Metformin In Cancer Treatment Research Articles

Metformin: A Dual-Role Player in Cancer Treatment and Prevention.

Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies.

Current status and frontier tracking of clinical trials on Metformin for cancer treatment.

Metformin has been used clinically for more than six decades. Over time, numerous remarkable effects of metformin beyond the clinic have been discovered and discussed. Metformin has been shown to have a favorable impact on cancer therapy in addition to its clinically recognized hypoglycemic effect. However, the antitumor efficacy of metformin in humans has not been clearly demonstrated yet. Hence, a systematic analysis of the existing trials is necessary. Here, we retrieved clinical trials from the Clinical Trials.gov database to overview the clinical development of metformin for the treatment of cancer, analyze existing clinical results, and summarize some promising applications for specific cancer therapies. The potential application of metformin contains three directions: Firstly, improvement of metabolic factors associated with treatment effects, such as insulin resistance and peripheral neuropathy. Secondly, in combination with immune checkpoint blockade effects. Finally, use it for the endocrine treatment of hormone-dependent cancers. Although the outcomes of metformin as a repurposed agent in some trials have been unsatisfactory, it still has the potential to be used in select cancer therapy settings.

Differential effects of cancer modifying agents during radiation therapy on Ehrlich solid tumor-bearing mice: A comparative investigation of metformin and ascorbic acid

BackgroundThis work was carried out to compare the modifying roles of ascorbic and metformin during Ehrlich (ESC) tumor-bearing mice irradiation. MethodsFifty Swiss albino male mice were segmented into seven groups, including one control group and six Ehrlich induced tumors treated with ascorbic, ascorbic plus radiation, metformin, metformin plus radiation, and radiation only. Many tests, including behavioral, biochemical, immunohistochemistry, gene expression, DNA fragmentation, oxidative stress markers, and EPR, were performed to interrogate the modifying effects on tumor and liver tissues. ResultsRemarkable apoptosis was found in metformin irradiated animals compared to irradiated ascorbic counterparts. The irradiated metformin mice showed the greatest reduction in PCNA. There was a significant reduction of DNA fragmentation in the liver tissues of the irradiated metformin group. Irradiated metformin and irradiated ascorbic acid animals showed a reduced signal of ERK as well as c-Fos genes. There was a tendency of metformin and metformin irradiated animals to reduce MDA levels in liver tissues. ESC-bearing mice treated with ascorbic or metformin showed an improvement in the spontaneous alternation percentage (SAP%) and improved short-term memory. There was also an improvement in long memory tests. ConclusionsThe study added more preclinical evidence on the utility of metformin in cancer treatment during radiotherapy. Metformin was shown to reduce lipid peroxidation in irradiated healthy tissues, increase tumor cytotoxicity, downregulate critical pathways involved in tumor progression and proliferation, and enhance tumor apoptosis. Controlled clinical trials using metformin are highly warranted.

Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin.

Metformin is a widely used antidiabetic drug for cancer prevention and treatment. However, the overproduction of lactic acid and its inefficiency in cancer therapy limit its application. Here, we demonstrate the synergistic effects of the lactate/GPR81 blockade (3-hydroxy-butyrate, 3-OBA) and metformin on inhibiting cancer cells growth in vitro. Simultaneously, this combination could inhibit glycolysis and OXPHOS metabolism, as well as inhibiting tumor growth and reducing serum lactate levels in tumor-bearing mice. Interestingly, we observed that this combination could enhance the functions of Jurkat cells in vitro and CD8+ T cells in vivo. In addition, considering that 3-OBA could recover the inhibitory effects of metformin on PD-1 expression, we further determined the dual blockade effects of PD-1/PD-L1 and lactate/GPR81 on the antitumor activity of metformin. Our results suggested that this dual blockade strategy could remarkably enhance the anti-tumor effects of metformin, or even lead to tumor regression. In conclusion, our study has proposed a novel and robust strategy for a future application of metformin in cancer treatment.

Multidimensional mechanisms of metformin in cancer treatment.

