldberg, R., Temprosa, M., Aroda, V.R., Barrett-Connor, E., Budoff, M., Crandall, J., Dabelea, D., Horton, E., Mather, K., Orchard, T., et al. (2015). Effect of long-term interventions in the Diabetes Prevention Program (DPP) and its outcome study on coronary artery calcium (CAC). Diabetes 64 (Suppl. 1A), LB5.Search in Google Scholar
Gollavilli, P.N., Kanugula, A.K., Koyyada, R., Karnewar, S., Neeli, P.K., and Kotamraju, S. (2015). AMPK inhibits MTDH expression via GSK3beta and SIRT1 activation: potential role in triple negative breast cancer cell proliferation. FEBS J. 282, 3971–3985.10.1111/febs.13391Search in Google Scholar PubMed
Gong, Z., Aragaki, A.K., Chlebowski, R.T., Manson, J.E., Rohan, T.E., Chen, C., Vitolins, M.Z., Tinker, L.F., LeBlanc, E.S., Kuller, L.H., et al. (2016). Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: results from the women’s health initiative. Int. J. Cancer 138, 1915–1927.10.1002/ijc.29944Search in Google Scholar PubMed PubMed Central
Gou, S., Cui, P., Li, X., Shi, P., Liu, T., and Wang, C. (2013). Low concentrations of metformin selectively inhibit CD133+ cell proliferation in pancreatic cancer and have anticancer action. PLoS One 8, e63969.10.1371/journal.pone.0063969Search in Google Scholar PubMed PubMed Central
Guo, M., Mi, J., Jiang, Q.M., Xu, J.M., Tang, Y.Y., Tian, G., and Wang, B. (2014). Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin. Exp. Pharmacol. Physiol. 41, 650–656.10.1111/1440-1681.12265Search in Google Scholar PubMed
Gwak, H., Kim, Y., An, H., Dhanasekaran, D.N., and Song, Y.S. (2017). Metformin induces degradation of cyclin D1 via AMPK/GSK3β axis in ovarian cancer. Mol. Carcinog. 56, 349–358.10.1002/mc.22498Search in Google Scholar PubMed
Haffner, S., Temprosa, M., Crandall, J., Fowler, S., Goldberg, R., Horton, E., Marcovina, S., Mather, K., Orchard, T., Ratner, R., et al. (2005). Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes 54, 1566–1572.10.2337/diabetes.54.5.1566Search in Google Scholar PubMed PubMed Central
Hakimi, A.A., Chen, L., Kim, P.H., Sjoberg, D., Glickman, L., Walker, M.R., and Russo, P. (2013). The impact of metformin use on recurrence and cancer-specific survival in clinically localized high-risk renal cell carcinoma. Can. Urol. Assoc. J. 7, E687–691.10.5489/cuaj.1447Search in Google Scholar PubMed PubMed Central
Han, K., Pintilie, M., Lipscombe, L.L., Lega, I.C., Milosevic, M.F., and Fyles, A.W. (2016). Association between metformin use and mortality after cervical cancer in older women with diabetes. Cancer Epidemiol. Biomarkers Prev. 25, 507–512.10.1158/1055-9965.EPI-15-1008Search in Google Scholar PubMed
Hart, T., Dider, S., Han, W., Xu, H., Zhao, Z., and Xie, L. (2016). Toward repurposing metformin as a precision anti-cancer therapy using structural systems pharmacology. Sci. Rep. 6, 20441.10.1038/srep20441Search in Google Scholar PubMed PubMed Central
Haukka, J., Niskanen, L., and Auvinen, A. (2017). Risk of cause-specific death in individuals with cancer-modifying role diabetes, statins and metformin. Int. J. Cancer 141, 2437–2449.10.1002/ijc.31016Search in Google Scholar
Hawley, S.A., Ford, R.J., Smith, B.K., Gowans, G.J., Mancini, S.J., Pitt, R.D., Day, E.A., Salt, I.P., Steinberg, G.R., and Hardie, D.G. (2016). The Na+/glucose cotransporter inhibitor canagliflozin activates AMPK by inhibiting mitochondrial function and increasing cellular AMP levels. Diabetes 65, 2784–2794.10.2337/db16-0058Search in Google Scholar
He, X.K., Su, T.T., Si, J.M., and Sun, L.M. (2016). Metformin is associated with slightly reduced risk of colorectal cancer and moderate survival benefits in diabetes mellitus: a meta-analysis. Medicine (Baltimore). 95, e2749.10.1097/MD.0000000000002749Search in Google Scholar
Hedrick, E., Crose, L., Linardic, C.M., and Safe, S. (2015). Histone deacetylase inhibitors inhibit rhabdomyosarcoma by reactive oxygen species-dependent targeting of specificity protein transcription factors. Mol. Cancer Ther. 14, 2143–2153.10.1158/1535-7163.MCT-15-0148Search in Google Scholar
Hedrick, E., Cheng, Y., Jin, U.H., Kim, K., and Safe, S. (2016). Specificity protein (Sp). transcription factors Sp1, Sp3 and Sp4 are non-oncogene addiction genes in cancer cells. Oncotarget 7, 22245–22256.10.18632/oncotarget.7925Search in Google Scholar
Hedrick, E., Li, X., and Safe, S. (2017). Penfluridol represses integrin expression in breast cancer through induction of reactive oxygen species and downregulation of Sp transcription factors. Mol. Cancer Ther. 16, 205–216.10.1158/1535-7163.MCT-16-0451Search in Google Scholar
Hicks, B.M., Yin, H., Sinyavskaya, L., Suissa, S., Azoulay, L., and Brassard, P. (2017). Metformin and the incidence of viral associated cancers in patients with type 2 diabetes. Int. J. Cancer 141, 121–128.10.1002/ijc.30733Search in Google Scholar
