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Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies

Kalyanaraman, Balaraman ; Cheng, Gang ; Hardy, Micael ; Ouari, Olivier ; Sikora, Adam ; Zielonka, Jacek ; Dwinell, Michael B.

Cell biochemistry and biophysics, 2017-12, Vol.75 (3-4), p.311-317 [Periódico revisado por pares]

New York: Springer US

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Título:
Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies
Autor: Kalyanaraman, Balaraman ; Cheng, Gang ; Hardy, Micael ; Ouari, Olivier ; Sikora, Adam ; Zielonka, Jacek ; Dwinell, Michael B.
Assuntos: Analogs ; Anticancer properties ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antitumor activity ; Bioavailability ; Biochemistry ; Biological and Medical Physics ; Biomedical and Life Sciences ; Biophysics ; Biotechnology ; Cancer ; Cell Biology ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; Chemical Sciences ; Diabetes mellitus ; Drugs ; Electron paramagnetic resonance ; Electron Spin Resonance Spectroscopy ; Electron transport chain ; Electron Transport Complex I - metabolism ; Epidemiology ; Humans ; Hydrogen peroxide ; Hydrogen Peroxide - chemistry ; Hydrogen Peroxide - metabolism ; Inhibition ; Kinases ; Life Sciences ; Lipophilic ; Low temperature ; Metformin ; Metformin - pharmacology ; Mitochondria ; Mitochondria - chemistry ; Mitochondria - drug effects ; Mitochondria - metabolism ; NADH-ubiquinone oxidoreductase ; Original Paper ; Oxidation-Reduction ; Pancreatic cancer ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Pharmacology/Toxicology ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Signal Transduction - drug effects ; Signaling ; Superoxide
É parte de: Cell biochemistry and biophysics, 2017-12, Vol.75 (3-4), p.311-317
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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PMCID: PMC5680142
Descrição: Metformin, one of the most widely prescribed antidiabetic drugs in the world, is being repurposed as a potential drug in cancer treatment. Epidemiological studies suggest that metformin exerts anticancer effects in diabetic patients with pancreatic cancer. However, at typical antidiabetic doses the bioavailability of metformin is presumably too low to exert antitumor effects. Thus, more potent analogs of metformin are needed in order to increase its anticancer efficacy. To this end, a new class of mitochondria-targeted metformin analogs (or mito-metformins) containing a positively-charged lipophilic triphenylphosphonium group was synthesized and tested for their antitumor efficacy in pancreatic cancer cells. Results indicate that the lead compound, mito-metformin 10 , was nearly 1000-fold more potent than metformin in inhibiting mitochondrial complex I activity, inducing reactive oxygen species (superoxide and hydrogen peroxide) that stimulate redox signaling mechanisms, including the activation of adenosinemonophosphate kinase and inhibition of proliferation of pancreatic cancer cells. The potential use of the low-temperature electron paramagnetic resonance technique in assessing the role of mitochondrial complexes including complex I in tumor regression in response to metformin and mito-metformins in the in vivo setting is discussed.
Editor: New York: Springer US
Idioma: Inglês

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Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies

Kalyanaraman, Balaraman ; Cheng, Gang ; Hardy, Micael ; Ouari, Olivier ; Sikora, Adam ; Zielonka, Jacek ; Dwinell, Michael B.

New York: Springer US

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