Metformin has been in clinical use for more than half a century, yet its molecular mechanism of action is not entirely understood. Metformin has been shown to have antiproliferative and synergistic effects on various types of cancers. The anticancer effects of metformin are potentially applicable to both diabetic and nondiabetic patients. Areas of ongoing investigation focus on metformin's ability to activate adenosine monophosphate kinase (AMPK), in addition to its effect on Myc mRNA, monocarboxylate transporter 1 (MCT1), hypoxia-inducible factor 1 (HIF1), mammalian target of rapamycin (mTOR), and human epidermal growth factor receptor 2 (HER2). Additional anticancer effects are exhibited by acting on liver kinase B1 (LKB1), CREB-regulated transcription coactivator 2 (CRTC2), nitric oxide, and reactive oxygen species. Further investigation will be focused on elucidating metformin's metal-binding properties and how they may be harnessed for their anticancer effect. The acquired knowledge about metformin properties has expanded the number of targets for drug discovery such as microRNA, hexokinase, adenylate cyclase, transcription factors, various cyclins, and copper. In order to design anticancer drugs that mimic metformin's mechanism of action, binding assay studies must be conducted to fully understand and utilize the AMPK-dependent and independent mechanisms. Metformin's complex mechanisms that can potentially make this drug a multifaceted therapy targeting tumorigenesis in addition to information from ongoing clinical trials implicate that metformin can be a potential chemotherapeutic drug or adjuvant that could prove to be vital to future strategies against several types of cancer.

GPD1 Enhances the Anticancer Effects of Metformin by Synergistically Increasing Total Cellular Glycerol-3-Phosphate.

Metformin is an oral drug widely used for the treatment of type 2 diabetes mellitus. Numerous studies have demonstrated the value of metformin in cancer treatment. However, for metformin to elicit effects on cancer often requires a high dosage, and any underlying mechanism for how to improve its inhibitory effects remains unknown. Here, we found that low mRNA expression of glycerol-3-phosphate dehydrogenase 1 (GPD1) may predict a poor response to metformin treatment in 15 cancer cell lines. In vitro and in vivo, metformin treatment alone significantly suppressed cancer cell proliferation, a phenotype enhanced by GPD1 overexpression. Total cellular glycerol-3-phosphate concentration was significantly increased by the combination of GPD1 overexpression and metformin treatment, which suppressed cancer growth via inhibition of mitochondrial function. Eventually, increased reactive oxygen species and mitochondrial structural damage was observed in GPD1-overexpressing cell lines treated with metformin, which may contribute to cell death. In summary, this study demonstrates that GPD1 overexpression enhances the anticancer activity of metformin and that patients with increased GPD1 expression in tumor cells may respond better to metformin therapy. SIGNIFICANCE: GPD1 overexpression enhances the anticancer effect of metformin through synergistic inhibition of mitochondrial function, thereby providing new insight into metformin-mediated cancer therapy.

Abstract 3609: Metformin treatment outcomes in relation to obesity and cation transporter expression in mouse models of endometrial cancer