Higurashi, T., Hosono, K., Takahashi, H., Komiya, Y., Umezawa, S., Sakai, E., Uchiyama, T., Taniguchi, L., Hata, Y., Uchiyama, S., et al. (2016). Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 17, 475–483.10.1016/S1470-2045(15)00565-3Search in Google Scholar
Hinke, S.A., Martens, G.A., Cai, Y., Finsi, J., Heimberg, H., Pipeleers, D., and Van de Casteele, M. (2007). Methyl succinate antagonises biguanide-induced AMPK-activation and death of pancreatic β-cells through restoration of mitochondrial electron transfer. Br. J. Pharmacol. 150, 1031–1043.10.1038/sj.bjp.0707189Search in Google Scholar PubMed PubMed Central
Horiuchi, T., Sakata, N., Narumi, Y., Kimura, T., Hayashi, T., Nagano, K., Liu, K., Nishibori, M., Tsukita, S., Yamada, T., et al. (2017). Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity. J. Biol. Chem. 292, 8436–8446.10.1074/jbc.M116.769380Search in Google Scholar PubMed PubMed Central
Hwang, I.C., Park, S.M., Shin, D., Ahn, H.Y., Rieken, M., and Shariat, S.F. (2015). Metformin association with lower prostate cancer recurrence in type 2 diabetes: a systematic review and meta-analysis. Asian Pac. J. Cancer Prev. 16, 595–600.10.7314/APJCP.2015.16.2.595Search in Google Scholar PubMed
Ichikawa, M., Sowa, Y., Iizumi, Y., Aono, Y., and Sakai, T. (2015). Resibufogenin induces G1-phase arrest through the proteasomal degradation of cyclin D1 in human malignant tumor cells. PLoS One 10, e0129851.10.1371/journal.pone.0129851Search in Google Scholar PubMed PubMed Central
Iglesias, D.A., Yates, M.S., van der Hoeven, D., Rodkey, T.L., Zhang, Q., Co, N.N., Burzawa, J., Chigurupati, S., Celestino, J., Bowser, J., et al. (2013). Another surprise from Metformin: novel mechanism of action via K-Ras influences endometrial cancer response to therapy. Mol. Cancer Ther. 12, 2847–2856.10.1158/1535-7163.MCT-13-0439Search in Google Scholar PubMed PubMed Central
Inzucchi, S.E., Bergenstal, R.M., Buse, J.B., Diamant, M., Ferrannini, E., Nauck, M., Peters, A.L., Tsapas, A., Wender, R., and Matthews, D.R. (2015). Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 38, 140–149.10.2337/dc14-2441Search in Google Scholar PubMed
Jan, H.J., Lee, C.C., Lin, Y.M., Lai, J.H., Wei, H.W., and Lee, H.M. (2009). Rosiglitazone reduces cell invasiveness by inducing MKP-1 in human U87MG glioma cells. Cancer Lett. 277, 141–148.10.1016/j.canlet.2008.11.033Search in Google Scholar PubMed
Jang, W.I., Kim, M.S., Kang, S.H., Jo, A.J., Kim, Y.J., Tchoe, H.J., Park, C.M., Kim, H.J., Choi, J.A., Choi, H.J., et al. (2017). Association between metformin use and mortality in patients with type 2 diabetes mellitus and localized resectable pancreatic cancer: a nationwide population-based study in Korea. Oncotarget 8, 9587–9596.10.18632/oncotarget.14525Search in Google Scholar PubMed PubMed Central
Jin, U.H., Cheng, Y., Zhou, B., and Safe, S. (2017). Bardoxolone methyl and a related triterpenoid downregulate cMyc expression in leukemia cells. Mol. Pharmacol. 91, 438–450.10.1124/mol.116.106245Search in Google Scholar PubMed PubMed Central
Jo, A., Kim, Y., Kang, S., Kim, M., and Ko, M. (2015). The effect of metformin use and mortality among those with pancreatic cancer and type 2 diabetes mellitus: findings from a nationwide population retrospective cohort study. Value Health 18, A439.10.1016/j.jval.2015.09.1072Search in Google Scholar
Jutooru, I., Chadalapaka, G., Abdelrahim, M., Basha, M.R., Samudio, I., Konopleva, M., Andreeff, M., and Safe, S. (2010a). Methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate decreases specificity protein transcription factors and inhibits pancreatic tumor growth: role of microRNA-27a. Mol. Pharmacol. 78, 226–236.10.1124/mol.110.064451Search in Google Scholar PubMed PubMed Central
Jutooru, I., Chadalapaka, G., Lei, P., and Safe, S. (2010b). Inhibition of NFkappaB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. J. Biol. Chem. 285, 25332–25344.10.1074/jbc.M109.095240Search in Google Scholar PubMed PubMed Central
Jutooru, I., Chadalapaka, G., Sreevalsan, S., Lei, P., Barhoumi, R., Burghardt, R., and Safe, S. (2010c). Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth. Exp. Cell Res. 316, 2174–2188.10.1016/j.yexcr.2010.04.027Search in Google Scholar PubMed PubMed Central
Jutooru, I., Guthrie, A.S., Chadalapaka, G., Pathi, S., Kim, K., Burghardt, R., Jin, U.H., and Safe, S. (2014). Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents. Mol. Cell Biol. 34, 2382–2395.10.1128/MCB.01602-13Search in Google Scholar PubMed PubMed Central
Karki, K., Hedrick, E., Kasiappan, R., Jin, U.H., and Safe, S. (2017). Piperlongumine induces reactive oxygen species (ROS)-dependent downregulation of specificity protein transcription factors. Cancer Prev. Res. (Phila.) 10, 467–477.10.1158/1940-6207.CAPR-17-0053Search in Google Scholar PubMed PubMed Central
