Metformin in prostate cancer: two for the price of one

Clements, Aine; Gao, Beixue; Yeap, Shang Heng; Wong, Matthew; Ali, Sayed; Gurney, Howard

doi:10.1093/annonc/mdr037

Cited by 69 publications

(45 citation statements)

References 57 publications

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“…12 Recently, metformin has been reported to hold potential for cancer treatment. [13][14][15] The anticarcinogenic affects appear to be associated with the regulation of NF-jB, matrix metalloproteinase (MMP)-2/9, AKT (also known as protein kinase B), and extracellular-signalrelated kinase (ERK)1/2 signaling pathways that are known to be important mediators of inflammation, tumor invasion and metastasis. 16 Recently, Quaile et al 17 reported that the no observable adverse effect level of metformin was 200 mg/kg/d (mean area under the curve 0-24 ¼ 41.1 lg h/mL; mean Cmax ¼ 10.3 lg/mL based on sex average week 13 values) in rats.…”

Section: Discussionmentioning

confidence: 99%

Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats

Kalariya

Mohammed

Ansari

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To investigate the therapeutic effects of metformin, a commonly used antidiabetic drug, in preventing endotoxininduced uveitis (EIU) in rats.METHODS. EIU in Lewis rats was developed by subcutaneous injection of lipopolysaccharide (LPS; 150 lg). Metformin (300 mg/kg body weight, intraperitoneally) or its carrier was injected either 12 hours before or 2 hours after LPS induction. Three and 24 hours after EIU, eyes were enucleated and aqueous humor (AqH) was collected. The MILLIPLEX-MAG Rat cytokine-chemokine magnetic bead array was used to determine inflammatory cytokines. The expression of Cox-2, phosphorylation of AMPK, and NF-jB (p65) were determined immunohistochemically. Primary human nonpigmented ciliary epithelial cells (HNPECs) were used to determine the in vitro efficacy of metformin.RESULTS. Compared with controls, the EIU rat AqH had significantly increased number of infiltrating cells and increased levels of various cytokines and chemokines (TNF-a, MCP-1, IL-1b, MIP-1a, IL-6, Leptin, and IL-18) and metformin significantly prevented the increase. Metformin also prevented the expression of Cox-2 and phosphorylation of p65, and increased the activation of AMPK in the ciliary bodies and retinal tissues. Moreover, metformin prevented the expression of Cox-2, iNOS, and activation of NF-kB in the HNPECs and decreased the levels of NO and PGE2 in cell culture media. CONCLUSIONS.Our results for the first time demonstrate a novel role of the antidiabetic drug, metformin, in suppressing uveitis in rats and suggest that this drug could be developed to prevent uveitis complications. (Invest Ophthalmol Vis Sci.

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Section: Discussionmentioning

confidence: 99%

Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats

Kalariya

Mohammed

Ansari

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…Interest in these compounds has been increased over the years. Several reports have shown greater type 1 and 2, 5α reductase expression in higher grade PCa [29] and due to the incidence of metabolic syndrome in PCa patients receiving ADT [30][31][32]. As specific alterations in intracellular pathways were observed with combination treatment compared to each compound alone, further investigation in this process is required with both androgen dependent and independent prostate cancer cells.…”

Section: Metforminmentioning

confidence: 99%

Dutasteride and Metformin Reduce the Growth of LNCaP Cells and Alter the SREBP-1 Pathway

Besla

Venier²,

Colquhoun³

et al. 2013

TOPCANJ

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Prostate cancer (PCa) is the second most prevalent cancer in men after lung cancer. Prostate cancer development and progression is associated with the dysregulation of a number of molecular pathways; hence, therapeutic strategies targeting such pathways bring great promise. Recently we have shown that metformin, the anti-diabetic drug, can inhibit tumor progression when combined with dutasteride, a 5-alpha-reductase inhibitor (5ARI). Interestingly, both metformin and dutasteride have been reported to alter the Sterol Regulatory Element Binding Proteins (SREBP) Fatty Acid Synthase (FASN) pathway. The SREBP pathway is involved with lipid and energy homeostasis. In our present study, we investigated if dutasteride in combination with metformin can reduce the proliferation of LNCaP PCa cells, and whether this is mediated through the SREBP-1/FASN pathway. Human PCa cells were treated with either dutasteride (0-100 µM) or metformin (0-50 mM) alone or in combination. The treated cells were then incubated for up to 24 hours, and proliferation assessed using the MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Western blot analysis was performed on cell lysates to assess alterations in key signaling molecules including cleaved SREBP-1, FASN, AR, PSA, pAMPK and apoptotic markers. Results revealed that there was a significant (p<0.05) decrease in cellular proliferation of LNCaP cells treated with a combination of metformin and dutasteride, this effect being greater than either treatment alone. Treating LNCaP cells with both metformin and dutasteride reduced the expression of FASN, cleaved SREBP-1 and pro-caspase-3 with expression of cleaved PARP; suggesting a possible interaction between FASN and apoptosis. All treatments resulted in reductions in AR, PSA and an upregulation of pAMPK, with the highest expression seen in combination treatment. We report for the first time that metformin and dutasteride in combination can reduce the proliferation of androgen-sensitive cell line through the activation of p-AMPK, and SREBP-1/FASN pathway and highlight the importance of targeting the SREBP-1 pathway, for improving future therapeutic strategies for prostate cancer.

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“…From the point of cancer prevention, metformin can be viewed as a “hybrid” drug. Not only it lowers the concentration of potential cancer “ligands” in the bloodstream (such as glucose and insulin), but also acts within the cell suppressing the AMPK/mTOR/p70S6K1 pathway [52], including specifically in PCa cell lines [53]. More recently, IGFR and p53 mediated mechanisms of its anticancer action were reported [54].…”

Section: Pca Chemoprevention In Aammentioning

confidence: 99%

Prostate cancer chemoprevention in men of African descent: current state of the art and opportunities for future research

Chornokur

Kumar

2013

Cancer Causes Control

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Prostate cancer is the most frequently diagnosed malignancy in men. However, African American / Black men are 60% more likely to be diagnosed with and 2.4 times more likely to die from prostate cancer, compared to Non-Hispanic White men. Despite the increased burden of this particular malignancy, no evidence-based recommendation regarding prostate cancer screening exists for the high risk population. Moreover, in addition to screening and detection, high-risk African American men may constitute a prime population for chemoprevention. Early detection and chemoprevention may thus represent an integral part of prostate cancer control in this population. Importantly, recent research have elucidated biological differences in the prostate tumors of African American compared to European American men,. The latter may enable a more favorable response in African American men to specific chemopreventive agents that target relevant signal transduction pathways. Based on this evolving evidence, the aims of this review are three-fold. First, we aim to summarize the biological differences that were reported in the prostate tumors of African American and European American men. Second, we will review the single and multi target chemopreventive agents placing specific emphasis on targeting the pathways implicated in prostate carcinogenesis. And lastly, we will discuss the most promising multi-target nutraceutical chemopreventive compounds. Our review underscores the promise of chemoprevention in prostate cancer control, as well as provides justification for further growth and investment in this filed to ultimately reduce prostate cancer morbidity and mortality in this high risk population of African American men.

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Metformin in prostate cancer: two for the price of one

Cited by 69 publications

References 57 publications

Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats

Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats

Dutasteride and Metformin Reduce the Growth of LNCaP Cells and Alter the SREBP-1 Pathway

Prostate cancer chemoprevention in men of African descent: current state of the art and opportunities for future research

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