2α-Hydroxyalantolactone from Pulicaria undulata: activity against multidrug-resistant tumor cells and modes of action
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Mohamed-Elamir F Hegazy
- Mona Dawood
- Nuha Mahmoud
- Mohamed Elbadawi
- Yoshikazu Sugimoto
- Sabine M Klauck
- Nagla Mohamed
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000605579700005&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.phymed.2020.153409
- eISSN
- 1618-095X
- Externe Identifier
- Clarivate Analytics Document Solution ID: PP0SH
- PubMed Identifier: 33341310
- ISSN
- 0944-7113
- Zeitschrift
- PHYTOMEDICINE
- Schlüsselwörter
- 2 alpha-Hydroxyalantolactone
- Cytotoxicity
- Mode of action
- G2/M cell cycle arrest
- DNA damage
- Pulicaria undulata
- Artikelnummer
- ARTN 153409
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Titel
- 2α-Hydroxyalantolactone from Pulicaria undulata: activity against multidrug-resistant tumor cells and modes of action
- Sub types
- Article
- Ausgabe der Zeitschrift
- 81
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Mohamed-Elamir F Hegazy
- Mona Dawood
- Nuha Mahmoud
- Mohamed Elbadawi
- Yoshikazu Sugimoto
- Sabine M Klauck
- Nagla Mohamed
- Thomas Efferth
- DOI
- 10.1016/j.phymed.2020.153409
- ISSN
- 0944-7113
- Zeitschrift
- Phytomedicine
- Sprache
- en
- Artikelnummer
- 153409
- Paginierung
- 153409 - 153409
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.phymed.2020.153409
- Datum der Datenerfassung
- 2022
- Titel
- 2α-Hydroxyalantolactone from Pulicaria undulata: activity against multidrug-resistant tumor cells and modes of action
- Ausgabe der Zeitschrift
- 81
Data source: Crossref
- Abstract
- <h4>Background</h4>Sesquiterpene lactones having α-methylene-γ-lactone moiety are promising natural metabolites showing various biological activity. One of the major metabolites isolated from Pulicaria undulata, 2α-hydroxyalantolactone (PU-1), has not been investigated in detail yet. Multidrug resistance (MDR) represents a major obstacle for cancer chemotherapy and the capability of novel natural products to overcoming MDR is of great interest.<h4>Purpose</h4>Exploring the molecular modes of action for potent natural product metabolites.<h4>Methods</h4>The resazurin reduction assay was employed to evaluate the cytotoxicity of PU-1 on sensitive and their corresponding drug-resistant cell lines (overexpressing P-glycoprotein, BCRP, ABCB5, ΔEGFR, or TP53 knockout). Gene expression profiling was performed by transcriptome-wide mRNA microarray in the human CCRF-CEM leukemic cells after treatment with PU-1. The top significantly up- or down-regulated genes were identified by Chipster program and analyzed using Ingenuity Pathway Analysis (IPA) software. Finally, flow cytometry and Western blotting were performed for cell cycle analyses and apoptosis detection.<h4>Results</h4>The sesquiterpene lactone, PU-1, showed potent cytotoxicity towards the drug-sensitive and -resistant cell lines. Transcriptome-wide mRNA expression profiling and pathway analysis pointed to genes involved in DNA damage response and G2/M cell cycle arrest. G2/M arrest was verified by flow cytometry and further confirmed by the upregulation of p21 and downregulation of p-CDC25C expression in Western blotting. Moreover, the suggested DNA damage checkpoint regulation was confirmed by immunofluorescence and Western blotting by upregulation of pS345 Chk1, p-H3 and γ-H2AX. Furthermore, PU-1 inhibited PI3K/AKT pathway, which is involved in signaling DNA damage and G2/M arrest. Cells ultimately induced apoptosis upon PU-1 treatment.<h4>Conclusions</h4>PU-1 is a potent natural product inhibiting otherwise drug-resistant human tumor cell growth through DNA damage, G2/M cell cycle arrest and apoptosis.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany; Phytochemistry Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt.
