Inhibition of mTORC1/P70S6K pathway by Metformin synergistically sensitizes Acute Myeloid Leukemia to Ara-C

Fang, Yuan; Cheng, Cong; Xiao, Fang; Liu, Hongcai; Cao, Shan; Zhang, Gan

doi:10.1016/j.lfs.2020.117276

Cited by 27 publications

(28 citation statements)

References 45 publications

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“…This is the first human study investigating the risk of leukemia after metformin use in T2DM patients. Unlike many previous studies that showed beneficial effects of metformin on the prevention of solid cancers (14) and some recent in vitro studies suggesting an inhibitory effect of metformin on the growth of leukemic cells (11,12), the findings of the present study did not support a beneficial effect of metformin on leukemia in human beings (Tables 2 and 3). In the main analyses, the risk of leukemia was neutral while comparing metformin (+) versus metformin (-) in either the intention-totreat or the per-protocol analysis ( Table 2).…”

Section: Discussioncontrasting

confidence: 99%

“…Though not yet clarified, one of the possible explanations for a neutral or even devastating effect of metformin on leukemia is that the beneficial effects observed in in vitro studies (11,12) could be obliterated by the deficiency in these micronutrients after long-term use of metformin.…”

Section: Discussionmentioning

confidence: 99%

“…Metformin is well known for its activation of AMPK and one of the mechanisms of preventing cancer is through its activation of AMPK resulting in the inhibition of mTOR (10,11). A recent in vitro study suggested another potential mechanism through the downregulation of the AXL receptor tyrosine kinase (12).…”

Section: Discussionmentioning

confidence: 99%

“…Firstly, in vitro studies usually investigate a specific pathway and ignore the complex actions of and interactions with other biological pathways. Therefore, we cannot readily interpret the findings of metformin benefits on leukemic cells derived from in vitro studies (6,7,11,12). Secondly, an overall neutral effect of metformin on leukemia risk ( Table 2) and the potentially higher risk observed in patients in persistent use (per-protocol analyses, Models VI and VII, Table 3), calls for a cautious attention to the ongoing preclinical trials investigating the use of metformin as a therapeutic agent for leukemia (14).…”

Section: Discussionmentioning

confidence: 99%

“…Some in vitro studies suggest that metformin may induce cell cycle arrest and apoptosis in leukemic cells (6,7), and leukemic cell growth is activated by the phosphatidylinositol 3-kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway (8,9). Therefore, being recognized for its activating effect on the liver kinase B1/adenosine monophosphate kinase (LKB1/AMPK) resulting in the inhibition of mTOR pathway, metformin theoretically inhibits leukemic cell growth (10,11). However, the involvement of other pathways may also provide a protective effect of metformin on leukemia because a recent in vitro study suggested that metformin may suppress the growth of leukemia cells through the downregulation of AXL receptor tyrosine kinase (12).…”

Section: Introductionmentioning

confidence: 99%

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Metformin Use and Leukemia Risk in Patients With Type 2 Diabetes Mellitus

Tseng

2020

Front. Endocrinol.

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Background: The effect of metformin on leukemia risk remains unknown. Methods: The Taiwan's National Health Insurance database was used to enroll 610,089 newly diagnosed type 2 diabetes patients on at least 2 anti-diabetic prescriptions during 1999-2009. We followed-up these patients until 31 December 2011, in order to determine the incidence of leukemia. We used Cox regression model (incorporated with the inverse probability of treatment-weighting using propensity scores) to estimate hazard ratios in both intention-to-treat and per-protocol analyses. Results: We enrolled 414,783 metformin initiators and 195,306 non-metformin initiators. Among them, 598 and 372 patients developed new-onset leukemia after a median followup period of 5.08 years and 6.79 years, respectively. The respective incidence rates were 26.52 and 28.40 per 100,000 person-years. The hazard ratio for metformin initiators versus non-metformin initiators was 0.943 (95% confidence interval 0.828-1.074) in the intention-to-treat analysis and 0.852 (95% confidence interval 0.705-1.031) in the perprotocol analysis. Sensitivity analyses after excluding patients using the exclusion criteria (a follow-up duration < 24 and < 36 months, respectively, patients with incretin-based therapies during follow-up, and patients enrolled during 2 different periods of 1999-2003 and 2004-2009) consistently showed a neutral effect. However, metformin initiators had a significantly higher risk of leukemia in the per-protocol analyses when censoring patients at a time without regular follow-up. Conclusion: Metformin use has an overall neutral effect on leukemia but we cannot exclude a significantly higher risk in patients who persistently use the drug.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metformin Use and Leukemia Risk in Patients With Type 2 Diabetes Mellitus

