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Jørgen Frøkiær

Results from (11)C-metformin-PET scans, tissue analysis and cellular drug-sensitivity assays questions the view that biguanides affects tumor respiration directly

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Results from (11)C-metformin-PET scans, tissue analysis and cellular drug-sensitivity assays questions the view that biguanides affects tumor respiration directly. / Iversen, Ane B; Horsman, Michael R; Jakobsen, Steen; Jensen, Jonas B; Garm, Christian; Jessen, Niels; Breining, Peter; Frøkiær, Jørgen; Busk, Morten.

In: Scientific Reports, Vol. 7, No. 1, 9436, 25.08.2017, p. 9436.

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@article{7d9755b88a2647aa85fea4ae1595a629,
title = "Results from (11)C-metformin-PET scans, tissue analysis and cellular drug-sensitivity assays questions the view that biguanides affects tumor respiration directly",
abstract = "The anti-diabetic biguanide drugs metformin (METF) and phenformin (PHEN) may have anti-cancer effects. Biguanides suppress plasma growth factors, but nonetheless, the view that these mitochondrial inhibitors accumulate in tumor tissue to an extent that leads to severe energetic stress or alleviation of hypoxia-induced radioresistance is gaining ground. Our cell studies confirm that biguanides inhibits cell proliferation by targeting respiration, but only at highly suprapharmacological concentrations due to low drug retention. Biodistribution/PET studies of (11)C-labeled metformin ((11)C-METF) revealed that plasma bioavailability remained well below concentrations with metabolic/anti-proliferative in vitro effects, following a high oral dose. Intraperitoneal administration resulted in higher drug concentrations, which affected metabolism in normal organs with high METF uptake (e.g., kidneys), but tumor drug retention peaked at low levels comparable to plasma levels and hypoxia was unaffected. Prolonged intraperitoneal treatment reduced tumor growth in two tumor models, however, the response did not reflect in vitro drug sensitivity, and tumor metabolism and hypoxia was unaffected. Our results do not support that direct inhibition of tumor cell respiration is responsible for reduced tumor growth, but future studies using (11)C-METF-PET are warranted, preferably in neoplasia's originating from tissue with high drug transport capacity, to investigate the controversial idea of direct targeting.",
keywords = "BREAST-CANCER, CELLS, COMPLEX-I, DIABETIC-PATIENTS, INHIBITS GROWTH, LUNG-CANCER NSCLC, METABOLISM, METFORMIN, PHENFORMIN, TUMORIGENESIS",
author = "Iversen, {Ane B} and Horsman, {Michael R} and Steen Jakobsen and Jensen, {Jonas B} and Christian Garm and Niels Jessen and Peter Breining and J{\o}rgen Fr{\o}ki{\ae}r and Morten Busk",
year = "2017",
month = aug,
day = "25",
doi = "10.1038/s41598-017-10010-z",
language = "English",
volume = "7",
pages = "9436",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

TY - JOUR

T1 - Results from (11)C-metformin-PET scans, tissue analysis and cellular drug-sensitivity assays questions the view that biguanides affects tumor respiration directly

AU - Iversen, Ane B

AU - Horsman, Michael R

AU - Jakobsen, Steen

AU - Jensen, Jonas B

AU - Garm, Christian

AU - Jessen, Niels

AU - Breining, Peter

AU - Frøkiær, Jørgen

AU - Busk, Morten

PY - 2017/8/25

Y1 - 2017/8/25

N2 - The anti-diabetic biguanide drugs metformin (METF) and phenformin (PHEN) may have anti-cancer effects. Biguanides suppress plasma growth factors, but nonetheless, the view that these mitochondrial inhibitors accumulate in tumor tissue to an extent that leads to severe energetic stress or alleviation of hypoxia-induced radioresistance is gaining ground. Our cell studies confirm that biguanides inhibits cell proliferation by targeting respiration, but only at highly suprapharmacological concentrations due to low drug retention. Biodistribution/PET studies of (11)C-labeled metformin ((11)C-METF) revealed that plasma bioavailability remained well below concentrations with metabolic/anti-proliferative in vitro effects, following a high oral dose. Intraperitoneal administration resulted in higher drug concentrations, which affected metabolism in normal organs with high METF uptake (e.g., kidneys), but tumor drug retention peaked at low levels comparable to plasma levels and hypoxia was unaffected. Prolonged intraperitoneal treatment reduced tumor growth in two tumor models, however, the response did not reflect in vitro drug sensitivity, and tumor metabolism and hypoxia was unaffected. Our results do not support that direct inhibition of tumor cell respiration is responsible for reduced tumor growth, but future studies using (11)C-METF-PET are warranted, preferably in neoplasia's originating from tissue with high drug transport capacity, to investigate the controversial idea of direct targeting.

AB - The anti-diabetic biguanide drugs metformin (METF) and phenformin (PHEN) may have anti-cancer effects. Biguanides suppress plasma growth factors, but nonetheless, the view that these mitochondrial inhibitors accumulate in tumor tissue to an extent that leads to severe energetic stress or alleviation of hypoxia-induced radioresistance is gaining ground. Our cell studies confirm that biguanides inhibits cell proliferation by targeting respiration, but only at highly suprapharmacological concentrations due to low drug retention. Biodistribution/PET studies of (11)C-labeled metformin ((11)C-METF) revealed that plasma bioavailability remained well below concentrations with metabolic/anti-proliferative in vitro effects, following a high oral dose. Intraperitoneal administration resulted in higher drug concentrations, which affected metabolism in normal organs with high METF uptake (e.g., kidneys), but tumor drug retention peaked at low levels comparable to plasma levels and hypoxia was unaffected. Prolonged intraperitoneal treatment reduced tumor growth in two tumor models, however, the response did not reflect in vitro drug sensitivity, and tumor metabolism and hypoxia was unaffected. Our results do not support that direct inhibition of tumor cell respiration is responsible for reduced tumor growth, but future studies using (11)C-METF-PET are warranted, preferably in neoplasia's originating from tissue with high drug transport capacity, to investigate the controversial idea of direct targeting.

KW - BREAST-CANCER

KW - CELLS

KW - COMPLEX-I

KW - DIABETIC-PATIENTS

KW - INHIBITS GROWTH

KW - LUNG-CANCER NSCLC

KW - METABOLISM

KW - METFORMIN

KW - PHENFORMIN

KW - TUMORIGENESIS

U2 - 10.1038/s41598-017-10010-z

DO - 10.1038/s41598-017-10010-z

M3 - Journal article

C2 - 28842630

VL - 7

SP - 9436

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 9436

ER -