title: Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance.
abstract: Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug's mechanism of action.
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, Frankfurt am Main 60596, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Voges
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, Frankfurt am Main 60596, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Rothweiler
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, Frankfurt am Main 60596, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schaller
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, Frankfurt am Main 60596, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Institute of Molecular Oncology, Philipps-University, Marburg 35037, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Politt
authors.affiliation: Institute of Molecular Oncology, Philipps-University, Marburg 35037, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Mernberger
authors.affiliation: Genomics Core Facility, Philipps-University, Marburg 35037, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nist
authors.affiliation: Institute of Molecular Oncology, Philipps-University, Marburg 35037, Germany.|Genomics Core Facility, Philipps-University, Marburg 35037, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stiewe
authors.affiliation: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Wass
authors.affiliation: Klinik für Strahlentherapie und Onkologie, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Rödel
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, Frankfurt am Main 60596, Germany.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009285:Naphthoquinones / Q000494:pharmacology*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D026901:Membrane Transport Proteins; D009285:Naphthoquinones; D010879:Piperazines; D034741:RNA, Small Interfering; C569094:SLC35F2 protein, human; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2; C523798:sepantronium