title: MDM2 antagonist nutlin-3a sensitizes tumors to V-ATPase inhibition.
abstract: Treating cancer is one of the big challenges of this century and it has become evident that single chemotherapeutic treatment is rarely effective. As tumors often carry multiple mutations using combination therapy which addresses different targets seems therefore more beneficial. One of the most frequently mutated genes in tumors is the tumor suppressor p53. Significant work has been put in the development of p53 activators, which are now in clinical studies against diverse cancers. Recently, we could show that inhibition of V-ATPase, a multisubunit proton pump, by archazolid induces p53 protein levels in cancer cells. In this study, we provide evidence that the combination of archazolid with the p53 activator nutlin-3a is synergistically inducing cell death in different p53 wild type tumor cell lines. Mechanistically, this effect could presumably be attributed to reduction of glycolysis as TIGAR mRNA levels were increased and glucose uptake and Glut1 protein levels were reduced. In addition, combination treatment highly activated pro-apoptotic pathways including IGFBP3 and Bax inducing caspase-9 and PARP cleavage. Remarkably, combination of archazolid and nutlin-3a was more efficient in reducing tumor growth compared to single dose treatment in a U87MG mouse model in vivo. Hence, our findings suggest the combination of archazolid and nutlin-3a as a highly promising strategy for the treatment of p53 wild type tumors.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Lina S
authors.initials: LS
authors.lastname: Schneider
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ulrich
authors.affiliation: Clinical Pharmacy, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehr
authors.affiliation: Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Menche
authors.affiliation: Saarland University, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, PO 151150, 66042 Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany. Electronic address: karin.von.schwarzenberg@cup.uni-muenchen.de.
authors.forename: Karin
authors.initials: K
authors.lastname: von Schwarzenberg
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C515497:IGFBP3 protein, human; D007093:Imidazoles; D018972:Insulin-Like Growth Factor Binding Protein 3; D010879:Piperazines; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2; D000251:Adenosine Triphosphatases
keywords: Cancer; Nutlin-3a; Therapy; V-ATPase; p53