Metformin and Cancer

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Metformin and cancer: Quo vadis et cui bono?

Metformin and cancer: Quo vadis et cui bono?

How many lives have already been saved by the anti-cancer drug metformin? Inadvertently perhaps, among the millions of type 2 diabetics with occult or known cancers and who have been prescribed metformin since the 1950s, thousands may have benefited from the anticancer properties of this first-line pharmacotherapy. Quo vadis? Now, researchers aim to move metformin from a non-targeted stage of cancer therapy that has been mostly developed retrospectively and empirically into a targeted therapy by following a biological rationale and a predefined mechanism of action. But, who might benefit from metformin? Cui bono? Because metformin is on the leading edge of a new generation of cancer metabolism-targeted therapies, perhaps it is the right time to provide solutions to the challenges that metformin and other onco-biguanides will face in the coming years before becoming incorporated into the therapeutic armamentarium against cancer.
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New insight for metformin against bladder cancer

New insight for metformin against bladder cancer

Thus, metformin has ability to decrease ATP synthesis [29]. As a result, the AMP: ATP ratio in the cell is in- creased, leading to energy stress and activation of AMPK (AMP-activated protein kinase), a primary metabolic sensor [30]. Hepatic AMPK activation can inhibit gluco- neogenesis and activates glycolysis. In addition, AMPK activation can increase glucose consumption in muscle. Both of these consequences of metformin can diminish hepatic glucose output leading to lower systemic glucose and insulin levels, which could contribute to therapeutic effect in type II diabetes and impair malignant growth indirectly without requiring accumulation of metformin in the tumor (indirect effect of metformin on tumors) [31]. Furthermore, activation of AMPK leads to a cascade of downstream events resulting in mammalian target of rapamycin (mTOR pathway) down-regulation, which eventually induces protein synthesis arrest and growth in- hibition [32, 33]. There are two different multiprotein complexes for mTOR, TORC1 and TORC2, which regu- late protein synthesis necessary for cell growth, prolifera- tion, angiogenesis, and other cellular endpoints [34]. Interestingly, mammalian target of rapamycin a member of the phosphatidylinositol 3-kinase (PI3K) cell survival pathway, plays an important role in the regulation of cell growth and proliferation by monitoring nutrient availabil- ity, cellular energy levels, oxygen levels and mitogenic signals [35]. Aberrant activation of the PI3K pathway has been widely implicated in many cancers, and increased ac- tivity of this pathway is often associated with resistance to cancer therapies [36].
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Repurposing metformin for cancer treatment: current clinical studies

Repurposing metformin for cancer treatment: current clinical studies

A considerable amount of focus has been laid on investigating metformin as a potential anti-cancer agent for cases of breast cancer. Eleven trials (20% of all ongoing trials using metformin as an anti-cancer agent; Tables 1-3) are focused on evaluating metformin as a treatment for breast cancer. Of these, two trials are using metformin as monotherapy. There are 9 trials using metformin in combination with other anti-cancer agents. These include capecitabine, cyclophosphamide, docetaxel, doxorubicin, erlotinib, epirubicin, exemestane, ganitumab, letrozole, sirolimus and temsirolimus. One trial is exploring the use of metformin plus atorvastatin combination as a possible treatment for breast cancer. Two trials using metformin combination therapy are also evaluating pathological complete response as a primary endpoint. Apart from the ongoing trials, data obtained from 5 completed trials (all using metformin monotherapy in a pre-surgical window of opportunity trial design) has facilitated a better understanding regarding the effects of metformin in breast cancer. In addition to survival outcomes, several surrogate markers are also being employed to study the effects of metformin on breast cancer cell population. These include Ki67, S6K, 4E-BP-1, AMPK and effects on AMPK/mTOR pathway.
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Metformin potentiates rapamycin and cisplatin in gastric cancer in mice