Abstract Purpose: Obesity is associated with increased risk and worse outcomes for endometrial cancer (EC). Metformin, a frontline therapy for type 2 diabetes, is thought to have both indirect and direct anti-cancer effects via decreasing circulating insulin/glucose and activating AMPK/inhibiting mTOR signaling, respectively. Due to its positive charge (pKa 12.4) and hydrophilicity (logD -6.13 at pH 7.4), metformin requires cation transporters for cellular uptake where it can then activate AMPK; and thus, variation in transporter expression may be critical for response to metformin for cancer treatment. Thus, we explored the inter-relationship of obesity, cation transporter expression and the anti-tumorigenic efficacy of metformin in a genetically engineered endometrioid EC mouse model. Methods: LKB1fl/fl p53fl/fl mice were fed a low-fat diet (10% calories from fat) vs. a high-fat diet (60% calories from fat) to mimic diet-induced obesity, starting at 3 weeks of age (n=10 mice/group). AdCre was injected at 6 weeks of age to induce EC. Mice were treated for four weeks with placebo or metformin (200 mg/kg/day, oral gavage) following tumor onset. Cell proliferation/apoptotic markers and downstream targets of AMPK/mTOR signaling were evaluated in the ECs by immunohistochemistry. Cation transporter expression was assessed in the ECs by Western blotting and RNA sequencing. Results: Obesity led to a doubling of endometrial tumor size in obese vs. lean mice (1.469g vs. 0.75g). Metformin was more potent in inhibiting tumor growth in obese vs. lean mice (78% vs. 60%) compared to the respective controls (p<0.05). Metformin (i) decreased expression of Ki-67 and cyclin D1 (cell proliferation markers) by 65% and 15%, respectively, in tumors from obese mice and by 18% and 5%, respectively, in tumors from lean mice vs. their respective controls (p<0.05); (ii) increased cleaved caspase-3 (marker of apoptosis) in tumors from obese and lean mice (2.3 fold and 2.1 fold) vs. their respective controls (p<0.05); (iii) increased phosphorylated AMPK expression and decreased expression of phosphorylated S6 in ECs from obese and lean mice vs. their respective controls (p<0.05); (iv) increased cation transporter OCT3 and PMAT gene expression in only tumors from obese mice, with a trend towards higher protein expression of OCT1 and 3 and MATE1 and 2 with metformin treatment in ECs from both lean and obese mice. Conclusion: Our data suggest that metformin has greater anti-tumorigenic efficacy in obese vs. lean mice with EC. In addition, cation transporters were expressed in the endometrial tumors and were affected by metformin treatment. Studies are underway in EC patients to understand the impact of obesity and transporter expression on response rates to metformin in the clinic. Note: This abstract was not presented at the meeting. Citation Format: Aruljothi Muralidharan, Hui Guo, Jianjun Han, Lu Zhang, Wenchuan Sun, Yajie Yin, Chunxiao Zhou, Ruth S. Everett, Dhiren R. Thakker, Victoria L. Bae-Jump. Metformin treatment outcomes in relation to obesity and cation transporter expression in mouse models of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3609.

Metformin in cancer treatment

Metformin in cancer treatment

Metformin's antitumour and anti-angiogenic activities are mediated by skewing macrophage polarization.

Beneficial effects of metformin on cancer risk and mortality have been proved by epidemiological and clinical studies, thus attracting research interest in elucidating the underlying mechanisms. Recently, tumour‐associated macrophages (TAMs) appeared to be implicated in metformin‐induced antitumour activities. However, how metformin inhibits TAMs‐induced tumour progression remains ill‐defined. Here, we report that metformin‐induced antitumour and anti‐angiogenic activities were not or only partially contributed by its direct inhibition of functions of tumour and endothelial cells. By skewing TAM polarization from M2‐ to M1‐like phenotype, metformin inhibited both tumour growth and angiogenesis. Depletion of TAMs by clodronate liposomes eliminated M2‐TAMs‐induced angiogenic promotion, while also abrogating M1‐TAMs‐mediated anti‐angiogenesis, thus promoting angiogenesis in tumours from metformin treatment mice. Further in vitro experiments using TAMs‐conditioned medium and a coculture system were performed, which demonstrated an inhibitory effect of metformin on endothelial sprouting and tumour cell proliferation promoted by M2‐polarized RAW264.7 macrophages. Based on these results, metformin‐induced inhibition of tumour growth and angiogenesis is greatly contributed by skewing of TAMs polarization in microenvironment, thus offering therapeutic opportunities for metformin in cancer treatment.

Metformin: Adjunct Therapy in Cancer Treatment.

An employee undergoing cancer treatment was prescribed metformin, a medication used in the treatment of type 2 diabetes and currently used as adjunct therapy for cancer. Metformin's anti-inflammatory properties inhibit tumor growth. It is speculated that cancer cells develop a metabolism that enhances aerobic glycolysis, which promotes cell growth and increases the need for glucose. Metformin decreases insulin in the blood, which decreases the amount of glucose available to cancer cells, thus starving the cells of nutrition, resulting in cell death. This case study explores the role of metformin in cancer treatment, with implications for occupational health nurses.

Combinational strategies of metformin and chemotherapy in cancers.

