title: The Effect of Metformin and GANT61 Combinations on the Radiosensitivity of Prostate Cancer Cells.
abstract: The anti-diabetes drug metformin has been shown to have anti-neoplastic effects in several tumor models through its effects on energy metabolism and protein synthesis. Recent studies show that metformin also targets Hedgehog (Hh) signaling, a developmental pathway re-activated in several tumor types, including prostate cancer (PCa). Furthermore, we and others have shown that Hh signaling is an important target for radiosensitization. Here, we evaluated the combination of metformin and the Hh inhibitor GANT61 (GLI-ANTagonist 61) with or without ionizing radiation in three PCa cell lines (PC3, DU145, 22Rv1). The effect on proliferation, radiosensitivity, apoptosis, cell cycle distribution, reactive oxygen species production, DNA repair, gene and protein expression was investigated. Furthermore, this treatment combination was also assessed in vivo. Metformin was shown to interact with Hh signaling by inhibiting the effector protein glioma-associated oncogene homolog 1 (GLI1) in PCa cells both in vitro and in vivo. The combination of metformin and GANT61 significantly inhibited PCa cell growth in vitro and enhanced the radiation response of 22Rv1 cells compared to either single agent. Nevertheless, neither the growth inhibitory effect nor the radiosensitization effect of the combination treatment observed in vitro was seen in vivo. Although the interaction between metformin and Hh signaling seems to be promising from a therapeutic point of view in vitro, more research is needed when implementing this combination strategy in vivo.
authors.affiliation: Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven-University of Leuven, 3000 Leuven, Belgium. annelies.gonnissen@kuleuven.be.|Department of Radiation Oncology, University Hospitals Leuven, 3000 Leuven, Belgium. annelies.gonnissen@kuleuven.be.
authors.forename: Annelies
authors.initials: A
authors.lastname: Gonnissen
authors.affiliation: Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven-University of Leuven, 3000 Leuven, Belgium. sofie.isebaert@uzleuven.be.|Department of Radiation Oncology, University Hospitals Leuven, 3000 Leuven, Belgium. sofie.isebaert@uzleuven.be.
authors.forename: Sofie
authors.initials: S
authors.lastname: Isebaert
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK. chad.mckee@oncology.ox.ac.uk.
authors.forename: Chad M
authors.initials: CM
authors.lastname: McKee
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK. ruth.muschel@oncology.ox.ac.uk.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.affiliation: Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven-University of Leuven, 3000 Leuven, Belgium. karin.haustermans@uzleuven.be.|Department of Radiation Oncology, University Hospitals Leuven, 3000 Leuven, Belgium. karin.haustermans@uzleuven.be.
authors.forename: Karin
authors.initials: K
authors.lastname: Haustermans
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C551027:GANT 61; D053823:Hedgehog Proteins; D011725:Pyridines; D011743:Pyrimidines; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: hedgehog pathway; metformin; prostate cancer; radiosensitization; xenograft mouse mode