Karnevi, E., Said, K., Andersson, R., and Rosendahl, A.H. (2013). Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. BMC Cancer 13, 235.10.1186/1471-2407-13-235Search in Google Scholar PubMed PubMed Central
Kasiappan, R., Jutooru, I., Karki, K., Hedrick, E., and Safe, S. (2016). Benzyl isothiocyanate (BITC) induces reactive oxygen species-dependent repression of STAT3 protein by down-regulation of specificity proteins in pancreatic cancer. J. Biol. Chem. 291, 27122–27133.10.1074/jbc.M116.746339Search in Google Scholar PubMed PubMed Central
Kickstein, E., Krauss, S., Thornhill, P., Rutschow, D., Zeller, R., Sharkey, J., Williamson, R., Fuchs, M., Kohler, A., Glossmann, H., et al. (2010). Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc. Natl. Acad. Sci. USA 107, 21830–21835.10.1073/pnas.0912793107Search in Google Scholar PubMed PubMed Central
Kim, M.J., Park, I.J., Yun, H., Kang, I., Choe, W., Kim, S.S., and Ha, J. (2010). AMP-activated protein kinase antagonizes pro-apoptotic extracellular signal-regulated kinase activation by inducing dual-specificity protein phosphatases in response to glucose deprivation in HCT116 carcinoma. J. Biol. Chem. 285, 14617–14627.10.1074/jbc.M109.085456Search in Google Scholar PubMed PubMed Central
Kim, H.G., Hien, T.T., Han, E.H., Hwang, Y.P., Choi, J.H., Kang, K.W., Kwon, K.I., Kim, B.H., Kim, S.K., Song, G.Y., et al. (2011). Metformin inhibits P-glycoprotein expression via the NF-κB pathway and CRE transcriptional activity through AMPK activation. Br. J. Pharmacol. 162, 1096–1108.10.1111/j.1476-5381.2010.01101.xSearch in Google Scholar PubMed PubMed Central
Kim, Y.I., Kim, S.Y., Cho, S.J., Park, J.H., Choi, I.J., Lee, Y.J., Lee, E.K., Kook, M.C., Kim, C.G., Ryu, K.W., et al. (2014). Long-term metformin use reduces gastric cancer risk in type 2 diabetics without insulin treatment: a nationwide cohort study. Aliment Pharmacol. Ther. 39, 854–863.10.1111/apt.12660Search in Google Scholar PubMed
Kim, H.J., Kwon, H., Lee, J.W., Kim, H.J., Lee, S.B., Park, H.S., Sohn, G., Lee, Y., Koh, B.S., Yu, J.H., et al. (2015). Metformin increases survival in hormone receptor-positive, HER2-positive breast cancer patients with diabetes. Breast Cancer Res. 17, 64.10.1186/s13058-015-0574-3Search in Google Scholar PubMed PubMed Central
Kisfalvi, K., Eibl, G., Sinnett-Smith, J., and Rozengurt, E. (2009). Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 69, 6539–6545.10.1158/0008-5472.CAN-09-0418Search in Google Scholar
Ko, E.M., Walter, P., Jackson, A., Clark, L., Franasiak, J., Bolac, C., Havrilesky, L.J., Secord, A.A., Moore, D.T., Gehrig, P.A., et al. (2014). Metformin is associated with improved survival in endometrial cancer. Gynecol. Oncol. 132, 438–442.10.1016/j.ygyno.2013.11.021Search in Google Scholar
Kong, F., Gao, F., Liu, H., Chen, L., Zheng, R., Yu, J., Li, X., Liu, G., and Jia, Y. (2015). Metformin use improves the survival of diabetic combined small-cell lung cancer patients. Tumour Biol. 36, 8101–8106.10.1007/s13277-015-3549-1Search in Google Scholar
Kordes, S., Pollak, M.N., Zwinderman, A.H., Mathot, R.A., Weterman, M.J., Beeker, A., Punt, C.J., Richel, D.J., and Wilmink, J.W. (2015). Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 16, 839–847.10.1016/S1470-2045(15)00027-3Search in Google Scholar
Kozak, M.M., Anderson, E.M., von Eyben, R., Pai, J.S., Poultsides, G.A., Visser, B.C., Norton, J.A., Koong, A.C., and Chang, D.T. (2016). Statin and metformin use prolongs survival in patients with resectable pancreatic cancer. Pancreas 45, 64–70.10.1097/MPA.0000000000000470Search in Google Scholar PubMed
Lai, S.W., Chen, P.C., Liao, K.F., Muo, C.H., Lin, C.C., and Sung, F.C. (2012). Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am. J. Gastroenterol. 107, 46–52.10.1038/ajg.2011.384Search in Google Scholar PubMed
Lee, J.H. and Kim, T.I. (2014). Type II diabetes, metformin use, and colorectal neoplasia: mechanisms of action and implications for future research. Curr. Colorectal. Cancer Rep. 10, 105–113.10.1007/s11888-013-0198-xSearch in Google Scholar
Lee, J.H., Kim, T.I., Jeon, S.M., Hong, S.P., Cheon, J.H., and Kim, W.H. (2012). The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int. J. Cancer 131, 752–759.10.1002/ijc.26421Search in Google Scholar PubMed
Lee, S.H., Yoon, S.H., Lee, H.S., Chung, M.J., Park, J.Y., Park, S.W., Song, S.Y., Chung, J.B., and Bang, S. (2016). Can metformin change the prognosis of pancreatic cancer? Retrospective study for pancreatic cancer patients with pre-existing diabetes mellitus type 2. Dig. Liver Dis. 48, 435–440.10.1016/j.dld.2015.12.006Search in Google Scholar PubMed
Lega, I.C., Shah, P.S., Margel, D., Beyene, J., Rochon, P.A., and Lipscombe, L.L. (2014). The effect of metformin on mortality following cancer among patients with diabetes. Cancer Epidemiol. Biomarkers Prev. 23, 1974–1984.10.1158/1055-9965.EPI-14-0327Search in Google Scholar PubMed