Chemotherapeutic regimens are the most common treatment to inhibit tumor growth, but there is great variability in clinical responses of cancer patients; cancer cells often develop resistance to chemotherapeutics which results in tumor recurrence and further progression. Metformin, an extensively prescribed and well-tolerated first-line therapeutic drug for type 2 diabetes mellitus, has recently been identified as a potential and attractive anticancer adjuvant drug combined with chemotherapeutic drugs to improve treatment efficacy and lower doses. In this review, we summarized the molecular mechanisms underlying anticancer effects of metformin, which included insulin- and AMPK-dependent effects, selectively targeting cancer stem cells, reversing multidrug resistance, inhibition of the tumor metastasis and described the antineoplastic effects of metformin combined with chemotherapeutic agents in digestive system cancers (colorectal, gastric, hepatic and pancreatic cancer), reproductive system cancers (ovarian and endometrial cancer), prostate cancer, breast cancer, lung cancer, etc. Moreover, the clinical trials regarding metformin in combination of chemotherapeutic drugs were presented and the clinical obstacle or limitation related to the potential role of metformin in cancer treatment was also discussed in this review.

Metformin and cancer: Technical and clinical implications for FDG-PET imaging.

Metformin is the most widely used hypoglycemic agent. Besides its conventional indications, increasing evidence demonstrate a potential efficacy of this biguanide as an anticancer drug. Possible mechanisms of actions seem to be independent from its hypoglycemic effect and seem to involve the interference with key pathways in cellular proliferation and glycolysis. To date, many clinical trials implying the use of metformin in cancer treatment are on-going. The increasing use of (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in cancer evaluation raises a number of questions about the possible interference of the biguanide on FDG distribution. In particular, the interferences exerted by metformin on AMP-activated protein kinase pathway (the cellular energy sensor), on insulin levels and on Hexokinase could potentially have repercussion on glucose handling and thus on FDG distribution. A better comprehension of the impact of metformin on FDG uptake is needed in order to optimize the use of PET in this setting. This evaluation would be useful to ameliorate scans interpretation in diabetic patients under chronic metformin treatment and to critically interpret images in the context of clinical trials. Furthermore, collecting prospective data in this setting would help to verify whether FDG-PET could be a valid tool to appreciate the anticancer effect of this new therapeutic approach.

Metformin in cancer treatment and prevention.

Patients with diabetes mellitus are at increased risk of cancer development. Metformin is a well-established, effective agent for the management of type 2 diabetes mellitus. Epidemiological studies have identified an association between metformin use and a beneficial effect on cancer prevention and treatment, which has led to increasing interest in the potential use of metformin as an anticancer agent. Basic science has provided a better understanding of the mechanism of action of metformin and the potential for metformin to modulate molecular pathways involved in cancer cell signaling and metabolism. This article outlines the link between metformin and cancer, the potential for metformin in oncology, and limitations of currently available evidence.

Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells.

Recent studies have demonstrated that the anti-diabetic drug, metformin, can exhibit direct antitumoral effects, or can indirectly decrease tumor proliferation by improving insulin sensitivity. Despite these recent advances, the underlying molecular mechanisms involved in decreasing tumor formation are not well understood. In this study, we examined the antiproliferative role and mechanism of action of metformin in MCF-7 cancer cells treated with 10 mM of metformin for 24, 48, and 72 hours. Using BrdU and the MTT assay, it was found that metformin demonstrated an antiproliferative effect in MCF-7 cells that occurred in a time- and concentration- dependent manner. Flow cytometry was used to analyze markers of cell cycle, apoptosis, necrosis and oxidative stress. Exposure to metformin induced cell cycle arrest in G0-G1 phase and increased cell apoptosis and necrosis, which were associated with increased oxidative stress. Gene and protein expression were determined in MCF-7 cells by real time RT-PCR and western blotting, respectively. In MCF-7 cells metformin decreased the activation of IRβ, Akt and ERK1/2, increased p-AMPK, FOXO3a, p27, Bax and cleaved caspase-3, and decreased phosphorylation of p70S6K and Bcl-2 protein expression. Co-treatment with metformin and H2O2 increased oxidative stress which was associated with reduced cell number. In the presence of metformin, treating with SOD and catalase improved cell viability. Treatment with metformin resulted in an increase in p-p38 MAPK, catalase, MnSOD and Cu/Zn SOD protein expression. These results show that metformin has an antiproliferative effect associated with cell cycle arrest and apoptosis, which is mediated by oxidative stress, as well as AMPK and FOXO3a activation. Our study further reinforces the potential benefit of metformin in cancer treatment and provides novel mechanistic insight into its antiproliferative role.