Metformin potentiates rapamycin and cisplatin in gastric cancer in mice

incidence increased two-fold for total, colorectal, and hepatic cancer. However, when patients were treated with metformin, the total, colorectal and hepatic cancer incidences decreased to near non-diabetic levels. Other studies in glioma, breast cancer and colon cancer models have shown that metformin effectively inhibited cell growth in vitro and significantly decreased the tumor burden in vivo [26–30]. Kim et al. [31] revealed that duration of metformin use was associated with the reduction in gastric cancer risk in type 2 diabetics without insulin treatment. Our results provided novel evidence that gastric cancer patients with 2DM receiving metformin treatment have longer survival duration than those without metformin treatment. This result is further supported by two newly published studies, which have confirmed the effect of metformin on gastric cancer [32, 33]. However, a multiple-center, larger cohort was needed to substantiate these results further. Previous data indicated that metformin exerted its growth inhibitory effects mainly by activating AMPK, which then suppressed the activity of mTOR and subsequently decreased its downstream effectors. In addition to suppressing the pivotal AMPK/ mTOR/P70S6K axis, metformin has also been shown to modulate several other targets, including p53, p21, Cyclin D1, survivin and other cancer-related tyrosine kinase receptors such as HER2 [34, 35].
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Metformin as a new anti-cancer drug in adrenocortical carcinoma

Metformin as a new anti-cancer drug in adrenocortical carcinoma

In H295R cells, we showed that the drug also interferes with the intracellular ERK and mTOR signaling pathways downstream from IGF-1R. We previously demonstrated that another class of anti-diabetic drugs, the thiazolidinediones, including rosiglitazone and pioglitazone, inhibits adrenocortical cancer cell proliferation [11] and stimulates cell differentiation [31, 32]. These drugs also restrained cell proliferation through IGF-1R signaling inhibition. However, while rosiglitazone acts on inhibition of both pathways, metformin seems to mainly affect ERK signaling, with no significant effect on phosphorylation/activation of Akt. A similar mechanism has been described in granulosa cells, where metformin inhibits IGF-1-stimulated cell growth through inhibition of ERK signaling and without affecting Akt [33]. Furthermore, the key role of ERK1/2 in mediating the anti-tumor effect of metformin has been confirmed by a xenograft mouse model using neuroblastoma cell lines, where a reduced ERK1/2 phosphorylation was observed in tumors of metformin-fed mice [34].
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Enhanced anti-tumor activity and cytotoxic effect on cancer stem cell population of metformin-butyrate compared with metformin HCl in breast cancer

Enhanced anti-tumor activity and cytotoxic effect on cancer stem cell population of metformin-butyrate compared with metformin HCl in breast cancer

(ER)-positive tumors has significantly decreased in recent years. In contrast, triple-negative breast cancers (TNBCs, which lack clinical expression of estrogen and progesterone receptors while showing overexpression of the HER-2 receptor) cannot be treated with current endocrine or HER2-targeting therapies. They also tend to relapse early and metastasize, leading to poor patient survival [40-43]. Therefore, it is urgent that we develop new therapeutic reagents for TNBC patients. Some in vitro studies have demonstrated that the antitumor effect of metformin is most prominent for TNBC, but that this effect requires a very high dose of the drug [15, 44, 45]. Consistent with these previous reports, we observed that metformin was preferentially cytotoxic to TNBC cell lines (mean IC 50 values of 31.2 and 17.2 mM in non-TNBC and TNBC, respectively). In contrast, MFB was not only more effective against breast cancer than metformin, it
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A REVIEW ON THE ANTI-TUMOR EFFECT OF METFORMIN IN CANCER

A REVIEW ON THE ANTI-TUMOR EFFECT OF METFORMIN IN CANCER

The potential for application of metformin in oncology was first recognized in retrospective epidemiological studies of diabetic patients with cancer. Numerous observational studies reported decreased cancer incidence and cancer-related mortality in diabetics receiving standard doses of metformin (1500 to 2250 mg/day in adults). While the majority of evidence supporting a role for metformin in the treatment of cancer has been derived from retrospective studies involving diabetics, some prospective clinical trials have been completed in nondiabetic patients. In a recent study, low doses of metformin (250 mg/day) reduced the number of rectal aberrant crypt foci (a surrogate marker for colorectal cancer) and decreased the proliferative activity of colonic epithelium (Dowling et al., 2007).
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Understanding the benefit of metformin use in cancer treatment

