Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Thompson, Alastair

doi:10.1158/1078-0432.ccr-13-0354

Cited by 42 publications

(59 citation statements)

References 74 publications

(70 reference statements)

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“…As expected with single drug, cytotoxicity was modest (ranging from 9.8–42.7%). Metformin inhibits the activity of mitochondrial respiratory chain complex 1 resulting in ATP depletion [27, 28] and 6-BT depletes ATP [26], so we hypothesized that the combination of these two agents might show improved cytotoxicity in the AML cell lines. We observed remarkable cytotoxicity (60–70%) in FLT3-ITD + MV4-11 and MOLM-14 cells at 48 hours after treatment with both drugs.…”

Section: Resultsmentioning

confidence: 99%

Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine

et al. 2016

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Current therapy for acute myeloid leukemia (AML) primarily includes high-dose cytotoxic chemotherapy with or without allogeneic stem cell transplantation. Targeting unique cellular metabolism of cancer cells is a potentially less toxic approach. Monotherapy with mitochondrial inhibitors like metformin have met with limited success since escape mechanisms such as increased glycolytic ATP production, especially in hyperglycemia, can overcome the metabolic blockade. As an alternative strategy for metformin therapy, we hypothesized that the combination of 6-benzylthioinosine (6-BT), a broad-spectrum metabolic inhibitor, and metformin could block this drug resistance mechanism. Metformin treatment alone resulted in significant suppression of ROS and mitochondrial respiration with increased glycolysis accompanied by modest cytotoxicity (10–25%). In contrast, 6-BT monotherapy resulted in inhibition of glucose uptake, decreased glycolysis, and decreased ATP with minimal changes in ROS and mitochondrial respiration. The combination of 6-BT with metformin resulted in significant cytotoxicity (60–70%) in monocytic AML cell lines and was associated with inhibition of FLT3-ITD activated STAT5 and reduced c-Myc and GLUT-1 expression. Therefore, although the anti-tumor and metabolic effects of metformin have been limited by the metabolic reprogramming within cells, the novel combination of 6-BT and metformin targets this bypass mechanism resulting in reduced glycolysis, STAT5 inhibition, and increased cell death.

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Section: Resultsmentioning

confidence: 99%

Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine

et al. 2016

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“…In recent years, antiobesity drugs such as metformin have been widely studied in preclinical models and clinical trials for their effectiveness in improving clinical outcomes for patients with breast cancer [55]. Further studies are required to explore the potential application of anti-inflammatory drugs for obese patients to reduce the risk of breast cancer progression for S100A7 + patients.…”

Section: Discussionmentioning

confidence: 99%

Interaction with adipocyte stromal cells induces breast cancer malignancy via S100A7 upregulation in breast cancer microenvironment

et al. 2017

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BackgroundBreast adipocytes play important roles in both the development and function of mammary epithelial cells. Therefore, carcinoma–adipose stromal cell (ASC) interactions have been considered pivotal in supporting tumor growth in breast cancer. In addition, it has been demonstrated that the biological features of cancer-associated adipocytes differ from those of normal ASCs. Therefore, we investigated an interaction between ASCs and carcinoma cell lines to identify genes associated with ASC invasion of carcinoma cells.Methods3T3-L1 ASC-derived conditioned medium (CM) was treated to measure the proliferation rate of breast cancer cells. To further examine the effect of ASCs, breast cancer cells were cocultivated with either primary human or 3T3-L1 ASCs for migration assays, DNA microarrays, quantitative real-time polymerase chain reactions, and Western blotting experiments. Furthermore, immunoreactivity of S100A7, the most upregulated gene in MCF7, after coculture with ASCs was evaluated for 150 breast cancer tissues to statistically analyze its association with clinicopathological parameters.ResultsWe first confirmed that ASC-derived CM treatment enhanced the cell proliferation rate of MCF7, T47D, SK-BR-3, and ZR-75-1 cell lines, whereas the migration rate of breast cancer cells was promoted by coculture with ASCs. We identified that a small calcium-binding protein, S100A7, was markedly upregulated (by 5.8-fold) in MCF7 cells after coculture with primary human ASCs. Knockdown of S100A7 significantly suppressed ASC-stimulated cell proliferation and migration rate, indicating a possible involvement of S100A7 in the carcinoma–ASC interaction in breast tumors. Furthermore, strong S100A7 immunoreactivity was detected at the invasive front of adipose stromal tissues compared with that at the intratumoral area. The status of S100A7 was also significantly correlated with adverse pathological parameters, and multivariate analysis revealed that S100A7 could be an independent prognostic marker for a poor relapse-free survival rate. Moreover, induction of oncostatin M was detected in cancer-stimulated ASCs, whereas the downstream S100A7 binding proteins/receptor for advanced glycation endproducts were significantly upregulated in correspondence with S100A7 expression in breast cancer cells after coculture with ASCs.ConclusionsThe results of our study suggest that paracrine production of cytokines from ASCs stimulates breast carcinoma cell growth via upregulation of S100A7 expression in breast cancer cell lines.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0863-0) contains supplementary material, which is available to authorized users.

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“…Recent epidemiological and laboratory studies have demonstrated that the anti-diabetic drug metformin has anticancer activity (Pollak 2012, Margel et al 2013, Yin et al 2013, Thompson 2014. Currently, there are more than 200 ongoing clinical trials in patients with breast, ovarian, lung, colorectal, and pancreatic cancers using metformin alone or in combination with other therapies (ClinicalTrials.gov).…”

Section: Introductionmentioning

confidence: 99%

Glucose-deprivation increases thyroid cancer cells sensitivity to metformin

Bikas¹,

Jensen²,

Patel³

et al. 2015

Endocrine-Related Cancer

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Metformin inhibits thyroid cancer cell growth. We sought to determine if variable glucose concentrations in medium alter the anti-cancer efficacy of metformin. Thyroid cancer cells (FTC133 and BCPAP) were cultured in high-glucose (20 mM) and low-glucose (5 mM) medium before treatment with metformin. Cell viability and apoptosis assays were performed. Expression of glycolytic genes was examined by real-time PCR, western blot, and immunostaining. Metformin inhibited cellular proliferation in high-glucose medium and induced cell death in low-glucose medium. In low-, but not in high-glucose medium, metformin induced endoplasmic reticulum stress, autophagy, and oncosis. At micromolar concentrations, metformin induced phosphorylation of AMP-activated protein kinase and blocked p-pS6 in low-glucose medium. Metformin increased the rate of glucose consumption from the medium and prompted medium acidification. Medium supplementation with glucose reversed metformin-inducible morphological changes. Treatment with an inhibitor of glycolysis (2-deoxy-D-glucose (2-DG)) increased thyroid cancer cell sensitivity to metformin. The combination of 2-DG with metformin led to cell death. Thyroid cancer cell lines were characterized by over-expression of glycolytic genes, and metformin decreased the protein level of pyruvate kinase muscle 2 (PKM2). PKM2 expression was detected in recurrent thyroid cancer tissue samples.In conclusion, we have demonstrated that the glucose concentration in the cellular milieu is a factor modulating metformin's anti-cancer activity. These data suggest that the combination of metformin with inhibitors of glycolysis could represent a new strategy for the treatment of thyroid cancer.

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Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Cited by 42 publications

References 74 publications

Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine

Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine

Interaction with adipocyte stromal cells induces breast cancer malignancy via S100A7 upregulation in breast cancer microenvironment

Glucose-deprivation increases thyroid cancer cells sensitivity to metformin

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