Metformin in cancer

Mallik, Ritwika; Chowdhury, Tahseen A

doi:10.1016/j.diabres.2018.05.023

Cited by 237 publications

(196 citation statements)

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“…It exerts its antidiabetic effects by decreasing hepatic glucose production, increasing glucose use by peripheral tissues, and enhancing insulin sensitivity (Ikhlas & Ahmad, 2017). The primary molecular targets of metformin include Complex I of the mitochondrial electron transport chain (ETC) and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) (Li et al, 2018a;Mallik & Chowdhury, 2018;Vancura et al, 2018). AMPK is a heterotrimeric serine/threonine protein kinase that plays a central role in metabolism and energy regulation by restricting anabolic processes while promoting catabolic processes (Ikhlas & Ahmad, 2017;Vancura et al, 2018).…”

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confidence: 99%

“…Activation of AMPK and inhibition of mechanistic/ mammalian target of rapamycin complex 1 (mTORC1) are the main mechanisms underlying the potential antineoplastic effects of metformin (Li et al, 2018a;Mallik & Chowdhury, 2018;Vancura et al, 2018). The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/mTOR pathway is important for cell proliferation and survival in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), two of the most common types of non-Hodgkin lymphoma (NHL) (Majchrzak et al, 2014;Pongas & Cheson, 2016).…”

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Impact of metformin use on the outcomes of newly diagnosed diffuse large B‐cell lymphoma and follicular lymphoma

et al. 2019

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Summary The diabetes mellitus (DM) drug metformin targets mechanistic/mammalian target of rapamycin and inhibits lymphoma growth in vitro. We investigated whether metformin affected outcomes of newly diagnosed diffuse large B‐cell (DLBCL, n = 869) and follicular lymphoma (FL, n = 895) patients enrolled in the Mayo component of the Molecular Epidemiology Resource cohort study between 2002 and 2015. Hazard ratios (HR) and 95% confidence intervals (CIs) adjusted for age, sex, body mass index, prognostic index and treatment were used to estimate the association of metformin exposure (No DM/No metformin; DM/No metformin; DM/Metformin) with event‐free (EFS), lymphoma‐specific (LSS) and overall (OS) survival. Compared to No DM/No metformin DLBCL patients, there was no association of DM/Metformin (n = 48; HR = 1·05, 95% CI 0·59–1·89) or DM/No metformin(n = 54; HR = 1·41, 95% CI 0·88–2·26) with EFS; results were similar for LSS and OS. Compared to No DM/No metformin FL patients, there was no association of DM/Metformin (n = 37; HR = 1·16, 95% CI 0·71–1·89) or DM/No metformin (n = 19; HR = 1·16, 95% CI 0·66–2·04) with EFS; results were similar for LSS. However, DM/Metformin was associated with inferior OS (HR = 2·17; 95% CI 1·19–3·95) compared to No DM/No metformin. In conclusion, we found no evidence that metformin use was associated with improved outcomes in newly diagnosed DLBCL and FL.

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Impact of metformin use on the outcomes of newly diagnosed diffuse large B‐cell lymphoma and follicular lymphoma

et al. 2019

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“…Diabetes is strongly associated with an increased incidence of cancer [21]. Many studies have shown that metformin can reduce the risk of cancer, including breast, colon, liver, and pancreatic cancers, and improve outcomes over those obtained with other antidiabetic treatments (sulfonylurea, insulin) in diabetic patients [9]. Whether metformin can reduce the risk of ovarian cancer has been investigated [22][23][24], but few studies have focused on the effects of metformin combined with commonly used rst-line chemotherapeutic drugs, such as carboplatin, and the underlying mechanisms [25].…”

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confidence: 99%

Synergistic therapeutic effects of metformin at a clinically relevant dosage in combination with chemotherapy via the AKT/mTOR pathway on ovarian cancer

