Metformin decreases growth of pancreatic cancer cells by decreasing reactive oxygen species: Role of NOX4

Cheng, Guanjun; Lanza-Jacoby, Susan

doi:10.1016/j.bbrc.2015.07.118

Cited by 60 publications

(50 citation statements)

References 37 publications

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“…A lot of the chemotherapeutic drugs work through reactive oxygen species (ROS; ref. 45) and metformin could mitigate the effects of chemotherapy by modifying ROS generation (46). These data should be interpreted with caution, given the limited number of patients and the presence of potential confounding biases and studies to better understand a potential antagonism between metformin and chemotherapy should be carried out in the future (47).…”

Section: Discussionmentioning

confidence: 99%

(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial

Reni

Dugnani

Cereda

et al. 2016

Clinical Cancer Research

155

127

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Purpose: We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action.Experimental Design:We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population.Results: Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n ¼ 31) or without metformin (n ¼ 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33-69] in the control group and 42% (95% CI, 24-59) in the metformin group (P ¼ 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin.Conclusions: Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy.

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Section: Discussionmentioning

confidence: 99%

(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial

Reni

Dugnani

Cereda

et al. 2016

Clinical Cancer Research

155

127

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“…This balance in p53 wild type malignant cells allows for cell growth and a control of the oxidative environment. Metformin, through its inhibition of mitochondrial complex I and associated mitigation of ROS production, as well as its anti-oxidant effects on NADPH enzymes Nox 2 and 4 (Cheng et al 2015, Bost et al 2012), has exhibited radio-protective effects on a variety of normal and p53 wild type tumor model systems irradiated under in vitro conditions. Consistent with our earlier report, metformin administered 30 min or 1 h prior to radiation exposure significantly protected p53 wild type SA-NH tumor cells (see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…It is currently invoking considerable interest for repurposing as a potential anti-cancer agent for use in radiation therapy (Song et al 2012, Zhang T et al 2014, Zhang Y et al 2014, Cheng et al 2015, Koritzinsky 2015). Metformin has been reported to moderately protect mouse embryo fibroblasts from cytotoxicity induced by ionizing radiation while being directly cytotoxic to human cancer cells (Muaddi et al 2013).…”

Section: Introductionmentioning

confidence: 99%

“…While metformin was observed to radio-sensitize various tumor cell lines to ionizing radiation (Song et al 2012, Zhang T et al 2014, Zhang Y et al 2014, Cheng et al 2015, Koritzinsky 2015) it has also been reported to protect human HCT116 colorectal cancer (Muaddi et al 2013, Skinner et al 2013) and A549 lung cancer cells (Skinner et al 2013) along with SA-NH murine sarcoma cells (Miller et al 2014). Its actions modifying radiation response have been linked to its ability to modify mitochondrial metabolism and associated reactive oxygen species (ROS) production (Wheaton et al 2014, Andrzejewski et al 2014, Weinberg et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…This has been observed following exposure of cancer cells to the mitochondrial complex I inhibitors BAY 87-2243 and rotenone (Wheaton et al 2014, Andrzejewski et al 2014, Weinberg et al 2015, Algire et al 2012, Schockel et al 2015, Cheng et al 2016). The role of metformin in affecting ROS production in cells is further complicated by observations in some cell systems that metformin can act as an anti-oxidant by inhibiting or repressing ROS production by the NADPH enzymes NOX 2 and 4 (Cheng et al 2015, Bost et al 2012), while elevating ROS production in other cell lines through the elevation of NOX 2 and 5 (Zhang Y et al 2014, Picone et al 2015). Caution is therefore required in interpreting metformin’s effects on modifying the intracellular redox environment of individual normal and malignant cell systems as it relates to expected changes in its use for affecting therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

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Altered expression of a metformin-mediated radiation response in SA-NH and FSa tumor cells treated under in vitro and in vivo growth conditions

Murley

Miller

Senlik

et al. 2017

International Journal of Radiation Biology

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Purpose To assess the radio-sensitizing effect of the biguanide drug Metformin used alone or in combination with reactive oxygen species (ROS) modifying agents N-acetyl-L-cysteine (NAC) or emodin, and contrasted to the mitochondrial complex 1 inhibitor rotenone in altering the radiation responses of the p53 wild type SA-NH and p53 mutant FSa mouse tumor lines grown either in vitro or in vivo. Materials and Methods Tumor cells were grown to confluence in vitro and exposed to a single 4 Gy dose in the presence or absence of Metformin (5 mM) and ROS modifiers or to 10 Gy with or without Metformin as tumors in the flanks of C3H mice using a tumor growth delay assay. Results Both Metformin and rotenone protected SA-NH (P<0.001) while sensitizing FSa (P<0.001) to 4 Gy. Neither NAC nor emodin altered Metformin’s action. Metformin was also directly toxic to FSa cells (P=0.002). In contrast, in vivo Metformin (250 mg/kg) sensitized both SA-NH (9 day growth delay, P<0.05) and FSa (4 day growth delay, P<0.05) tumors if administered 1 h before irradiation. Conclusion Metformin effects on tumor cells measured under in vitro conditions may differ from those determined in vivo due to p53 and heterogeneous environmental factors.

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Trace elements in pancreatic cancer

Yanjun,

Jing,

Yifei

et al. 2024

Cancer Medicine

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BackgroundPancreatic cancer (PCA) is an extremely aggressive malignant cancer with an increasing incidence and a low five‐year survival rate. The main reason for this high mortality is that most patients are diagnosed with PCA at an advanced stage, missing early treatment options and opportunities. As important nutrients of the human body, trace elements play an important role in maintaining normal physiological functions. Moreover, trace elements are closely related to many diseases, including PCA.ReviewThis review systematically summarizes the latest research progress on selenium, copper, arsenic, and manganese in PCA, elucidates their application in PCA, and provides a new reference for the prevention, diagnosis and treatment of PCA.ConclusionTrace elements such as selenium, copper, arsenic and manganese are playing an important role in the risk, pathogenesis, diagnosis and treatment of PCA. Meanwhile, they have a certain inhibitory effect on PCA, the mechanism mainly includes: promoting ferroptosis, inducing apoptosis, inhibiting metastasis, and inhibiting excessive proliferation.

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Metformin decreases growth of pancreatic cancer cells by decreasing reactive oxygen species: Role of NOX4

Cited by 60 publications

References 37 publications

(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial

(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial

Altered expression of a metformin-mediated radiation response in SA-NH and FSa tumor cells treated under in vitro and in vivo growth conditions

Trace elements in pancreatic cancer

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