Li, D. and Abbruzzese, J.L. (2010). New strategies in pancreatic cancer: emerging epidemiologic and therapeutic concepts. Clin. Cancer Res. 16, 4313–4318.10.1158/1078-0432.CCR-09-1942Search in Google Scholar PubMed PubMed Central
Li, D., Yeung, S.C., Hassan, M.M., Konopleva, M., and Abbruzzese, J.L. (2009). Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 137, 482–488.10.1053/j.gastro.2009.04.013Search in Google Scholar PubMed PubMed Central
Li, Y., Li, L., Zhang, G., Wang, Y., Chen, H., Kong, R., Pan, S., and Sun, B. (2017). Crucial microRNAs and genes in metformin’s anti-pancreatic cancer effect explored by microRNA-mRNA integrated analysis. Invest. New Drugs, 1–8. doi: 10.1007/s10637-017-0508-2. [Epub ahead of print]10.1007/s10637-017-0508-2Search in Google Scholar PubMed
Liang, X., Chien, H.C., Yee, S.W., Giacomini, M.M., Chen, E.C., Piao, M., Hao, J., Twelves, J., Lepist, E.I., Ray, A.S., et al. (2015). Metformin Is a substrate and inhibitor of the human thiamine transporter, THTR-2 (SLC19A3). Mol. Pharm. 12, 4301–4310.10.1021/acs.molpharmaceut.5b00501Search in Google Scholar PubMed PubMed Central
Lin, J.J., Gallagher, E.J., Sigel, K., Mhango, G., Galsky, M.D., Smith, C.B., LeRoith, D., and Wisnivesky, J.P. (2015). Survival of patients with stage IV lung cancer with diabetes treated with metformin. Am. J. Respir. Crit. Care Med. 191, 448–454.10.1164/rccm.201407-1395OCSearch in Google Scholar PubMed PubMed Central
Lin, J., Gill, A., Zahm, S.H., Carter, C.A., Shriver, C.D., Nations, J.A., Anderson, W.F., McGlynn, K.A., and Zhu, K. (2017). Metformin use and survival after non-small cell lung cancer: a cohort study in the US Military health system. Int. J. Cancer 141, 254–263.10.1002/ijc.30724Search in Google Scholar PubMed PubMed Central
Liu, X., Jutooru, I., Lei, P., Kim, K., Lee, S.O., Brents, L.K., Prather, P.L., and Safe, S. (2012). Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a:ZBTB10 in breast cancer. Mol. Cancer Ther. 11, 1421–1431.10.1158/1535-7163.MCT-12-0026Search in Google Scholar PubMed PubMed Central
Logie, L., Harthill, J., Patel, K., Bacon, S., Hamilton, D.L., Macrae, K., McDougall, G., Wang, H.H., Xue, L., Jiang, H., et al. (2012). Cellular responses to the metal-binding properties of metformin. Diabetes 61, 1423–1433.10.2337/db11-0961Search in Google Scholar PubMed PubMed Central
Lonardo, E., Cioffi, M., Sancho, P., Sanchez-Ripoll, Y., Trabulo, S.M., Dorado, J., Balic, A., Hidalgo, M., and Heeschen, C. (2013). Metformin targets the metabolic Achilles heel of human pancreatic cancer stem cells. PLoS One 8, e76518.10.1371/journal.pone.0076518Search in Google Scholar PubMed PubMed Central
Madiraju, A.K., Erion, D.M., Rahimi, Y., Zhang, X.M., Braddock, D.T., Albright, R.A., Prigaro, B.J., Wood, J.L., Bhanot, S., MacDonald, M.J., et al. (2014). Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542–546.10.1038/nature13270Search in Google Scholar PubMed PubMed Central
Mc Menamin, U.C., Murray, L.J., Hughes, C.M., and Cardwell, C.R. (2016). Metformin use and survival after colorectal cancer: a population-based cohort study. Int. J. Cancer 138, 369–379.10.1002/ijc.29720Search in Google Scholar PubMed
Meng, F., Song, L., and Wang, W. (2017). Metformin improves overall survival of colorectal cancer patients with diabetes: a meta-analysis. J. Diabetes Res. 2017, 5063239.10.1155/2017/5063239Search in Google Scholar PubMed PubMed Central
Mertens-Talcott, S.U., Chintharlapalli, S., Li, X., and Safe, S. (2007). The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res. 67, 11001–11011.10.1158/0008-5472.CAN-07-2416Search in Google Scholar PubMed
Mitsuhashi, A., Kiyokawa, T., Sato, Y., and Shozu, M. (2014). Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. Cancer 120, 2986–2995.10.1002/cncr.28853Search in Google Scholar PubMed
Nair, V., Pathi, S., Jutooru, I., Sreevalsan, S., Basha, R., Abdelrahim, M., Samudio, I., and Safe, S. (2013). Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. Carcinogenesis 34, 2870–2879.10.1093/carcin/bgt231Search in Google Scholar PubMed PubMed Central
Nair, V., Sreevalsan, S., Basha, R., Abdelrahim, M., Abudayyeh, A., Rodrigues Hoffman, A., and Safe, S. (2014). Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors. J. Biol. Chem. 289, 27692–27701.10.1074/jbc.M114.592576Search in Google Scholar PubMed PubMed Central
Nakamichi, N., Shima, H., Asano, S., Ishimoto, T., Sugiura, T., Matsubara, K., Kusuhara, H., Sugiyama, Y., Sai, Y., Miyamoto, K., et al. (2013). Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin. J. Pharm. Sci. 102, 3407–3417.10.1002/jps.23595Search in Google Scholar PubMed