- Autoren
- Mohamed-Elamir F Hegazy
- Mona Dawood
- Nuha Mahmoud
- Mohamed Elbadawi
- Yoshikazu Sugimoto
- Sabine M Klauck
- Nagla Mohamed
- Thomas Efferth
- DOI
- 10.1016/j.phymed.2020.153409
- eISSN
- 1618-095X
- Externe Identifier
- PubMed Identifier: 33341310
- Funding acknowledgements
- Alexander von Humboldt-Stiftung:
- Open access
- false
- ISSN
- 0944-7113
- Zeitschrift
- Phytomedicine : international journal of phytotherapy and phytopharmacology
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Leukemia
- DNA Damage
- Sesquiterpenes
- Antineoplastic Agents, Phytogenic
- Apoptosis
- Gene Expression Regulation, Neoplastic
- Drug Resistance, Neoplasm
- Pulicaria
- Phosphatidylinositol 3-Kinases
- G2 Phase Cell Cycle Checkpoints
- Phosphoinositide-3 Kinase Inhibitors
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2020
- Paginierung
- 153409
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum der Datenerfassung
- 2020
- Titel
- 2α-Hydroxyalantolactone from Pulicaria undulata: activity against multidrug-resistant tumor cells and modes of action.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 81
Data source: Europe PubMed Central
- Abstract
- BACKGROUND: Sesquiterpene lactones having α-methylene-γ-lactone moiety are promising natural metabolites showing various biological activity. One of the major metabolites isolated from Pulicaria undulata, 2α-hydroxyalantolactone (PU-1), has not been investigated in detail yet. Multidrug resistance (MDR) represents a major obstacle for cancer chemotherapy and the capability of novel natural products to overcoming MDR is of great interest. PURPOSE: Exploring the molecular modes of action for potent natural product metabolites. METHODS: The resazurin reduction assay was employed to evaluate the cytotoxicity of PU-1 on sensitive and their corresponding drug-resistant cell lines (overexpressing P-glycoprotein, BCRP, ABCB5, ΔEGFR, or TP53 knockout). Gene expression profiling was performed by transcriptome-wide mRNA microarray in the human CCRF-CEM leukemic cells after treatment with PU-1. The top significantly up- or down-regulated genes were identified by Chipster program and analyzed using Ingenuity Pathway Analysis (IPA) software. Finally, flow cytometry and Western blotting were performed for cell cycle analyses and apoptosis detection. RESULTS: The sesquiterpene lactone, PU-1, showed potent cytotoxicity towards the drug-sensitive and -resistant cell lines. Transcriptome-wide mRNA expression profiling and pathway analysis pointed to genes involved in DNA damage response and G2/M cell cycle arrest. G2/M arrest was verified by flow cytometry and further confirmed by the upregulation of p21 and downregulation of p-CDC25C expression in Western blotting. Moreover, the suggested DNA damage checkpoint regulation was confirmed by immunofluorescence and Western blotting by upregulation of pS345 Chk1, p-H3 and γ-H2AX. Furthermore, PU-1 inhibited PI3K/AKT pathway, which is involved in signaling DNA damage and G2/M arrest. Cells ultimately induced apoptosis upon PU-1 treatment. CONCLUSIONS: PU-1 is a potent natural product inhibiting otherwise drug-resistant human tumor cell growth through DNA damage, G2/M cell cycle arrest and apoptosis.
- Date of acceptance
- 2020
- Autoren
- Mohamed-Elamir F Hegazy
- Mona Dawood
- Nuha Mahmoud
- Mohamed Elbadawi
- Yoshikazu Sugimoto
- Sabine M Klauck
- Nagla Mohamed
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/33341310
- DOI
- 10.1016/j.phymed.2020.153409
- eISSN
- 1618-095X
- Zeitschrift
- Phytomedicine
- Schlüsselwörter
- 2α-Hydroxyalantolactone
- Cytotoxicity
- DNA damage
- G2/M cell cycle arrest
- Mode of action
- Pulicaria undulata
- Antineoplastic Agents, Phytogenic
- Apoptosis
- Cell Line, Tumor
- DNA Damage
- Drug Resistance, Neoplasm
- G2 Phase Cell Cycle Checkpoints
- Gene Expression Regulation, Neoplastic
- Humans
- Leukemia
- Phosphatidylinositol 3-Kinases
- Phosphoinositide-3 Kinase Inhibitors
- Pulicaria
- Sesquiterpenes
- Sprache
- eng
- Country
- Germany
- Paginierung
- 153409
- PII
- S0944-7113(20)30240-3
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2021
- Titel
- 2α-Hydroxyalantolactone from Pulicaria undulata: activity against multidrug-resistant tumor cells and modes of action.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 81
Data source: PubMed
- Beziehungen:
- Property of