Metformin and Pancreatic Cancer Metabolism

Cantoria, Mary Jo; Hitendra, Patel; Boros, László G.; Meuillet, Emmanuelle J.

doi:10.5772/57432

Cited by 9 publications

(8 citation statements)

References 126 publications

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“…It has since been studied in pre-clinical settings using in vitro cancer cell models [14][15][16] , animal models [17][18][19][20][21] , and consequently over 300 clinical trials are found when searching "metformin AND cancer" in clinicaltrial.gov. The high number of initiated clinical trials reflect both the low cost of the drug and the extensive use with minimal side effects reported since it was approved as a drug nearly 60 years ago 22,23 . However, many of these studies have so far been inconclusive, and have not shown major treatment effects nor improved survival [23][24][25][26] .…”

mentioning

confidence: 99%

“…Metformin became an interest in the cancer field due to studies reporting that diabetic colorectal cancer (CRC) patients taking metformin had a better overall survival compared to those treated with other glucose lowering drugs 14,26,32,33 . This effect has largely been tied to the lowering of insulin growth factor and activation of AMPK 22,[34][35][36] . Hence, the potential anticancer effect of metformin is most likely not due to expected lowering of blood glucose, but rather due to intracellular effects of metformin in the tumour cells 37 .…”

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confidence: 99%

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Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells

Alhourani

Tidwell

Bokil

et al. 2021

Sci Rep

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Cancer cells exhibit altered metabolism, a phenomenon described a century ago by Otto Warburg. However, metabolic drug targeting is considered an underutilized and poorly understood area of cancer therapy. Metformin, a metabolic drug commonly used to treat type 2 diabetes, has been associated with lower cancer incidence, although studies are inconclusive concerning effectiveness of the drug in treatment or cancer prevention. The aim of this study was to determine how glucose concentration influences cancer cells’ response to metformin, highlighting why metformin studies are inconsistent. We used two colorectal cancer cell lines with different growth rates and clinically achievable metformin concentrations. We found that fast growing SW948 are more glycolytic in terms of metabolism, while the slower growing SW1116 are reliant on mitochondrial respiration. Both cell lines show inhibitory growth after metformin treatment under physiological glucose conditions, but not in high glucose conditions. Furthermore, SW1116 converges with SW948 at a more glycolytic phenotype after metformin treatment. This metabolic shift is supported by changed GLUT1 expression. Thus, cells having different metabolic phenotypes, show a clear differential response to metformin treatment based on glucose concentration. This demonstrates the importance of growth conditions for experiments or clinical studies involving metabolic drugs such as metformin.

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confidence: 99%

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confidence: 99%

Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells

Alhourani

Tidwell

Bokil

et al. 2021

Sci Rep

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“…Metformin is introduced for this purpose. Metformin, not only decreases mitochondrial TCA cycle intermediates but also directly inhibits lipogenesis [ 219 , 220 ]. Since metformin suppresses NOX activity, its intake would cicumvent the potential hazardous impacts of high intracellular NADPH levels (due to upregulated PPP) in terms of generating higher ROS (contributing to the detrimental function of proinflammatory cells) and creating intracellular oxidative stress (contributing to increased SARS-CoV-2 infectivity in the host cell), as well.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, metformin also directly hinders lipogenesis. Direct anti-lipogenic activities of metformin are mediated through inhibition of key metabolic enzymes including ATP citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS) complex, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA) [ 220 ]. Of note, metformin hinders ROS production by suppressing NOX activity [ 221 ].…”

Section: Metabolic Interventions In Covid-19mentioning

confidence: 99%

Can a metabolism-targeted therapeutic intervention successfully subjugate SARS-COV-2? A scientific rational

Mansouri

Rastegari-Pouyani

Ghanbri-Movahed

et al. 2020

Biomedicine & Pharmacotherapy

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“…Orange circles show Phenformin and Gleevec sharing phenethylcarbamimidoyl- and pyridine-methyl-guanidine groups. Lactic acidosis is a common side effect of diguanidine drugs, which is also described in Gleevec [ 6 ] and Metformin [ 12 , 31 ] treated cell cultures, as well as in Gleevec treated clinically drug resistant cells [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Structural homologies between phenformin, lipitor and gleevec aim the same metabolic oncotarget in leukemia and melanoma

Somlyai¹,

Collins²,

Meuillet

et al. 2017

Oncotarget

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Phenformin's recently demonstrated efficacy in melanoma and Gleevec's demonstrated anti-proliferative action in chronic myeloid leukemia may lie within these drugs' significant pharmacokinetics, pharmacodynamics and structural homologies, which are reviewed herein. Gleevec's success in turning a fatal leukemia into a manageable chronic disease has been trumpeted in medical, economic, political and social circles because it is considered the first successful targeted therapy. Investments have been immense in omics analyses and while in some cases they greatly helped the management of patients, in others targeted therapies failed to achieve clinically stable recurrence-free disease course or to substantially extend survival. Nevertheless protein kinase controlling approaches have persisted despite early warnings that the targeted genomics narrative is overblown. Experimental and clinical observations with Phenformin suggest an alternative explanation for Gleevec's mode of action. Using 13C-guided precise flux measurements, a comparative multiple cell line study demonstrated the drug's downstream impact on submolecular fatty acid processing metabolic events that occurred independent of Gleevec's molecular target. Clinical observations that hyperlipidemia and diabetes are both reversed in mice and in patients taking Gleevec support the drugs' primary metabolic targets by biguanides and statins. This is evident by structural data demonstrating that Gleevec shows pyridine- and phenyl-guanidine homology with Phenformin and identical phenylcarbamoyl structural and ligand binding homology with Lipitor. The misunderstood mechanism of action of Gleevec is emblematic of the pervasive flawed reasoning that genomic analysis will lead to targeted, personalized diagnosis and therapy. The alternative perspective for Gleevec's mode of action may turn oncotargets towards metabolic channel reaction architectures in leukemia and melanoma, as well as in other cancers.

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Metformin and Pancreatic Cancer Metabolism

Cited by 9 publications

References 126 publications

Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells

Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells

Can a metabolism-targeted therapeutic intervention successfully subjugate SARS-COV-2? A scientific rational

Structural homologies between phenformin, lipitor and gleevec aim the same metabolic oncotarget in leukemia and melanoma

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