Nathan, D.M., Buse, J.B., Davidson, M.B., Ferrannini, E., Holman, R.R., Sherwin, R., Zinman, B., American Diabetes Association, and European Association for Study of Diabetes. (2009). Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32, 193–203.10.2337/dc08-9025Search in Google Scholar PubMed PubMed Central
Negrotto, L., Farez, M.F., and Correale, J. (2016). Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome and multiple sclerosis. J. Am. Med. Assoc. Neurol. 73, 520–528.10.1001/jamaneurol.2015.4807Search in Google Scholar PubMed
Nevadunsky, N.S., Van Arsdale, A., Strickler, H.D., Moadel, A., Kaur, G., Frimer, M., Conroy, E., Goldberg, G.L., and Einstein, M.H. (2014). Metformin use and endometrial cancer survival. Gynecol. Oncol. 132, 236–240.10.1016/j.ygyno.2013.10.026Search in Google Scholar PubMed PubMed Central
Nonn, L., Duong, D., and Peehl, D.M. (2007). Chemopreventive anti-inflammatory activities of curcumin and other phytochemicals mediated by MAP kinase phosphatase-5 in prostate cells. Carcinogenesis 28, 1188–1196.10.1093/carcin/bgl241Search in Google Scholar PubMed
Oppong, B.A., Pharmer, L.A., Oskar, S., Eaton, A., Stempel, M., Patil, S., and King, T.A. (2014). The effect of metformin on breast cancer outcomes in patients with type 2 diabetes. Cancer Med. 3, 1025–1034.10.1002/cam4.259Search in Google Scholar PubMed PubMed Central
Ouyang, J., Parakhia, R.A., and Ochs, R.S. (2011). Metformin activates AMP kinase through inhibition of AMP deaminase. J. Biol. Chem. 286, 1–11.10.1074/jbc.M110.121806Search in Google Scholar PubMed PubMed Central
Owen, M.R., Doran, E., and Halestrap, A.P. (2000). Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607–614.10.1042/bj3480607Search in Google Scholar
Park, J.W., Lee, J.H., Park, Y.H., Park, S.J., Cheon, J.H., Kim, W.H., and Kim, T.I. (2017). Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients. World J. Gastroenterol. 23, 5196–5205.10.3748/wjg.v23.i28.5196Search in Google Scholar PubMed PubMed Central
Patel, J.P., Lee, E.H., Mena, C.I., and Walker, C.N. (2017). Effects of metformin on endothelial health and erectile dysfunction. Transl. Androl. Urol. 6, 556–565.10.21037/tau.2017.03.52Search in Google Scholar PubMed PubMed Central
Pathi, S.S., Jutooru, I., Chadalapaka, G., Sreevalsan, S., Anand, S., Thatcher, G.R., and Safe, S. (2011a). GT-094, a NO-NSAID, inhibits colon cancer cell growth by activation of a reactive oxygen species-microRNA-27a: ZBTB10-specificity protein pathway. Mol. Cancer Res. 9, 195–202.10.1158/1541-7786.MCR-10-0363Search in Google Scholar PubMed PubMed Central
Pathi, S.S., Lei, P., Sreevalsan, S., Chadalapaka, G., Jutooru, I., and Safe, S. (2011b). Pharmacologic doses of ascorbic acid repress specificity protein (Sp). transcription factors and Sp-regulated genes in colon cancer cells. Nutr. Cancer 63, 1133–1142.10.1080/01635581.2011.605984Search in Google Scholar PubMed PubMed Central
Pathi, S., Jutooru, I., Chadalapaka, G., Nair, V., Lee, S.O., and Safe, S. (2012). Aspirin inhibits colon cancer cell and tumor growth and downregulates specificity protein (sp) transcription factors. PLoS One 7, e48208.10.1371/journal.pone.0048208Search in Google Scholar PubMed PubMed Central
Pathi, S., Li, X., and Safe, S. (2014). Tolfenamic acid inhibits colon cancer cell and tumor growth and induces degradation of specificity protein (Sp) transcription factors. Mol. Carcinog. 53 (Suppl. 1), E53–E61.10.1002/mc.22010Search in Google Scholar PubMed
Paulus, J.K., Williams, C.D., Cossor, F.I., Kelley, M.J., and Martell, R.E. (2016). Metformin, diabetes, and survival among U.S. veterans with colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 25, 1418–1425.10.1158/1055-9965.EPI-16-0312Search in Google Scholar PubMed PubMed Central
Perez-Lopez, F.R., Pasupuleti, V., Gianuzzi, X., Palma-Ardiles, G., Hernandez-Fernandez, W., and Hernandez, A.V. (2017). Systematic review and meta-analysis of the effect of metformin treatment on overall mortality rates in women with endometrial cancer and type 2 diabetes mellitus. Maturitas 101, 6–11.10.1016/j.maturitas.2017.04.001Search in Google Scholar PubMed
Pernicova, I. and Korbonits, M. (2014). Metformin--mode of action and clinical implications for diabetes and cancer. Nat. Rev. Endocrinol. 10, 143–156.10.1038/nrendo.2013.256Search in Google Scholar PubMed
Pollak, M. (2012). Metformin and pancreatic cancer: a clue requiring investigation. Clin. Cancer Res. 18, 2723–2725.10.1158/1078-0432.CCR-12-0694Search in Google Scholar PubMed
Pollak, M. (2017). The effects of metformin on gut microbiota and the immune system as research frontiers. Diabetologia 60, 1662–1667.10.1007/s00125-017-4352-xSearch in Google Scholar PubMed
Psutka, S.P., Boorjian, S.A., Lohse, C.M., Stewart, S.B., Tollefson, M.K., Cheville, J.C., Leibovich, B.C., and Thompson, R.H. (2015). The association between metformin use and oncologic outcomes among surgically treated diabetic patients with localized renal cell carcinoma. Urol. Oncol. 33, 67 e15–23.10.1016/j.urolonc.2014.07.008Search in Google Scholar PubMed