Understanding the benefit of metformin use in cancer treatment

Metformin also displays significant growth inhibitory effects in several cancer cell and mouse tumor models. In cell culture, metformin inhibits the proliferation of a range of cancer cells including breast, prostate, colon, endometrial, ovarian, and glioma [34-40]. The effects of metformin on cancer cell proliferation were associated with AMPK activation, reduced mammalian target of rapamycin (mTOR) signaling and protein synthesis, as well as a variety of other responses including decreased epidermal growth factor receptor (EGFR), Src, and mito- gen-activated protein kinase (MAPK) activation, decreased expression of cyclins, and increased expres- sion of p27. While not universally observed in all cells, metformin has been found to induce apoptosis in cer- tain cell lines derived from endometrial cancers, glioma, and triple negative breast tumors [38,39,41].
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Metformin targets multiple signaling pathways in cancer

Metformin targets multiple signaling pathways in cancer

cell cycle arrest induced by metformin. Their subsequent study showed that a negative regulator of mammalian tar- get of rapamycin (mTOR), regulated in development and DNA damage 1 (REDD1), mediated the effects of met- formin on the cell cycle arrest and cyclin D1 alteration [39]. Similarly, Yasmeen et al. [40] found that metformin- induced apoptosis of human ovarian cancer cells was independent of AMPK. In addition, AMPK deficiency sensitized cancer cells to the growth-inhibitory effects of metformin [41]. Arai et  al. [42] demonstrated that metformin-mediated repression of chronic inflammatory responses was associated with inhibition of tumor necro- sis factor alpha (TNFα) production in human monocytes, an event that was most likely independent of AMPK acti- vation. Chronic inflammation may provide a basis for cancer progression, but there was no obvious change in phosphor-AMPKα observed after metformin treatment [43]. Collectively, these studies provide compelling evi- dence that certain antitumor effects of metformin are independent of the AMPK signaling pathway [38–43].
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Effects of metformin treatment on radiotherapy efficacy in patients with cancer and diabetes: a systematic review and meta-analysis

Effects of metformin treatment on radiotherapy efficacy in patients with cancer and diabetes: a systematic review and meta-analysis

The following eligibility criteria were applied to the articles: 1) described a population-based cohort study; 2) involved patients in a treatment group who had cancer and DM and received metformin and radiotherapy; 3) involved patients in a control group with or without DM, but no control patient received metformin; 4) included outcome measures of qualitative improvement in tumor response and OS; 5) was a high-quality study, based on a Newcastle–Ottawa Scale (NOS) score of ≥ 6; and 6) was written in English or Chinese. Two reviewers independently assessed the articles based on titles and abstracts and excluded studies that addressed animal models or in vitro experiments, lacked original data, were not related to metformin and radiotherapy, or duplicated a study that had already been recovered from the literature search. After this screen, full-text articles of the studies deemed relevant were retrieved. These articles were reviewed and were excluded from the study if the comparison group did not conform to the inclusion/exclusion criteria. At this stage, studies were excluded that did not present data on efficacy or survival outcomes or that presented inconsistent data. Disagreements about eligibility were resolved by discussion between the authors (MR and CG). If agreement could not be reached, a third arbiter (YX) was consulted.
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Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells

Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells

Both dichloroacetate (DCA) and metformin (Met) have shown promising antitumor efficacy by regulating cancer cell metabolism. However, the DCA-mediated protective autophagy and Met-induced lactate accumulation limit their tumor-killing potential respectively. So overcoming the corresponding shortages will improve their therapeutic effects. In the present study, we found that DCA and Met synergistically inhibited the growth and enhanced the apoptosis of ovarian cancer cells. Interestingly, we for the first time revealed that Met sensitized DCA via dramatically attenuating DCA-induced Mcl-1 protein and protective autophagy, while DCA sensitized Met through markedly alleviating Met-induced excessive lactate accumulation and glucose consumption. The in vivo experiments in nude mice also showed that DCA and Met synergistically suppressed the growth of xenograft ovarian tumors. These results may pave a way for developing novel strategies for the treatment of ovarian cancer based on the combined use of DCA and Met.
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Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti- apoptotic proteins Mcl-1 and Bcl-2

Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti- apoptotic proteins Mcl-1 and Bcl-2

