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

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

doi:10.1007/s12013-017-0796-3

Cited by 18 publications

(14 citation statements)

References 40 publications

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“…Another successful antiproliferative strategy may be to increase in reactive oxygen species (ROS) production and subsequent induction of apoptosis [ 49 , 50 ]. It was also proposed for biguanides that their primary antiproliferative effect is manifested through increase in ROS production [ 21 , 23 ], which also holds true for the mitochondria-targeted analogs [ 51 ]. In this case, the mitochondrial ROS also interfered with redox signaling events.…”

Section: Resultsmentioning

confidence: 99%

Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

Pecinová

Drahota

Kovalčíková

et al. 2017

Oxidative Medicine and Cellular Longevity

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Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin) on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria. We demonstrate that biguanides nonspecifically target the activities of all respiratory chain dehydrogenases (mitochondrial NADH, succinate, and glycerophosphate dehydrogenases), but only at very high concentrations (10−2–10−1 M) that highly exceed cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also trigger burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, can be toxic for the organism. We conclude that the beneficial effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain.

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Section: Resultsmentioning

confidence: 99%

Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

Pecinová

Drahota

Kovalčíková

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…Firstly, in intestine where CRC is located, at standard doses for diabetic patients, metformin could reach mM levels, which is most probably due to the high expression of OCTs in enterocytes ( Bailey et al, 2008 ). Of note, efforts have been made to augment the activity of metformin; by attaching a lipophilic substituent, inhibitory effect of metformin toward complex I is potentiated about 1000-fold ( Kalyanaraman et al, 2017 ). Secondly, it has been shown that cancer cells exhibiting higher mitochondrial respiratory activity are more sensitive to biguanide drugs ( Hsu et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Antidiabetic Biguanides Radiosensitize Hypoxic Colorectal Cancer Cells Through a Decrease in Oxygen Consumption

et al. 2018

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Background and Purpose: The anti-diabetic biguanide drugs metformin and phenformin exhibit antitumor activity in various models. However, their radiomodulatory effect under hypoxic conditions, particularly for phenformin, is largely unknown. This study therefore examines whether metformin and phenformin as mitochondrial complex I blockades could overcome hypoxic radioresistance through inhibition of oxygen consumption.Materials and Methods: A panel of colorectal cancer cells (HCT116, DLD-1, HT29, SW480, and CT26) was exposed to metformin or phenformin for 16 h at indicated concentrations. Afterward, cell viability was measured by MTT and colony formation assays. Apoptosis and reactive oxygen species (ROS) were detected by flow cytometry. Phosphorylation of AMP-activated protein kinase (AMPK) was examined by western blot. Mitochondria complexes activity and oxygen consumption rate (OCR) were measured by seahorse analyzer. The radiosensitivity of tumor cells was assessed by colony formation assay under aerobic and hypoxic conditions. The in vitro findings were further validated in colorectal CT26 tumor model.Results: Metformin and phenformin inhibited mitochondrial complex I activity and subsequently reduced OCR in a dose-dependent manner starting at 3 mM and 30 μM, respectively. As a result, the hypoxic radioresistance of tumor cells was counteracted by metformin and phenformin with an enhancement ratio about 2 at 9 mM and 100 μM, respectively. Regarding intrinsic radioresistance, both of them did not exhibit any effect although there was an increase of phosphorylation of AMPK and ROS production. In tumor-bearing mice, metformin or phenformin alone did not show any anti-tumor effect. While in combination with radiation, both of them substantially delayed tumor growth and enhanced radioresponse, respectively, by 1.3 and 1.5-fold.Conclusion: Our results demonstrate that metformin and phenformin overcome hypoxic radioresistance through inhibition of mitochondrial respiration, and provide a rationale to explore metformin and phenformin as hypoxic radiosensitizers.

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“…(Modified from Ref. [87] . Reprinted from Cell Biochemistry and Biophysics, Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies, 75, 2017, 311-7, B. Kalyanaraman, G. Cheng, M. Hardy, O. Ouari, A. Sikora, J. Zielonka, M.B.…”

Section: Monitoring Intracellular Fluorescence Derived From Redox Promentioning

confidence: 99%

Teaching the basics of reactive oxygen species and their relevance to cancer biology: Mitochondrial reactive oxygen species detection, redox signaling, and targeted therapies

et al. 2018

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Reactive oxygen species (ROS) have been implicated in tumorigenesis (tumor initiation, tumor progression, and metastasis). Of the many cellular sources of ROS generation, the mitochondria and the NADPH oxidase family of enzymes are possibly the most prevalent intracellular sources. In this article, we discuss the methodologies to detect mitochondria-derived superoxide and hydrogen peroxide using conventional probes as well as newly developed assays and probes, and the necessity of characterizing the diagnostic marker products with HPLC and LC-MS in order to rigorously identify the oxidizing species. The redox signaling roles of mitochondrial ROS, mitochondrial thiol peroxidases, and transcription factors in response to mitochondria-targeted drugs are highlighted. ROS generation and ROS detoxification in drug-resistant cancer cells and the relationship to metabolic reprogramming are discussed. Understanding the subtle role of ROS in redox signaling and in tumor proliferation, progression, and metastasis as well as the molecular and cellular mechanisms (e.g., autophagy) could help in the development of combination therapies. The paradoxical aspects of antioxidants in cancer treatment are highlighted in relation to the ROS mechanisms in normal and cancer cells. Finally, the potential uses of newly synthesized exomarker probes for in vivo superoxide and hydrogen peroxide detection and the low-temperature electron paramagnetic resonance technique for monitoring oxidant production in tumor tissues are discussed.

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

Cited by 18 publications

References 40 publications

Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

Antidiabetic Biguanides Radiosensitize Hypoxic Colorectal Cancer Cells Through a Decrease in Oxygen Consumption

Teaching the basics of reactive oxygen species and their relevance to cancer biology: Mitochondrial reactive oxygen species detection, redox signaling, and targeted therapies

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