Rajeshkumar, N.V., Yabuuchi, S., Pai, S.G., De Oliveira, E., Kamphorst, J.J., Rabinowitz, J.D., Tejero, H., Al-Shahrour, F., Hidalgo, M., Maitra, A., et al. (2017). Treatment of pancreatic cancer patient-derived xenograft panel with metabolic inhibitors reveals efficacy of phenformin. Clin. Cancer Res. 23, 5639–5647.10.1158/1078-0432.CCR-17-1115Search in Google Scholar PubMed PubMed Central
Ramjeesingh, R., Orr, C., Bricks, C.S., Hopman, W.M., and Hammad, N. (2016). A retrospective study on the role of diabetes and metformin in colorectal cancer disease survival. Curr. Oncol. 23, e116–122.10.3747/co.23.2809Search in Google Scholar PubMed PubMed Central
Raval, A.D., Thakker, D., Vyas, A., Salkini, M., Madhavan, S., and Sambamoorthi, U. (2015). Impact of metformin on clinical outcomes among men with prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 18, 110–121.10.1038/pcan.2014.52Search in Google Scholar PubMed PubMed Central
Reni, M., Dugnani, E., Cereda, S., Belli, C., Balzano, G., Nicoletti, R., Liberati, D., Pasquale, V., Scavini, M., Maggiora, P., et al. (2016). (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase II trial. Clin. Cancer Res. 22, 1076–1085.10.1158/1078-0432.CCR-15-1722Search in Google Scholar PubMed
Romero, R., Erez, O., Huttemann, M., Maymon, E., Panaitescu, B., Conde-Agudelo, A., Pacora, P., Yoon, B.H., and Grossman, L.I. (2017). Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am. J. Obstet. Gynecol. 217, 282–302.10.1016/j.ajog.2017.06.003Search in Google Scholar PubMed PubMed Central
Rozengurt, E., Sinnett-Smith, J., and Kisfalvi, K. (2010). Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: a novel target for the antidiabetic drug metformin in pancreatic cancer. Clin. Cancer Res. 16, 2505–2511.10.1158/1078-0432.CCR-09-2229Search in Google Scholar PubMed PubMed Central
Sadeghi, N., Abbruzzese, J.L., Yeung, S.C., Hassan, M., and Li, D. (2012). Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin. Cancer Res. 18, 2905–2912.10.1158/1078-0432.CCR-11-2994Search in Google Scholar PubMed PubMed Central
Safe, S. and Abdelrahim, M. (2005). Sp transcription factor family and its role in cancer. Eur. J. Cancer 41, 2438–2448.10.1016/j.ejca.2005.08.006Search in Google Scholar PubMed
Safe, S. and Kasiappan, R. (2016). Natural products as mechanism-based anticancer agents: Sp transcription factors as targets. Phytother. Res. 30, 1723–1732.10.1002/ptr.5669Search in Google Scholar PubMed
Sayed, R., Saad, A.S., El Wakeel, L., Elkholy, E., and Badary, O. (2015). Metformin addition to chemotherapy in stage IV non-small cell lung cancer: an open label randomized controlled study. Asian Pac. J. Cancer Prev. 16, 6621–6626.10.7314/APJCP.2015.16.15.6621Search in Google Scholar
Segal, E.D., Yasmeen, A., Beauchamp, M.C., Rosenblatt, J., Pollak, M., and Gotlieb, W.H. (2011). Relevance of the OCT1 transporter to the antineoplastic effect of biguanides. Biochem. Biophys. Res. Commun. 414, 694–699.10.1016/j.bbrc.2011.09.134Search in Google Scholar PubMed
Singh, S., Singh, P.P., Singh, A.G., Murad, M.H., and Sanchez, W. (2013). Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am. J. Gastroenterol. 108, 881–891.10.1038/ajg.2013.5Search in Google Scholar PubMed
Sinnett-Smith, J., Kisfalvi, K., Kui, R., and Rozengurt, E. (2013). Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: dependence on glucose concentration and role of AMPK. Biochem. Biophys. Res. Commun. 430, 352–357.10.1016/j.bbrc.2012.11.010Search in Google Scholar PubMed PubMed Central
Sivalingam, V.N., Kitson, S., McVey, R., Roberts, C., Pemberton, P., Gilmour, K., Ali, S., Renehan, A.G., Kitchener, H.C., and Crosbie, E.J. (2016). Measuring the biological effect of presurgical metformin treatment in endometrial cancer. Br. J. Cancer 114, 281–289.10.1038/bjc.2015.453Search in Google Scholar PubMed PubMed Central
Soares, H.P., Ni, Y., Kisfalvi, K., Sinnett-Smith, J., and Rozengurt, E. (2013). Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells. PLoS One 8, e57289.10.1371/journal.pone.0057289Search in Google Scholar PubMed PubMed Central
Spillane, S., Bennett, K., Sharp, L., and Barron, T.I. (2013). A cohort study of metformin exposure and survival in patients with stage I-III colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 22, 1364–1373.10.1158/1055-9965.EPI-13-0347Search in Google Scholar PubMed
Sreevalsan, S. and Safe, S. (2013). The cannabinoid WIN 55,212-2 decreases specificity protein transcription factors and the oncogenic cap protein eIF4E in colon cancer cells. Mol. Cancer Ther. 12, 2483–2493.10.1158/1535-7163.MCT-13-0486Search in Google Scholar PubMed PubMed Central
Sterne, J. (1959). Treatment of diabetes mellitus with N,N-dimethylguanylguanidine (LA. 6023, glucophage). Therapie 14, 625–630.Search in Google Scholar
