Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance
| Autor: | Mark N. Wass, Marco Mernberger, Martin Michaelis, Andrea Nist, Constanze Schneider, Jindrich Cinatl, Franz Rödel, Torsten Schaller, Thorsten Stiewe, Katharina Politt, Florian Rothweiler, Yvonne Voges |
|---|---|
| Přispěvatelé: | Oberst, A. |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
RM Cancer Research ATP Binding Cassette Transporter Subfamily B DNA damage Cell Survival Survivin Immunology Drug resistance Biology Pharmacology Piperazines Inhibitor of Apoptosis Proteins 03 medical and health sciences Cellular and Molecular Neuroscience Neuroblastoma 0302 clinical medicine Downregulation and upregulation Cell Line Tumor medicine Humans ddc:610 RNA Small Interfering neoplasms Imidazoles Membrane Transport Proteins Proto-Oncogene Proteins c-mdm2 Cell Biology medicine.disease Kinetics 030104 developmental biology Mechanism of action Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell Mutation Cancer research biology.protein Mdm2 Original Article medicine.symptom Tumor Suppressor Protein p53 DNA Damage Naphthoquinones |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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