Cytotoxicity of cucurbitacin E from Citrullus colocynthis against multidrug-resistant cancer cells

Publication type:
Journal article
Metadata:
Autoren
  • Mohamed EM Saeed
  • Joelle C Boulos
  • Gihan Elhaboub
  • Daniela Rigano
  • Antoine Saab
  • Monica R Loizzo
  • Loiy EA Hassan
  • Yoshikazu Sugimoto
  • Sonia Piacente
  • Rosa Tundis
  • Sakina Yagi
  • Hassan Khalid
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000500559500014&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.phymed.2019.152945
eISSN
1618-095X
Externe Identifier
  • Clarivate Analytics Document Solution ID: JS8NV
  • PubMed Identifier: 31132750
ISSN
0944-7113
Zeitschrift
PHYTOMEDICINE
Schlüsselwörter
  • Citrullus colocynthis
  • Cancer
  • Drug resistance
  • Microarray
  • Traditional herbal medicine
Artikelnummer
ARTN 152945
Datum der Veröffentlichung
2019
Status
Published
Titel
Cytotoxicity of cucurbitacin E from <i>Citrullus colocynthis</i> against multidrug-resistant cancer cells
Sub types
  • Article
Ausgabe der Zeitschrift
62

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Mohamed EM Saeed
  • Joelle C Boulos
  • Gihan Elhaboub
  • Daniela Rigano
  • Antoine Saab
  • Monica R Loizzo
  • Loiy EA Hassan
  • Yoshikazu Sugimoto
  • Sonia Piacente
  • Rosa Tundis
  • Sakina Yagi
  • Hassan Khalid
  • Thomas Efferth
DOI
10.1016/j.phymed.2019.152945
ISSN
0944-7113
Zeitschrift
Phytomedicine
Sprache
en
Artikelnummer
152945
Paginierung
152945 - 152945
Datum der Veröffentlichung
2019
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.phymed.2019.152945
Datum der Datenerfassung
2019
Titel
Cytotoxicity of cucurbitacin E from Citrullus colocynthis against multidrug-resistant cancer cells
Ausgabe der Zeitschrift
62

Data source: Crossref

Abstract
<h4>Background</h4>Cucurbitacin E (CuE) is an oxygenated tetracyclic triterpenoid isolated from the fruits of Citrullus colocynthis (L.) Schrad.<h4>Purpose</h4>This study outlines CuE's cytotoxic activity against drug-resistant tumor cell lines. Three members of ABC transporters superfamily, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and ABCB5 were investigated, whose overexpression in tumors is tightly linked to multidrug resistance. Further factors of drug resistance studied were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR).<h4>Methods</h4>Cytotoxicity assays (resazurin assays) were used to investigate the activity of Citrullus colocynthis and CuE towards multidrug resistant cancer cells. Molecular docking (In silico) has been carried out to explore the CuE's mode of binding to ABC transporters (P-gp, BCRP and ABCB5). The visualization of doxorubicin uptake was done by a Spinning Disc Confocal Microscope. The assessment of proteins expression was done by western blotting analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to cucurbitacins (CuA, CuB, CuE, CuD, CuI, and CuK).<h4>Results</h4>Multidrug-resistant cells overexpressing P-gp or BCRP were cross-resistant to CuE. By contrast, TP53 knock-out cells were sensitive to CuE. Remarkably, resistant cells transfected with oncogenic ΔEGFR or ABCB5 were hypersensitive (collateral sensitive) to CuE. In silico analyses demonstrated that CuE is a substrate for P-gp and BCRP. Immunoblot analyses highlighted that CuE targeted EGFR and silenced its downstream signaling cascades. The most striking result that emerged from the doxorubicin uptake by ABCB5 overexpressing cells is that CuE is an effective inhibitor for ABCB5 transporter when compared with verapamil. The COMPARE analyses of transcriptome-wide expression profiles of tumor cell lines of the NCI identified common genes involved in cell cycle regulation, cellular adhesion and intracellular communication for different cucurbitacins.<h4>Conclusion</h4>CuE represents a potential therapeutic candidate for the treatment of certain types of refractory tumors. To best of our knowledge, this is the first time to identify CuE and verapamil as inhibitors for ABCB5 transporter.
Addresses
  • Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
  • Mohamed EM Saeed
  • Joelle C Boulos
  • Gihan Elhaboub
  • Daniela Rigano
  • Antoine Saab
  • Monica R Loizzo
  • Loiy EA Hassan
  • Yoshikazu Sugimoto
  • Sonia Piacente
  • Rosa Tundis
  • Sakina Yagi
  • Hassan Khalid
  • Thomas Efferth
DOI
10.1016/j.phymed.2019.152945
eISSN
1618-095X
Externe Identifier
  • PubMed Identifier: 31132750
Open access
false
ISSN
0944-7113
Zeitschrift
Phytomedicine : international journal of phytotherapy and phytopharmacology
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Leukemia
  • Triterpenes
  • Doxorubicin
  • Neoplasm Proteins
  • Antineoplastic Agents, Phytogenic
  • Gene Expression Regulation, Neoplastic
  • Drug Resistance, Neoplasm
  • Tumor Suppressor Protein p53
  • Gene Knockout Techniques
  • Molecular Docking Simulation
  • ErbB Receptors
  • Citrullus colocynthis
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
Sprache
eng
Medium
Print-Electronic
Online publication date
2019
Paginierung
152945
Datum der Veröffentlichung
2019
Status
Published
Datum der Datenerfassung
2019
Titel
Cytotoxicity of cucurbitacin E from Citrullus colocynthis against multidrug-resistant cancer cells.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
62