Stopsack, K.H., Ziehr, D.R., Rider, J.R., and Giovannucci, E.L. (2016). Metformin and prostate cancer mortality: a meta-analysis. Cancer Causes Control 27, 105–113.10.1007/s10552-015-0687-0Search in Google Scholar PubMed
Storozhuk, Y., Hopmans, S.N., Sanli, T., Barron, C., Tsiani, E., Cutz, J.C., Pond, G., Wright, J., Singh, G., and Tsakiridis, T. (2013). Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK. Br. J. Cancer 108, 2021–2032.10.1038/bjc.2013.187Search in Google Scholar PubMed PubMed Central
Takayama, H., Misu, H., Iwama, H., Chikamoto, K., Saito, Y., Murao, K., Teraguchi, A., Lan, F., Kikuchi, A., Saito, R., et al. (2014). Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes. J. Biol. Chem. 289, 335–345.10.1074/jbc.M113.479386Search in Google Scholar PubMed PubMed Central
Taoka, R., Jinesh, G.G., Xue, W., Safe, S., and Kamat, A.M. (2017). CF3DODA-Me induces apoptosis, degrades Sp1, and blocks the transformation phase of the blebbishield emergency program. Apoptosis 22, 719–729.10.1007/s10495-017-1359-1Search in Google Scholar PubMed
Tian, R.H., Zhang, Y.G., Wu, Z., Liu, X., Yang, J.W., and Ji, H.L. (2016). Effects of metformin on survival outcomes of lung cancer patients with type 2 diabetes mellitus: a meta-analysis. Clin. Transl. Oncol. 18, 641–649.10.1007/s12094-015-1412-xSearch in Google Scholar PubMed
Tsai, M.J., Yang, C.J., Kung, Y.T., Sheu, C.C., Shen, Y.T., Chang, P.Y., Huang, M.S., and Chiu, H.C. (2014). Metformin decreases lung cancer risk in diabetic patients in a dose-dependent manner. Lung Cancer 86, 137–143.10.1016/j.lungcan.2014.09.012Search in Google Scholar PubMed
Tzvetkov, M.V., Vormfelde, S.V., Balen, D., Meineke, I., Schmidt, T., Sehrt, D., Sabolic, I., Koepsell, H., and Brockmoller, J. (2009). The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin. Pharmacol. Ther. 86, 299–306.10.1038/clpt.2009.92Search in Google Scholar PubMed
Vazquez-Martin, A., Oliveras-Ferraros, C., and Menendez, J.A. (2009). The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle 8, 88–96.10.4161/cc.8.1.7499Search in Google Scholar PubMed
Victor, V.M., Rovira-Llopis, S., Banuls, C., Diaz-Morales, N., Lopez-Domenech, S., Escribano-Lopez, I., Rios-Navarro, C., Alvarez, A., Gomez, M., Rocha, M., et al. (2015). Metformin modulates human leukocyte/endothelial cell interactions and proinflammatory cytokines in polycystic ovary syndrome patients. Atherosclerosis 242, 167–173.10.1016/j.atherosclerosis.2015.07.017Search in Google Scholar PubMed
Vissers, P.A., Cardwell, C.R., van de Poll-Franse, L.V., Young, I.S., Pouwer, F., and Murray, L.J. (2015). The association between glucose-lowering drug use and mortality among breast cancer patients with type 2 diabetes. Breast Cancer Res. Treat. 150, 427–437.10.1007/s10549-015-3331-5Search in Google Scholar PubMed
Wakatsuki, S., Tokunaga, S., Shibata, M., and Araki, T. (2017). GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration. J. Cell Biol. 216, 477–493.10.1083/jcb.201606020Search in Google Scholar PubMed PubMed Central
Walker, E.J., Ko, A.H., Holly, E.A., and Bracci, P.M. (2015). Metformin use among type 2 diabetics and risk of pancreatic cancer in a clinic-based case-control study. Int J. Cancer 136, E646–653.10.1002/ijc.29120Search in Google Scholar PubMed PubMed Central
Wan, G., Yu, X., Chen, P., Wang, X., Pan, D., Wang, X., Li, L., Cai, X., and Cao, F. (2016). Metformin therapy associated with survival benefit in lung cancer patients with diabetes. Oncotarget 7, 35437–35445.10.18632/oncotarget.8881Search in Google Scholar PubMed PubMed Central
Wang, C.P., Lehman, D.M., Lam, Y.F., Kuhn, J.G., Mahalingam, D., Weitman, S., Lorenzo, C., Downs, J.R., Stuart, E.A., Hernandez, J., et al. (2016). Metformin for reducing racial/ethnic difference in prostate cancer incidence for men with type II diabetes. Cancer Prev. Res. (Phila.) 9, 779–787.10.1158/1940-6207.CAPR-15-0425Search in Google Scholar PubMed PubMed Central
Wei, D., Wang, L., He, Y., Xiong, H.Q., Abbruzzese, J.L., and Xie, K. (2004). Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res. 64, 2030–2038.10.1158/0008-5472.CAN-03-1945Search in Google Scholar
Wheaton, W.W., Weinberg, S.E., Hamanaka, R.B., Soberanes, S., Sullivan, L.B., Anso, E., Glasauer, A., Dufour, E., Mutlu, G.M., Budigner, G.S., et al. (2014). Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 3, e02242.10.7554/eLife.02242Search in Google Scholar PubMed PubMed Central
Witters, L.A. (2001). The blooming of the French lilac. J. Clin. Invest. 108, 1105–1107.10.1172/JCI14178Search in Google Scholar PubMed PubMed Central
Wu, W., Merriman, K., Nabaah, A., Seval, N., Seval, D., Lin, H., Wang, M., Qazilbash, M.H., Baladandayuthapani, V., Berry, D., et al. (2014). The association of diabetes and anti-diabetic medications with clinical outcomes in multiple myeloma. Br. J. Cancer 111, 628–636.10.1038/bjc.2014.307Search in Google Scholar PubMed PubMed Central