Wen¹,

Sung²,

Wu³

et al. 2020

Preprint

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BackgroundOvarian cancer is the leading cause of cancer-related death among women. Complete cytoreductive surgery followed by platinum-taxene chemotherapy has been the gold standard for a long time. Various compounds have been assessed in an attempt to combine them with conventional chemotherapy to improve survival rates or even overcome chemoresistance. Many studies have shown that an antidiabetic drug, metformin, has cytotoxic activity in different cancer models. However, the synergism of metformin as a neoadjuvant formula plus chemotherapy in clinical trials and basic studies remains unclear for ovarian cancer.MethodsWe applied two clinical databases to survey metformin use and ovarian cancer survival rate. The Cancer Genome Atlas dataset, an L1000 microarray with Gene Set Enrichment Analysis (GSEA) analysis, Western blot analysis and an animal model were used to study the activity of the AKT/mTOR pathway in response to the synergistic effects of neoadjuvant metformin combined with chemotherapy.ResultsWe found that ovarian cancer patients treated with metformin had significantly longer overall survival than patients treated without metformin. The protein profile induced by low- concentration metformin in ovarian cancer predominantly involved the AKT/mTOR pathway. In combination with chemotherapy, the neoadjuvant metformin protocol showed beneficial synergistic effects in vitro and in vivo.ConclusionsThis study shows that neoadjuvant metformin at clinically relevant dosages is efficacious in treating ovarian cancer, and the results can be used to guide clinical trials.

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“…Thus, it may be that tumor size combined with insulin cpeptide status may predict an increased effect of adjuvant metformin or other insulin lowering drugs in the adjuvant treatment of breast cancer patients. Metformin attenuates the systemic biological effect of IR /IGF on tumor promoting signaling by improving insulin sensitivity and suppressing liver glucose output, which leads to reduced levels of systemic circulating insulin [14]. This will further mitigate paracrine signaling, overcome endocrine resistance [51,57] and improve prognosis in breast cancer [58][59][60][61].…”

Section: Discussionmentioning

confidence: 99%

Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

Lende

Austdal

Varhaugvik

et al. 2019

Preprint

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Background The influence of carbohydrates in breast cancer is conflicting.Objective To determine whether preoperative per-oral carbohydrate load influences proliferation in breast tumors.Design Randomized controlled trial.Setting University hospital with primary and secondary care functions in South-West Norway.Patients A population-based cohort of 61 patients with operable breast cancer.Intervention Per-oral carbohydrate load (preOp™) 18 and 2-4 hours before surgery (n=26) or standard pre-operative fasting procedure with free consume of tap water (n=35).Measurements Primary outcome was post-operative tumor proliferation measured as mitotic activity index (MAI). Secondary outcomes were changes in serum insulin, insulin-c-peptide, glucose, IGF-1 and IGFBP3. Other secondary outcomes were patients´ well-being and clinical outcome (median follow-up 88, range 33-97 months).Results In the estrogen receptor (ER) positive subgroup (n=50), high proliferation (MAI≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p=0.038). Progesterone receptor (PR) was more frequently negative in the CH-group (p=0.014). CH-patients had a significant between group rise in insulin (+ 24.31 mIE/L, 95% CI, 15.34 mIE/L to 33.27 mIE/L), insulin c-peptide (+ 1.39 nM, 95% CI, 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (– 0.26 nM; 95% CI, – 0.46 nM to – 0.051 nM). CH-Intervention ER-positive patients had poorer relapse free survival (73%) than the fasting group (100%) (p=0.012; HR= 9.3 (95%CI, 1.1 to 77.7)). In the ER-positive patients, only tumor size (p=0.021; HR=6.07, 95%CI=1.31 to 28.03) and CH-or-fasting grouping (p=0.040; HR=9.30, 95% CI=1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with Relapse Free Survival of 100% in the fasting group vs. 33% in the CH-group (p=0.015; HR= inf). The CH-group reported less pain on day 5 and 6 compared to the control group (p<0.001) but showed otherwise no factors related to well-being.Limitation Only applicable to ER-positive breast cancer patients with T2-tumors.Conclusions Preoperative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2-patients.

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Metformin in cancer

Cited by 237 publications

References 83 publications

Impact of metformin use on the outcomes of newly diagnosed diffuse large B‐cell lymphoma and follicular lymphoma

Impact of metformin use on the outcomes of newly diagnosed diffuse large B‐cell lymphoma and follicular lymphoma

Synergistic therapeutic effects of metformin at a clinically relevant dosage in combination with chemotherapy via the AKT/mTOR pathway on ovarian cancer

Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

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