Metformin inhibits renal cell carcinoma in vitro and in vivo xenograft

Liu, Jun; Li, Ming; Song, Bo; Jia, Chunhong; Zhang, Lichao; Bai, Xiaochun; Hu, Weilie

doi:10.1016/j.urolonc.2011.01.003

Cited by 85 publications

(81 citation statements)

References 26 publications

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“…CAKI-2 cells were inhibited in their proliferation after MF treatment even at low concentrations, as shown before [7,8,11]. In addition, we observed a significant proliferation inhibition of CAKI-1 cells only at higher concentrations of MF (20 mmol/l), indicating a varying MF sensitivity in the 2 RCC cell lines.…”

Section: Discussionsupporting

confidence: 83%

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Metformin-Derived Growth Inhibition in Renal Cell Carcinoma Depends on miR-21-Mediated PTEN Expression

Kalogirou¹,

Schafer²,

Krebs³

et al. 2015

Urol Int

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Purpose: Metformin (MF) acts as a tumour-suppressor in renal cell carcinoma (RCC) by inhibiting the AKT/mTOR pathway via AMPK activation. Here, we explore the influence of miR-21 and its target gene PTEN on MF effects in CAKI-1 and CAKI-2 cells. Methods: Proliferation assays (MTS) and qRT-PCR after transient transfection with pre- and anti-miR-21 and MF treatment were conducted. AMPK-dependency was assessed via transfection of siAMPK. The expression of PTEN, AKT and miR-21 after transient pre-miR-21 transfection and MF treatment was analysed. Results: We demonstrate that CAKI-1 cells, which were found to be less sensitive towards MF, showed a significant higher miR-21 and lower PTEN expression than CAKI-2. This was confirmed in a primary RCC collective (n = 28): miR-21 and PTEN expression correlated negatively. MF treatment lowered miR-21 AMPK-dependently and increased PTEN expression in the cell lines. Ectopic miR-21 regulation modulated MF sensitivity. Western blot analysis showed that pre-miR-21 transfection and MF treatment regulated PTEN expression with impact on pAKT levels in the cells. Conclusions: We show that differing MF sensitivity in RCC cells is associated with and mediated through the regulation of miR-21/PTEN expression with an impact on subsequent AKT signalling. This provides imaginable clinical implications regarding MF therapy of RCC patients for the future.

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Section: Discussionsupporting

confidence: 83%

“…In vitro, it was shown that RCC growth in mouse xenografts and established cell lines was inhibited by MF treatment [7,8]. In other solid cancers, when combined with subclinical doses of standard chemotherapeutics (paclitaxel, carboplatin and doxorubicin), MF was able to prolong tumour remission [9].…”

Section: Purposementioning

confidence: 99%

Metformin-Derived Growth Inhibition in Renal Cell Carcinoma Depends on miR-21-Mediated PTEN Expression

Kalogirou¹,

Schafer²,

Krebs³

et al. 2015

Urol Int

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“…Tumors were excised from the pancreas, weighed, and measured using digital calipers, and tumor volume (V) was calculated by the formula V = (largest tumor dimension) × (smallest tumor dimension) 2 × 0.52 (39,(49)(50)(51). Once a tumor volume of 50 mm 3 was reached (4 wk postimplantation), mice were treated with 12.5 mg/kg BPTES by intraperitoneal injection, 200 mg/kg CB-839 twice per d by oral gavage, 54 mg/kg BPTES-NPs (1.2 mg BPTES in 100 μL nanoparticles per mouse) by intravenous injection, blank-NPs (100 μL per mouse) by intravenous injection, 25 mg/kg gemcitabine intraperitoneally (25,26), 250 mg/kg metformin intraperitoneally daily (32,33), or a combination of BPTES-NPs with gemcitabine or metformin. BPTES-NPs were injected once every 3 d for a total of six injections over 16 d.…”