A phase II randomized, placebo controlled study to evaluate the efficacy of the combination of gemcitabine, erlotinib, and metformin in patients with locally advanced or metastatic pancreatic cancer.

4021 Background: In addition to clinical data from retrospective observational studies, there is a strong preclinical rationale for a beneficial effect of metformin in cancer treatment. Therefore w...

Abstract 2271: Metformin pharmacogenomics: A genome-wide associate study to identify genetic and epigenetic biomarkers involved in metformin response.

Abstract BACKGROUND Metformin, a widely used anti-diabetic drug, is being considered as a highly promising agent for treatment and prevention of many types of cancer, including breast cancer. Although the exact mechanism of action of metformin is unknown, it is thought that metformin is an AMPK activator. To better individualize metformin therapy and explore additional underlying molecular mechanism associated with metformin action, we conducted a metformin pharmacogenomic study using 266 genomic data-enriched lymphoblastoid cell lines (LCLs). METHODS Genome-wide microarray data were generated for all LCLs, including 1.3 million SNPs, 485K DNA methylation probes and 54K mRNA expression probe sets. Metformin cytotoxicity assay was performed using MTS assay. Genome-wide association (GWA) analyses and integrated analyses using all the genomic data and metformin cytotoxicity (IC50 value) were performed to identify top candidate genes for functional validation in breast cancer cell lines, MDA-MB 231 and Hs578T, using siRNA screening approach. Further mechanistic study was performed to investigate the role of candidates in regulation of AMPK activity. RESULTS GWA analyses in LCLs identified 198 mRNA expression probe sets and 210 DNA methylation probes associated with metformin IC50 with p-value <10-4, respectively. Analysis of 1.3 million SNPs found 12 loci (a region containing at least 1 SNP of p-value <10-5 and 1 SNP of p-value <10-3 within 50kb) that were associated with metformin IC50. Integrated SNP loci-mRNA expression-IC50 analysis indicated that the SNP loci on chromosome 16 was associated with metformin IC50 through a trans-regulation of expression of 7 genes with p-value <10-4. Integrated methylation-mRNA expression-IC50 analysis showed that 15 DNA methylation probes in 6 genes were associated with metformin IC50 through both cis- and trans-regulation of expression of 48 genes with p-value <10-4, including 4 methylation probes in 3 of those 6 genes that were cis-correlated with its own gene expression. Ingenuity pathway analysis of top 62 candidate genes identified four major pathways and 55 genes within those pathways were selected for functional validation in breast cancer cell lines. The knockdown experiment showed that down regulation of 25 genes significantly altered metformin sensitivity in MDA-MB231, and 14 of them also showed the same effect in Hs578T. Preliminary mechanistic experiment indicated that knockdown of 7 genes significantly reduced AMPK activity in MDA-MB231 and 3 of them had same effect in Hs578T. CONCLUSIONS GWAS using a genomic data-enriched LCL model system, together with functional validation in breast cancer cell lines, could help us to identify novel genetic and epigenetic biomarkers involved in metformin response and help us to better understand the mechanisms of metformin in cancer treatment. Citation Format: Nifang Niu, Xianglin Tan, Brooke L. Fridley, Daniel J. Schaid, Ryan P. Abo, Anthony Batzler, Erin E. Carlson, Gregory Jenkins, Sebastian Moran, Holger Andrea Heyn, Manel Esteller Badosa, Liewei Wang. Metformin pharmacogenomics: A genome-wide associate study to identify genetic and epigenetic biomarkers involved in metformin response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2271. doi:10.1158/1538-7445.AM2013-2271