Metformin and Cancer, an Ambiguanidous Relationship

Skuli, Nicolas; Alomari, Safwan; Gaitsch, Hallie; Bakayoko, A’ishah; Skuli, Nicolas; Tyler, Betty

doi:10.3390/ph15050626

Cited by 28 publications

(25 citation statements)

References 163 publications

(174 reference statements)

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“…However, the high concentrations of metformin used in in vitro studies might not be readily translated to effects in preclinical and clinical studies 24,189 , which raises questions as to what the appropriate drug exposure to obtain a direct anticancer effect might be. Importantly, supportive evidence for a protective effect of metformin on cancer risk was not always consistent 190,191 . Thus, validation of the advantage of metformin treatment as a single agent or as an adjuvant in cancer therapy, notably for its emerging role in regulating cancer immunity, awaits further clarification.…”

Section: An Anticancer Agentmentioning

confidence: 99%

Metformin: update on mechanisms of action and repurposing potential

2023

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Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. Initial studies have shown that metformin targets hepatic mitochondria; however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.

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Section: An Anticancer Agentmentioning

confidence: 99%

Metformin: update on mechanisms of action and repurposing potential

2023

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“…For instance, metformin, also known as a fasting-mimicking substance, reduces blood cholesterol and triglycerides in hyperglycemic and diabetic patients. However, to date the use of metformin has not (yet) been proven beneficial in combination with anti-tumor therapies [ 156 ]. The use of statins, which reduces blood cholesterol by HMG-CoA reductase inhibition, was found to improve patients’ survival in several solid tumor entities, such as breast cancer, pancreatic cancer, gastric cancer and lung cancer [ 157 ].…”

Section: Discussionmentioning

confidence: 99%

Lipotoxicity as a Barrier for T Cell-Based Therapies

et al. 2022

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Nowadays, T-cell-based approaches play an increasing role in cancer treatment. In particular, the use of (genetically engineered) T-cells has heralded a novel era for various diseases with previously poor outcomes. Concurrently, the relationship between the functional behavior of immune cells and their metabolic state, known as immunometabolism, has been found to be an important determinant for the success of immunotherapy. In this context, immune cell metabolism is not only controlled by the expression of transcription factors, enzymes and transport proteins but also by nutrient availability and the presence of intermediate metabolites. The lack of as well as an oversupply of nutrients can be detrimental and lead to cellular dysfunction and damage, potentially resulting in reduced metabolic fitness and/or cell death. This review focusses on the detrimental effects of excessive exposure of T cells to fatty acids, known as lipotoxicity, in the context of an altered lipid tumor microenvironment. Furthermore, implications of T cell-related lipotoxicity for immunotherapy will be discussed, as well as potential therapeutic approaches.

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“…While it might sounds difficult to target cancer cell metabolic profile without strongly affecting heathy and stromal cells function, retrospective studies highlighted the fact that Metformin, a component used to treat diabetes seems to increase ICB efficacy in patients from multiple cancer types. The mechanisms through which it might work remains to be better understood yet but the impact on cancer cell metabolism seems obvious, thus multiple clinical trials are ongoing [for review see ( 71 )].…”

Section: Section 2: Cancer Cell Characteristics Linked With Icb Refra...mentioning

confidence: 99%

Intrinsic features of the cancer cell as drivers of immune checkpoint blockade response and refractoriness

et al. 2023

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Immune checkpoint blockade represents the latest revolution in cancer treatment by substantially increasing patients’ lifetime and quality of life in multiple neoplastic pathologies. However, this new avenue of cancer management appeared extremely beneficial in a minority of cancer types and the sub-population of patients that would benefit from such therapies remain difficult to predict. In this review of the literature, we have summarized important knowledge linking cancer cell characteristics with the response to immunotherapy. Mostly focused on lung cancer, our objective was to illustrate how cancer cell diversity inside a well-defined pathology might explain sensitivity and refractoriness to immunotherapies. We first discuss how genomic instability, epigenetics and innate immune signaling could explain differences in the response to immune checkpoint blockers. Then, in a second part we detailed important notions suggesting that altered cancer cell metabolism, specific oncogenic signaling, tumor suppressor loss as well as tight control of the cGAS/STING pathway in the cancer cells can be associated with resistance to immune checkpoint blockade. At the end, we discussed recent evidences that could suggest that immune checkpoint blockade as first line therapy might shape the cancer cell clones diversity and give rise to the appearance of novel resistance mechanisms.

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Metformin and Cancer, an Ambiguanidous Relationship

Cited by 28 publications

References 163 publications

Metformin: update on mechanisms of action and repurposing potential

Metformin: update on mechanisms of action and repurposing potential

Lipotoxicity as a Barrier for T Cell-Based Therapies

Intrinsic features of the cancer cell as drivers of immune checkpoint blockade response and refractoriness

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