Section: Methodsmentioning

confidence: 99%

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Elgogary

Poore

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

186

149

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Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.pancreatic ductal adenocarcinoma | glutaminolysis | glucose metabolism | KRAS mutation | intratumoral hypoxia P atients with pancreatic ductal adenocarcinoma (PDAC) have among the highest fatality rates of all cancers (1). Pancreatic cancer is predicted to become the second-leading cause of cancer death in the United States by the year 2030 (2). Over 90% of PDACs display mutations in oncogenic KRAS (Kirsten rat sarcoma viral oncogene homolog) (3, 4), a known regulator of glutamine metabolism that can render cancer cells dependent on glutamine for survival and proliferation (5, 6)-a state known as "glutamine addiction" (7, 8)-suggesting that dependency on glutamine could be exploited to develop new therapies for KRAS-mutated PDAC. The first step of glutamine metabolism is the conversion of glutamine to glutamate and ammonia, which is catalyzed by glutaminase (GLS). Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), which is an allosteric, time-dependent (9), and specific inhibitor of GLS1, exhibits unique binding at the oligomerization interface of the glutaminase tetramer (10, 11). Although BPTES is more selective than other prototype glutaminase inhibitors, such as 6-diazo-5-oxo-L-norleucine (12) or ebselen (9), and can effectively inhibit GLS1 (13) and tumor growth (13-15), poor solubility (0.144 μg/mL) (16) has limited its clinical development. Recently, CB-839 (17) was tested in a phase I clinical trial. Abnormal liver and kidney function tests, lymphop...

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“…18,19 Liu and colleagues assessed the in vitro effects of metformin on 2 RCC cell lines. 10 The investi- Time from nephrectomy (years) hakimi et al…”

Section: Discussionmentioning

confidence: 99%

“…6,7 In vitro and in vivo evidence suggest anti-neoplastic effects of metformin on breast cancer, 8 colon cancer, 9 and most recently RCC. 10 The putative mechanism is through inhibition of the AKT/mammalian target of rapamycin (mTOR) signaling pathway via activation of adenosine monophosphate-activated protein kinase (AMPK), a negative regulator of the mTOR pathway. We sought to determine the effect of metformin use on the risk of recurrence following resection of clinically localized higher-risk RCC, which we defined as pT2 and pT3 according to the TNM Classification of Malignant Tumors system by the American Joint Committee on Cancer/Union for International Cancer Control.…”

Section: Introductionmentioning

confidence: 99%

The impact of metformin use on recurrence and cancer-specific survival in clinically localized high-risk renal cell carcinoma

Hakimi

Chen²,

Kim³

et al. 2013

CUAJ

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Background: Recent data suggest that metformin may have antineoplastic properties. We sought to determine what effect metformin had on recurrence and cancer-specific survival (CSS) rates of patients with clinically localized pT2 and pT3 renal cell carcinoma (RCC) following radical or partial nephrectomy. Methods: We obtained data on 784 patients who underwent partial or radical nephrectomy for pT2 or pT3 tumours at our centre between 1996 and 2011. Patients with benign masses, nodal positivity, or metastasis at the time of surgery were excluded. Using a competing-risks regression model, we compared differences in probability of recurrence between patients who used metformin versus those who did not. Results: The patients on metformin at the time of surgery had worse disease recurrence than patients not on metformin. However, this was not statistically significant on multivariate analysis when controlling for age, race, body mass index, glomerular filtration rate, and tumour stage and grade (hazard ratio [HR], 1.22; 95% confidence interval [CI], 0.66-2.27 [p = 0.5]). Metformin use was associated with a lower risk of cancer-specific mortality, but this was not statistically significant when adjusted for clinical and tumour characteristics (HR, 0.76;). Limitations include the retrospective nature of the study and the lack on information on duration of metformin use. Conclusions: Metformin use at the time of surgery for high-risk clinically localized RCC is not protective in terms of recurrence or CSS. Further studies should be done to confirm these findings and determine what effect concurrent metformin use might have on improved response to targeted therapies in the metastatic setting.

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Metformin inhibits renal cell carcinoma in vitro and in vivo xenograft

Cited by 85 publications

References 26 publications

Metformin-Derived Growth Inhibition in Renal Cell Carcinoma Depends on miR-21-Mediated <b><i>PTEN</i></b> Expression

Metformin-Derived Growth Inhibition in Renal Cell Carcinoma Depends on miR-21-Mediated <b><i>PTEN</i></b> Expression

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

The impact of metformin use on recurrence and cancer-specific survival in clinically localized high-risk renal cell carcinoma

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