Lawsone derivatives target the Wnt/β-catenin signaling pathway in multidrug-resistant acute lymphoblastic leukemia cells
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Sami Hamdoun
- Edmond Fleischer
- Anette Klinger
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000417963800006&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.bcp.2017.10.008
- eISSN
- 1873-2968
- Externe Identifier
- Clarivate Analytics Document Solution ID: FP9JR
- PubMed Identifier: 29061340
- ISSN
- 0006-2952
- Zeitschrift
- BIOCHEMICAL PHARMACOLOGY
- Schlüsselwörter
- Cancer
- Collateral sensitivity
- Drug resistance
- Frizzled
- Signal transduction
- Paginierung
- 63 - 73
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Titel
- Lawsone derivatives target the Wnt/β-catenin signaling pathway in multidrug-resistant acute lymphoblastic leukemia cells
- Sub types
- Article
- Ausgabe der Zeitschrift
- 146
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Sami Hamdoun
- Edmond Fleischer
- Anette Klinger
- Thomas Efferth
- DOI
- 10.1016/j.bcp.2017.10.008
- ISSN
- 0006-2952
- Zeitschrift
- Biochemical Pharmacology
- Sprache
- en
- Paginierung
- 63 - 73
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.bcp.2017.10.008
- Datum der Datenerfassung
- 2020
- Titel
- Lawsone derivatives target the Wnt/β-catenin signaling pathway in multidrug-resistant acute lymphoblastic leukemia cells
- Ausgabe der Zeitschrift
- 146
Data source: Crossref
- Abstract
- Multidrug resistance (MDR) represents a serious problem in cancer treatment. One strategy to overcome this obstacle is to identify agents that are selectively lethal to MDR cells. The aim of this study was to discover novel compounds against MDR leukemia and to determine the molecular mechanisms behind collateral sensitivity. A library of 1162 compounds was tested against parental, drug-sensitive CCRF-CEM cells using the resazurin assay. A total of 302 compounds showed reasonable activity (less than 50% cell viability). Eleven out of 30 lawsone derivatives revealed considerable collateral sensitivity in MDR P-glycoprotein (Pgp)-overexpressing CEM/ADR5000 cells. They reduced β-catenin activity in a Wnt/β-catenin reporter cell line. Their activities significantly correlated with apolar desolvation (R = 0.819). Compound (1) (3-hydroxy-1,4-dioxo-N-phenyl-naphthalene-2-carboxamide) was the most active compound and dose-dependently down-regulated protein expression of β-catenin, c-MYC, Pgp and Frizzled 7. By molecular docking, we predicted that compound (1) bound to the palmitoyl-binding groove of the cysteine-rich domain of Frizzled-7 and Frizzled-8. Compound (1) neither stimulated ATPase activity of Pgp nor reactive oxygen species generation, both of which have been previously described as possible mechanisms of collateral sensitivity. Instead, we found that Wnt/β-catenin signaling was selectively inhibited in CEM/ADR5000 cells, but not in CCRF-CEM cells. In conclusion, we found for the first time that the inhibition of Wnt/β-catenin signaling may represent a novel molecular mechanism of collateral sensitivity in MDR cells. Wnt/β-catenin signaling, therefore, represents a potential therapeutic target for the selective killing of Pgp-mediated MDR.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
- Autoren
- Sami Hamdoun
- Edmond Fleischer
- Anette Klinger
- Thomas Efferth
- Thomas Efferth
- DOI
- 10.1016/j.bcp.2017.10.008
- eISSN
- 1873-2968
- Externe Identifier
- PubMed Identifier: 29061340
- Open access
- false
- ISSN
- 0006-2952
- Zeitschrift
- Biochemical pharmacology
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Reactive Oxygen Species
- Naphthoquinones
- Antineoplastic Agents
- Signal Transduction
- Molecular Structure
- Dose-Response Relationship, Drug
- Drug Resistance, Neoplasm
- Wnt Proteins
- beta Catenin
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2017
- Paginierung
- 63 - 73
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Datum der Datenerfassung
- 2017
- Titel
- Lawsone derivatives target the Wnt/β-catenin signaling pathway in multidrug-resistant acute lymphoblastic leukemia cells.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 146
Data source: Europe PubMed Central
- Abstract
- Multidrug resistance (MDR) represents a serious problem in cancer treatment. One strategy to overcome this obstacle is to identify agents that are selectively lethal to MDR cells. The aim of this study was to discover novel compounds against MDR leukemia and to determine the molecular mechanisms behind collateral sensitivity. A library of 1162 compounds was tested against parental, drug-sensitive CCRF-CEM cells using the resazurin assay. A total of 302 compounds showed reasonable activity (less than 50% cell viability). Eleven out of 30 lawsone derivatives revealed considerable collateral sensitivity in MDR P-glycoprotein (Pgp)-overexpressing CEM/ADR5000 cells. They reduced β-catenin activity in a Wnt/β-catenin reporter cell line. Their activities significantly correlated with apolar desolvation (R = 0.819). Compound (1) (3-hydroxy-1,4-dioxo-N-phenyl-naphthalene-2-carboxamide) was the most active compound and dose-dependently down-regulated protein expression of β-catenin, c-MYC, Pgp and Frizzled 7. By molecular docking, we predicted that compound (1) bound to the palmitoyl-binding groove of the cysteine-rich domain of Frizzled-7 and Frizzled-8. Compound (1) neither stimulated ATPase activity of Pgp nor reactive oxygen species generation, both of which have been previously described as possible mechanisms of collateral sensitivity. Instead, we found that Wnt/β-catenin signaling was selectively inhibited in CEM/ADR5000 cells, but not in CCRF-CEM cells. In conclusion, we found for the first time that the inhibition of Wnt/β-catenin signaling may represent a novel molecular mechanism of collateral sensitivity in MDR cells. Wnt/β-catenin signaling, therefore, represents a potential therapeutic target for the selective killing of Pgp-mediated MDR.
- Date of acceptance
- 2017
- Autoren
- Sami Hamdoun
- Edmond Fleischer
- Anette Klinger
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/29061340
- DOI
- 10.1016/j.bcp.2017.10.008
- eISSN
- 1873-2968
- Zeitschrift
- Biochem Pharmacol
- Schlüsselwörter
- Cancer
- Collateral sensitivity
- Drug resistance
- Frizzled
- Signal transduction
- Antineoplastic Agents
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Drug Resistance, Neoplasm
- Humans
- Molecular Structure
- Naphthoquinones
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Reactive Oxygen Species
- Signal Transduction
- Wnt Proteins
- beta Catenin
- Sprache
- eng
- Country
- England
- Paginierung
- 63 - 73
- PII
- S0006-2952(17)30638-X
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2017
- Titel
- Lawsone derivatives target the Wnt/β-catenin signaling pathway in multidrug-resistant acute lymphoblastic leukemia cells.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 146
Data source: PubMed
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