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

• DOI: 10.1038/s41598-017-10010-z
• Publication Date: 2017-08-21T09:25:20Z
• Authors: Ane B. Iversen; Michael R. Horsman; Steen Jakobsen; Jonas B. Jensen; Christian Garm; Niels Jessen; Peter Breining; Jørgen Frøkiær; Morten Busk
• Keywords: Phenformin; Biguanide; Hypoxia; Tumor Hypoxia

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 leads severe energetic stress or alleviation of hypoxia-induced radioresistance is gaining ground. Our cell studies confirm biguanides inhibits proliferation by targeting respiration, only at highly suprapharmacological concentrations due low drug retention. Biodistribution/PET 11C-labeled (11C-METF) revealed bioavailability remained well below with metabolic/anti-proliferative vitro effects, following a high oral dose. Intraperitoneal administration resulted higher concentrations, which affected metabolism normal organs METF uptake (e.g., kidneys), retention peaked levels comparable hypoxia was unaffected. Prolonged intraperitoneal treatment reduced two models, however, response did not reflect sensitivity, results do support direct inhibition respiration responsible for growth, future using 11C-METF-PET are warranted, preferably neoplasia's originating from transport capacity, investigate controversial idea targeting.