Apoptotic cell death is tightly regulated by Bcl- 2 family protein members. The anti-apoptotic Bcl-2 family proteins, such as Bcl-2 and Mcl-1, bind to their pro-apoptotic relatives and neutralize their pro-apoptotic activity [31]. Of the BH3-only proteins, Bim and Puma are the least selective, binding to all five anti-apoptotic proteins [32]. Cancer cells evolve diverse strategies to evade apoptosis by disturbing the intrinsic apoptotic pathway. They can achieve this goal by increasing the expression level of anti-apoptotic regulators such as Bcl- 2 and Mcl-1, or downregulating pro-apoptotic proteins such as Bim and Puma [33]. Several Bcl-2 inhibitors have shown efficacy as chemotherapy agents in clinical trials [34]. However, there are some cancers that cannot be treated with these Bcl-2 inhibitors, in which the upregulation of Mcl-1 may play a key role [32]. Both metformin and aspirin can induce apoptosis in different cancer cells, including pancreatic cancer cells [9, 35-43]. However, the molecular mechanism for the apoptosis induced by metformin or aspirin has not yet been clearly elucidated.
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Original Article Study on inhibitory effect of metformin in bladder cancer and its mechanism

Original Article Study on inhibitory effect of metformin in bladder cancer and its mechanism

5637 cells representing high risk of superficial bladder cancer and T24 cells representing infil- tration bladder cancer were selected as cell models for in vitro experiment, and were treat- ed with different concentrations of metformin. The results of the research showed that after the treatment with different concentrations of metformin (2, 5, 10 and 20 mM) for 48 hours, the cell activity of 5637 cells was (81.51 ± 3.95)%, (56.52 ± 6.85%), (46.84 ± 5.72%) and (35.14 ± 5.46)% respectively, and the cell via- bility of T24 cells was (88.35 ± 4.22)%, (63.62 ± 8.15%), (56.32 ± 5.37%) and (46.25 ± 5.35)% respectively, compared with the control group, the differences were statistically significant (all P<0.05). This study shows that metformin can inhibit the extracorporeal proliferation of blad- der cancer cells in a dose-dependent manner. The inhibitory effect of metformin in this study is essentially consistent with the results from other studies that conducted on other types of tumor cells [15, 16].
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<p>Statin and metformin therapy in prostate cancer patients with hyperlipidemia who underwent radiotherapy: a population-based cohort study</p>

<p>Statin and metformin therapy in prostate cancer patients with hyperlipidemia who underwent radiotherapy: a population-based cohort study</p>

To the best of our knowledge, this is the first retrospective study that evaluated if the use of statins and/or metformin improved survival in Taiwanese prostate cancer patients who had hyperlipidemia and received radiotherapy. Use of statins or metformin, alone or in combination, did not improve survival time compared with patients who had received nei- ther therapy. However, multivariate analysis found patients without these treatments were associated with higher risk of mortality, although the finding was not statistically signifi- cant. Patients who received statins after diagnosis of prostate cancer had a longer average survival time compared with patients who persistently used statins or had statin therapy prior to diagnosis. Similarly, patients who used statins after diagnosis were associated with a reduced risk of mortal- ity compared to those who did not receive or persistently used statins. Patients who received metformin therapy after diagnosis of prostate cancer had a longer average survival time than patients who persistently used the drug or received metformin treatment after diagnosis. However, the use of metformin in patients before diagnosis was significantly
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Evaluation of antagonistic effects of metformin with Cisplatin in gastric cancer cells.

Evaluation of antagonistic effects of metformin with Cisplatin in gastric cancer cells.

is not in line with previous reports. Thus, it is reasonable to conclude that the effect of metformin on cisplatin may be dependent to the cell type and possibly to the type of cancer. In this study, we evaluated the combinational effect of metformin and cisplatin on gastric cancer MKN-45 cell line. As a result of MTT and flow cytometry, metformin antagonizes the effect of cisplatin in MKN-45 cell line. Moreover, this study suggests that this antagonism may be through up-regulation in transcription of survivin. Survivin is detected during mitosis and specifically binds to terminal effector cell death proteases, caspase 3 and caspase 7, thus decreases apoptosis. 25 It has been reported that
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Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects

Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects

The increased risk of cancer among diabetic patient is postulated to be associated with the hyperglycemic char- acteristic of the cancer cells that require high glucose usage to compensate the high metabolic activity. There- fore, various in vivo studies have investigated the benefi- cial use of metformin as antidiabetic and anticancer agent in CRC. The use of metformin as an anticancer agent against CRC can be associated with the inhibition of polyps growth in the intestine. In Apc mutated mice, metformin treatment (250 mg/kg/day for 10 weeks) sig- nificantly decreases the number of polyps ranging 2.0– 2.5 mm in diameter but increases the number of polyps ranging 1.0–1.5 mm in diameter in Apc Min/+ mice [55]. Moreover, the analysis of BrdU index, PCNA index, per- centage of apoptotic cells, and gene expression of cyclin D1 and c-myc in tumor tissues of metformin-treated group demonstrates no significant alteration as com- pared to untreated group. The authors reported that metformin treatment did not significantly reduce the total number of polyps in the small intestine as com- pared to the untreated groups (42.11 ± 4.76 vs 38.22 ± 4.53; number of polyp/mouse, respectively). These ob- servations suggest that metformin inhibits the intestinal polyps growth by reducing their size but not by inhibit- ing the total number of intestinal polyps, tumour cell proliferation or activation of apoptosis. In a follow up study, treatment with metformin (250 mg/kg/day) and basal diet combination for 6–32 weeks significantly in- hibits the development of aberrant crypt foci (ACF) per mouse by 68.5 and 58.6%, respectively against azoxy- methane (AZM)-induced mice [56]. Metformin treat- ment for 32 weeks also modestly suppressed the total number of polyp formation (20% reduction) and polyp expansion (11% size reduction) where the appearances of polyps that are larger than 3 mm were abolished in the metformin-treated mice. Additionally, metformin de- creased the BrdU and PCNA indices but did not induce apoptosis in the AZM-induced mice, which indicates that metformin suppresses the ACF formation by sup- pressing the colonic epithelial cell proliferation.
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<p>The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances</p>

<p>The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances</p>

results in AMPK preventing the transcription of the gene responsible for glycogenesis in liver cells (Figure 2). In this process, glycogenosis decreases and, as a result, glucose uptake in muscle cells increases. Glucose uptake in the muscle cells leads to a decrease in blood glucose levels and subsequently insulin levels. Since high levels of insulin in the blood, due to the high number of insulin receptors in the cancer cells, have mitogenic effects and can cause tumor growth and proliferation, reducing insulin levels in the blood reduces the likelihood of malignity and prevents can- cer cell proliferation. 20–24 It should also be noted that patients with type II diabetes, due to the low sensitivity of their cells to insulin (insulin resistance) compared to other patients, are more at risk for various types of cancers due to mitogenic effects of insulin that cause excessive cell growth. For exam- ple, several studies have shown metformin use to lower insulin levels in the blood for the treatment of breast cancer in women. 10,20 Studies have also shown that there is an increased risk of various cancers, including colon, breast, pancreas and uterus cancers in diabetic and obese patients. 20 The direct effect of metformin (independent of insulin) is related to the activation of AMPK and the inhibi- tion of mTOR activity. 63–66 The activation of AMPK during the above-mentioned process results in activation of TSC2, and thus mTOR activity reduction. Preventing mTOR activ- ity reduces the levels of 4E-BPs (4E-binding proteins) and S6Ks (ribosomal protein S6 kinase) factors and decreases protein synthesis and proliferation. Thus, the metformin affects AMPK and mTOR and inhibits cancer cell growth and proliferation. 4,10,21 Other studies have also shown that activation of AMPK can reduce fatty acid synthase (FAS). 10,24 On the other hand, AMPK can activate ACC (acetyl coenzyme A carboxylase) and thus can increase the level of ATP in the cell. 10,23 ACC is responsible for the cellular metabolism regulation by reducing anabolism pro- cesses and increasing catabolism processes. 23
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Metformin therapy associated with survival benefit in lung cancer patients with diabetes