Tseng

2020

Front. Endocrinol.

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Metformin use and mortality in Asian, diabetic patients with prostate cancer on androgen deprivation therapy: A population‐based study

et al. 2022

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Background This study aims to examine the associations between metformin use concurrent with androgen deprivation therapy (ADT) and mortality risks in Asian, diabetic patients with prostate cancer (PCa). Methods This study identified diabetic adults with PCa receiving any ADT attending public hospitals in Hong Kong between December 1999 and March 2021 retrospectively, with follow‐up until September 2021. Patients with <6 months of medical castration without subsequent bilateral orchidectomy, <6 months of concurrent metformin use and ADT, or missing baseline HbA1c were excluded. Metformin users had ≥180 days of concurrent metformin use and ADT, while non‐users had no concurrent metformin use and ADT or never used metformin. The primary outcome was PCa‐related mortality. The secondary outcome was all‐cause mortality. The study used inverse probability treatment weighting to balance covariates. Results The analyzed cohort consisted of 1971 patients (1284 metformin users and 687 non‐users; mean age 76.2 ± 7.8 years). Over a mean follow‐up of 4.1 ± 3.2 years, metformin users had significantly lower risks of PCa‐related mortality (weighted hazard ratio [wHR]: 0.49 [95% confidence interval, CI: 0.39–0.61], p < 0.001) and all‐cause mortality (wHR 0.53 [0.46–0.61], p < 0.001), independent of diabetic control or status of chronic kidney disease. Such effects appeared stronger in patients with less advanced PCa, which is reflected by the absence of androgen receptor antagonist or chemotherapy use (p value for interaction: 0.017 for PCa‐related mortality; 0.048 for all‐cause mortality). Conclusions Metformin use concurrent with ADT was associated with lower risks of mortality in Asian, diabetic patients with PCa.

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Research Progress on the Use of Metformin in Leukemia Treatment

Wang,

Wei

2024

Curr. Treat. Options in Oncol.

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Opinion statementMetformin is a first-line drug in the clinical treatment of type 2 diabetes. Its main molecular mechanism involves the activation of adenosine 5′-monophosphate-activated protein kinase (AMPK), which regulates cell energy metabolism. Many clinical studies have shown that metformin can reduce the incidence and mortality of cancer in patients with or without diabetes. In vitro studies also confirmed that metformin can inhibit proliferation, promote apoptosis, and enhance the response of cells to chemical drugs and other anticancer effects on a variety of leukemia cells. In recent years, leukemia has become one of the most common malignant diseases. Although great progress has been made in therapeutic approaches for leukemia, novel drugs and better treatments are still needed to improve the therapeutic efficacy of these treatments. This article reviews the application status and possible mechanism of metformin in the treatment of leukemia to further understand the anticancer mechanism of metformin and expand its clinical application.

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Inhibition of mTORC1/P70S6K pathway by Metformin synergistically sensitizes Acute Myeloid Leukemia to Ara-C

Cited by 27 publications

References 45 publications

Metformin Use and Leukemia Risk in Patients With Type 2 Diabetes Mellitus

Metformin Use and Leukemia Risk in Patients With Type 2 Diabetes Mellitus

Metformin use and mortality in Asian, diabetic patients with prostate cancer on androgen deprivation therapy: A population‐based study

Research Progress on the Use of Metformin in Leukemia Treatment

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