Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Nuha Mahmoud
- Mohamed EM Saeed
- Yoshikazu Sugimoto
- Sabine M Klauck
- Henry J Greten
- Thomas Efferth
- DOI
- 10.18632/oncotarget.26299
- eISSN
- 1949-2553
- Ausgabe der Veröffentlichung
- 87
- Zeitschrift
- Oncotarget
- Sprache
- en
- Online publication date
- 2018
- Paginierung
- 35762 - 35779
- Datum der Veröffentlichung
- 2018
- Status
- Published
- Herausgeber
- Impact Journals, LLC
- Herausgeber URL
- http://dx.doi.org/10.18632/oncotarget.26299
- Datum der Datenerfassung
- 2020
- Titel
- Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation
- Ausgabe der Zeitschrift
- 9
Data source: Crossref
- Other metadata sources:
-
- Abstract
- Nimbolide is considered a promising natural product in cancer prevention and treatment. However, it is not known yet, whether the different mechanisms of multidrug resistance (MDR) influence its anticancer activity. In this study, well-known MDR mechanisms (<i>ABCB1</i>, <i>ABCG2</i>, <i>ABCB</i>5, <i>TP53</i>, <i>EGFR</i>) were evaluated against nimbolide. The P-glycoprotein (<i>ABCB1</i>/<i>MDR1</i>)-overexpressing CEM/ADR5000 cell line displayed remarkable hypersensitivity to nimbolide, which was mediated through upregulation of the tumor suppressor, PTEN, and its downstream components resulted in significant downregulation in <i>ABCB1</i>/<i>MDR1</i> mRNA and P-glycoprotein. In addition, nimbolide targeted essential cellular metabolic-regulating elements including HIF1α, FoxO1, MYC and reactive oxygen species. The expression of breast cancer resistance protein (BCRP) as well as epidermal growth factor receptor (EGFR) and mutant tumor suppressor <i>TP53</i> did not correlate to nimbolide's activity. Furthermore, this paper looked for other molecular determinants that might determine tumor cellular response towards nimbolide. COMPARE and hierarchical cluster analyses of transcriptome-wide microarray-based mRNA expressions of the NCI 60 cell line panel were performed, and a set of 40 genes from different functional groups was identified. The data suggested NF-κB as master regulator of nimbolide's activity. Interestingly, <i>HIF1α</i> was determined by COMPARE analysis to mediate sensitivity to nimbolide, which would be of great benefit in targeted therapy.
- Addresses
- Department of Pharmaceutical Biology, Johannes Gutenberg University, Mainz, Germany.
- Autoren
- Nuha Mahmoud
- Mohamed EM Saeed
- Yoshikazu Sugimoto
- Sabine M Klauck
- Henry J Greten
- Thomas Efferth
- DOI
- 10.18632/oncotarget.26299
- eISSN
- 1949-2553
- Externe Identifier
- PubMed Identifier: 30515268
- PubMed Central ID: PMC6254660
- Open access
- true
- ISSN
- 1949-2553
- Ausgabe der Veröffentlichung
- 87
- Zeitschrift
- Oncotarget
- Sprache
- eng
- Medium
- Electronic-eCollection
- Online publication date
- 2018
- Open access status
- Open Access
- Paginierung
- 35762 - 35779
- Datum der Veröffentlichung
- 2018
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2018
- Titel
- Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 9
Files
https://www.oncotarget.com/article/26299/pdf/ https://europepmc.org/articles/PMC6254660?pdf=render
Data source: Europe PubMed Central
- Abstract
- Nimbolide is considered a promising natural product in cancer prevention and treatment. However, it is not known yet, whether the different mechanisms of multidrug resistance (MDR) influence its anticancer activity. In this study, well-known MDR mechanisms (ABCB1, ABCG2, ABCB5, TP53, EGFR) were evaluated against nimbolide. The P-glycoprotein (ABCB1/MDR1)-overexpressing CEM/ADR5000 cell line displayed remarkable hypersensitivity to nimbolide, which was mediated through upregulation of the tumor suppressor, PTEN, and its downstream components resulted in significant downregulation in ABCB1/MDR1 mRNA and P-glycoprotein. In addition, nimbolide targeted essential cellular metabolic-regulating elements including HIF1α, FoxO1, MYC and reactive oxygen species. The expression of breast cancer resistance protein (BCRP) as well as epidermal growth factor receptor (EGFR) and mutant tumor suppressor TP53 did not correlate to nimbolide's activity. Furthermore, this paper looked for other molecular determinants that might determine tumor cellular response towards nimbolide. COMPARE and hierarchical cluster analyses of transcriptome-wide microarray-based mRNA expressions of the NCI 60 cell line panel were performed, and a set of 40 genes from different functional groups was identified. The data suggested NF-κB as master regulator of nimbolide's activity. Interestingly, HIF1α was determined by COMPARE analysis to mediate sensitivity to nimbolide, which would be of great benefit in targeted therapy.
- Date of acceptance
- 2018
- Autoren
- Nuha Mahmoud
- Mohamed EM Saeed
- Yoshikazu Sugimoto
- Sabine M Klauck
- Henry J Greten
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/30515268
- DOI
- 10.18632/oncotarget.26299
- eISSN
- 1949-2553
- Externe Identifier
- PubMed Central ID: PMC6254660
- Ausgabe der Veröffentlichung
- 87
- Zeitschrift
- Oncotarget
- Schlüsselwörter
- HIF1α
- MDR
- NF-κB
- limonoids
- reactive oxygen species
- Sprache
- eng
- Country
- United States
- Paginierung
- 35762 - 35779
- PII
- 26299
- Datum der Veröffentlichung
- 2018
- Status
- Published online
- Titel
- Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 9
Data source: PubMed
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