Metformin therapy associated with survival benefit in lung cancer patients with diabetes

reported that metformin was able to depress IL-6-induced EMT possibly by blocking STAT3 phosphorylation, thereby inhibiting the growth and metastasis of lung adenocarcinoma [14]. Additionally, metformin was found to possibly underlie its ability to prevent the development of lung cancer by reducing circulating levels of IGF-I and insulin and mediate its effects through inhibition of the IGF-I/insulin receptor signaling and receptor tyrosine kinases (RTK) signal pathways [33, 34]. Over the recent years, a series of observational investigations has reported that metformin might modulate the clinical outcomes of lung cancer patients with diabetes, however obtained inconsistent or even controversial results probably due to the sample size, study design or other variation affecting the prognosis, which prompted us to perform comprehensive analyses to address the issues concerned.
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Metformin: A possible drug for treatment of endometrial cancer

Metformin: A possible drug for treatment of endometrial cancer

Evaluation of studies on antitumor effects of metformin require careful consideration of the administered concen- tration. In vitro, 0.01 to 5 mM metformin is commonly used, whereas the upper limit of the dose per day in treatment of type 2 diabetes is 2250 mg/day, which cor- responds to a blood level of 20 µM [40]. Therefore, the concentration at which metformin shows antitumor ef- fects is well above the concentration range in which it can be used safely in vivo. Thus, managing side effects may be problematic in clinical use of metformin as an antitumor agent. However, this problem requires further study, since in experiments in vitro the cancer cell lines are exposed to a super-nutrient state and receive exces- sive growth signals compared with cells in vivo. It is also known that the levels of metformin that accumulate in tissues are several times higher than that in blood, and thus metformin acts at a much higher level in target or- gans [41]. Furthermore, the efficacy of metformin for TN breast cancer has been shown to occur in the concentra- tion range used for treatment of type 2 diabetes, as de- scribed above [28]. Potential therapy also requires ex-
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Metformin: Multi-faceted protection against cancer

Metformin: Multi-faceted protection against cancer

crypt foci via the inhibition of the mTOR pathway and through the activation of AMPK [184]. Based on these data, Hosono et al. [185] recently conducted a pilot clinical trial providing evidence that short-term, low-dose metformin (250 mg once daily for 1 month versus the typical 500 mg three times daily in type 2 diabetes) safely and directly suppresses both colorectal epithelial proliferation and aberrant crypt formation, an endoscopic surrogate marker of colorectal cancer, in prospectively randomized nondiabetic patients [185]. The gastrointestinal tract may be a special case where metformin appears to act locally from the lumen following oral administration; this raises the question of whether one could expect more enhanced benefits by achieving more continuous exposure to metformin (e.g., using the low-release metformin preparations developed for dosing convenience). This first reported trial demonstrated the potential for metformin in the chemoprevention of colorectal cancer. These findings were extended to lung tumors in the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3- pyridil)-1-butanone (NNK)-induced lung cancer mouse model. Using this model, Memmott et al. [186] recently demonstrated that treatment with high-dose metformin remarkably decreased tumor burden ( ∼ 70%) without affecting tumor incidence, providing strong rationale for clinical prevention trials for lung cancer in heavy smokers. While there was no evidence of metformin-induced activation of AMPK in lung tumors, metformin led to decreased levels of circulating insulin and IGF as well as decreased phosphorylation of IGF-IR, AKT and mTOR in tumor tissue. Thus, the profound effects on tumor growth may have been a consequence of perturbation of glucose homeostasis and hormone levels leading to the indirect inhibition of mTOR by decreasing activation of IR/IGF-IR and AKT upstream of mTOR. A completely different picture was observed in a study with chemically induced mammary cancer in female Sprague-Dawley rats. Zhu et al. [187] reported that while a dosing regimen of 1.0%/0.25% metformin was capable of reducing palpable mammary carcinoma incidence, multiplicity and tumor burden and prolonged latency, lower doses of metformin failed to inhibit carcinogenesis despite reducing plasma insulin. Notably, metformin appeared to offer protection against new tumor occurrence following release from the combined treatment of metformin with dietary energy restriction. Because flow cytometry analyses indicated the presence of tumor-initiating cells in chemically induced mammary carcinomas, these findings support the hypothesis that metformin may be an effective component of multi-agent interventions against CSCs [187].
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