Data source: Europe PubMed Central

Abstract
BACKGROUND: Cucurbitacin E (CuE) is an oxygenated tetracyclic triterpenoid isolated from the fruits of Citrullus colocynthis (L.) Schrad. PURPOSE: This study outlines CuE's cytotoxic activity against drug-resistant tumor cell lines. Three members of ABC transporters superfamily, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and ABCB5 were investigated, whose overexpression in tumors is tightly linked to multidrug resistance. Further factors of drug resistance studied were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). METHODS: Cytotoxicity assays (resazurin assays) were used to investigate the activity of Citrullus colocynthis and CuE towards multidrug resistant cancer cells. Molecular docking (In silico) has been carried out to explore the CuE's mode of binding to ABC transporters (P-gp, BCRP and ABCB5). The visualization of doxorubicin uptake was done by a Spinning Disc Confocal Microscope. The assessment of proteins expression was done by western blotting analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to cucurbitacins (CuA, CuB, CuE, CuD, CuI, and CuK). RESULTS: Multidrug-resistant cells overexpressing P-gp or BCRP were cross-resistant to CuE. By contrast, TP53 knock-out cells were sensitive to CuE. Remarkably, resistant cells transfected with oncogenic ΔEGFR or ABCB5 were hypersensitive (collateral sensitive) to CuE. In silico analyses demonstrated that CuE is a substrate for P-gp and BCRP. Immunoblot analyses highlighted that CuE targeted EGFR and silenced its downstream signaling cascades. The most striking result that emerged from the doxorubicin uptake by ABCB5 overexpressing cells is that CuE is an effective inhibitor for ABCB5 transporter when compared with verapamil. The COMPARE analyses of transcriptome-wide expression profiles of tumor cell lines of the NCI identified common genes involved in cell cycle regulation, cellular adhesion and intracellular communication for different cucurbitacins. CONCLUSION: CuE represents a potential therapeutic candidate for the treatment of certain types of refractory tumors. To best of our knowledge, this is the first time to identify CuE and verapamil as inhibitors for ABCB5 transporter.
Date of acceptance
2019
Autoren
  • Mohamed EM Saeed
  • Joelle C Boulos
  • Gihan Elhaboub
  • Daniela Rigano
  • Antoine Saab
  • Monica R Loizzo
  • Loiy EA Hassan
  • Yoshikazu Sugimoto
  • Sonia Piacente
  • Rosa Tundis
  • Sakina Yagi
  • Hassan Khalid
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/31132750
DOI
10.1016/j.phymed.2019.152945
eISSN
1618-095X
Zeitschrift
Phytomedicine
Schlüsselwörter
  • Cancer
  • Citrullus colocynthis
  • Drug resistance
  • Microarray
  • Traditional herbal medicine
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antineoplastic Agents, Phytogenic
  • Cell Line, Tumor
  • Citrullus colocynthis
  • Doxorubicin
  • Drug Resistance, Neoplasm
  • ErbB Receptors
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • Humans
  • Leukemia
  • Molecular Docking Simulation
  • Neoplasm Proteins
  • Triterpenes
  • Tumor Suppressor Protein p53
Sprache
eng
Country
Germany
Paginierung
152945
PII
S0944-7113(19)30114-X
Datum der Veröffentlichung
2019
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2020
Titel
Cytotoxicity of cucurbitacin E from Citrullus colocynthis against multidrug-resistant cancer cells.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
62

Data source: PubMed

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