Wu, L., Zhu, J., Prokop, L.J., and Murad, M.H. (2015). Pharmacologic therapy of diabetes and overall cancer risk and mortality: a meta-analysis of 265 studies. Sci. Rep. 5, 10147.10.1038/srep10147Search in Google Scholar PubMed PubMed Central
Wu, H., Esteve, E., Tremaroli, V., Khan, M.T., Caesar, R., Manneras-Holm, L., Stahlman, M., Olsson, L.M., Serino, M., Planas-Felix, M., et al. (2017). Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858.10.1038/nm.4345Search in Google Scholar PubMed
Xiao, Y., Zhang, S., Hou, G., Zhang, X., Hao, X., and Zhang, J. (2014). Clinical pathological characteristics and prognostic analysis of diabetic women with luminal subtype breast cancer. Tumour Biol. 35, 2035–2045.10.1007/s13277-013-1270-5Search in Google Scholar PubMed
Yang, T., Yang, Y., and Liu, S. (2015). Association between metformin therapy and breast cancer incidence and mortality: evidence from a meta-analysis. J. Breast Cancer 18, 264–270.10.4048/jbc.2015.18.3.264Search in Google Scholar PubMed PubMed Central
Yee, S.W., Lin, L., Merski, M., Keiser, M.J., Gupta, A., Zhang, Y., Chien, H.C., Shoichet, B.K., and Giacomini, K.M. (2015). Prediction and validation of enzyme and transporter off-targets for metformin. J. Pharmacokinet. Pharmacodyn. 42, 463–475.10.1007/s10928-015-9436-ySearch in Google Scholar PubMed PubMed Central
Yi, Y., Chen, D., Ao, J., Sun, S., Wu, M., Li, X., Bergholz, J., Zhang, Y., and Xiao, Z.X. (2017). Metformin promotes AMP-activated protein kinase-independent suppression of ΔNp63α protein expression and inhibits cancer cell viability. J. Biol. Chem. 292, 5253–5261.10.1074/jbc.M116.769141Search in Google Scholar PubMed PubMed Central
Yu, H., Yin, L., Jiang, X., Sun, X., Wu, J., Tian, H., Gao, X., and He, X. (2014). Effect of metformin on cancer risk and treatment outcome of prostate cancer: a meta-analysis of epidemiological observational studies. PLoS One 9, e116327.10.1371/journal.pone.0116327Search in Google Scholar PubMed PubMed Central
Zakikhani, M., Dowling, R.J., Sonenberg, N., and Pollak, M.N. (2008). The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev. Res. (Phila.) 1, 369–375.10.1158/1940-6207.CAPR-08-0081Search in Google Scholar PubMed
Zhang, J., Li, G., Chen, Y., Fang, L., Guan, C., Bai, F., Ma, M., Lyu, J., and Meng, Q.H. (2017). Metformin Inhibits tumorigenesis and tumor growth of breast cancer cells by upregulating miR-200c but downregulating AKT2 expression. J. Cancer 8, 1849–1864.10.7150/jca.19858Search in Google Scholar PubMed PubMed Central
Zheng, L., Yang, W., Wu, F., Wang, C., Yu, L., Tang, L., Qiu, B., Li, Y., Guo, L., Wu, M., et al. (2013). Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clin. Cancer Res. 19, 5372–5380.10.1158/1078-0432.CCR-13-0203Search in Google Scholar PubMed
©2018 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Reviews
- Biomechanistic insights into the roles of oxidative stress in generating complex neurological disorders
- Metformin-induced anticancer activities: recent insights
- Research Articles/Short Communications
- Protein Structure and Function
- Interaction of the middle domains stabilizes Hsp90α dimer in a closed conformation with high affinity for p23
- How human serum albumin recognizes DNA and RNA
- In vitro reconstitution and biochemical characterization of human phospholipid scramblase 3: phospholipid specificity and metal ion binding studies
- Cell Biology and Signaling
- LncRNA KCNQ1OT1 ameliorates particle-induced osteolysis through inducing macrophage polarization by inhibiting miR-21a-5p
- LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells
- High-content hydrogen water-induced downregulation of miR-136 alleviates non-alcoholic fatty liver disease by regulating Nrf2 via targeting MEG3
Articles in the same Issue
- Frontmatter
- Reviews
- Biomechanistic insights into the roles of oxidative stress in generating complex neurological disorders
- Metformin-induced anticancer activities: recent insights
- Research Articles/Short Communications
- Protein Structure and Function
- Interaction of the middle domains stabilizes Hsp90α dimer in a closed conformation with high affinity for p23
- How human serum albumin recognizes DNA and RNA
- In vitro reconstitution and biochemical characterization of human phospholipid scramblase 3: phospholipid specificity and metal ion binding studies
- Cell Biology and Signaling
- LncRNA KCNQ1OT1 ameliorates particle-induced osteolysis through inducing macrophage polarization by inhibiting miR-21a-5p
- LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells
- High-content hydrogen water-induced downregulation of miR-136 alleviates non-alcoholic fatty liver disease by regulating Nrf2 via targeting MEG3
