The multifaceted effects of metformin on tumor microenvironment

Kurelac, Ivana; Ganesh, Nikkitha Umesh; Iorio, Maria; Porcelli, Anna Maria; Gasparre, Giuseppe

doi:10.1016/j.semcdb.2019.05.010

Cited by 63 publications

(52 citation statements)

References 51 publications

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“…Considering the indirect beneficial effects of metformin in cancer, studies indicated that metformin could regulate angiogenesis, fibroblasts, tumor-associated macrophages, and immunosuppression, changing the tumor microenvironment (61). As an anti-diabetic drug, metformin decreases plasma glucose levels, thereby inhibiting cancer cell proliferation and survival (62).…”

Section: Metformin and Cancermentioning

confidence: 99%

Metformin and Its Benefits for Various Diseases

2020

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Metformin is a widely used biguanide drug due to its safety and low cost. It has been used for over 60 years to treat type 2 diabetes at the early stages because of its outstanding ability to decrease plasma glucose levels. Over time, different uses of metformin were discovered, and the benefits of metformin for various diseases and even aging were verified. These diseases include cancers (e.g., breast cancer, endometrial cancer, bone cancer, colorectal cancer, and melanoma), obesity, liver diseases, cardiovascular disease, and renal diseases. Metformin exerts different effects through different signaling pathways. However, the underlying mechanisms of these different benefits remain to be elucidated. The aim of this review is to provide a brief summary of the benefits of metformin and to discuss the possible underlying mechanisms.

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Section: Metformin and Cancermentioning

confidence: 99%

Metformin and Its Benefits for Various Diseases

2020

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“…Metabolic actions have been proposed related to gluconeogenesis, mitochondrial function, and cellular metabolism [ 86 , 87 ]. Metformin reduces cellular respiration by inhibiting respiratory-chain complex 1 limiting the cancer cell’s metabolic plasticity [ 73 , 88 , 89 ]. However, cancer cells try to compensate the suppression of oxidative phosphorylation by enhancing glycolysis that is p53-dependent [ 89 ].…”

Section: Drug Repurposing For Ovarian Cancer Therapymentioning

confidence: 99%

Recycling the Purpose of Old Drugs to Treat Ovarian Cancer

Nunes

Abreu

Bartosch

et al. 2020

IJMS

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The main challenge in ovarian cancer treatment is the management of recurrences. Facing this scenario, therapy selection is based on multiple factors to define the best treatment sequence. Target therapies, such as bevacizumab and polymerase (PARP) inhibitors, improved patient survival. However, despite their achievements, ovarian cancer survival remains poor; these therapeutic options are highly costly and can be associated with potential side effects. Recently, it has been shown that the combination of repurposed, conventional, chemotherapeutic drugs could be an alternative, presenting good patient outcomes with few side effects and low costs for healthcare institutions. The main aim of this review is to strengthen the importance of repurposed drugs as therapeutic alternatives, and to propose an in vitro model to assess the therapeutic value. Herein, we compiled the current knowledge on the most promising non-oncological drugs for ovarian cancer treatment, focusing on statins, metformin, bisphosphonates, ivermectin, itraconazole, and ritonavir. We discuss the primary drug use, anticancer mechanisms, and applicability in ovarian cancer. Finally, we propose the use of these therapies to perform drug efficacy tests in ovarian cancer ex vivo cultures. This personalized testing approach could be crucial to validate the existing evidences supporting the use of repurposed drugs for ovarian cancer treatment.

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“…Another relevant function by Metformin is its antitumor effect; in fact, reduced tumor angiogenesis is induced in mice upon metformin treatment [92], which candidate this drug as a potential cancer-preventive agent. Indeed, metformin inhibits the formation of capillary-like networks by endothelial cells in an AMPK-dependent manner [93], although some conflicting data showing upregulation of VEGF in breast cancer and melanoma have emerged, as well as complex effects on the tumor microenvironment [94].…”

Section: Drugs Targeting Metabolic Pathwaysmentioning

confidence: 99%

Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer

et al. 2020

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Metabolic reprogramming, carried out by cancer cells to rapidly adapt to stress such as hypoxia and limited nutrient conditions, is an emerging concepts in tumor biology, and is now recognized as one of the hallmarks of cancer. In contrast with conventional views, based on the classical Warburg effect, these metabolic alterations require fully functional mitochondria and finely-tuned regulations of their activity. In turn, the reciprocal regulation of the metabolic adaptations of cancer cells and the microenvironment critically influence disease progression and response to therapy. This is also realized through the function of specific stress-adaptive proteins, which are able to relieve oxidative stress, inhibit apoptosis, and facilitate the switch between metabolic pathways. Among these, the molecular chaperone tumor necrosis factor receptor associated protein 1 (TRAP1), the most abundant heat shock protein 90 (HSP90) family member in mitochondria, is particularly relevant because of its role as an oncogene or a tumor suppressor, depending on the metabolic features of the specific tumor. This review highlights the interplay between metabolic reprogramming and cancer progression, and the role of mitochondrial activity and oxidative stress in this setting, examining the possibility of targeting pathways of energy metabolism as a therapeutic strategy to overcome drug resistance, with particular emphasis on natural compounds and inhibitors of mitochondrial HSP90s.

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The multifaceted effects of metformin on tumor microenvironment

Cited by 63 publications

References 51 publications

Metformin and Its Benefits for Various Diseases

Metformin and Its Benefits for Various Diseases

Recycling the Purpose of Old Drugs to Treat Ovarian Cancer

Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer

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