Cytotoxicity of the sesquiterpene lactones neoambrosin and damsin from ambrosia maritima against multidrug-resistant cancer cells

Autoren

Mohamed Saeed
Stefan Jacob
Louis P Sandjo
Yoshikazu Sugimoto
Hassan E Khalid
Till Opatz
Eckhard Thines
Thomas Efferth

Autoren-URL

https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000366124100001&DestLinkType=FullRecord&DestApp=WOS_CPL

DOI

10.3389/fphar.2015.00267

Externe Identifier

Clarivate Analytics Document Solution ID: CY0VF
PubMed Identifier: 26617519

ISSN

1663-9812

Zeitschrift

FRONTIERS IN PHARMACOLOGY

Schlüsselwörter

ABC-transporters
Asteraceae
EGFR
p53
Src inhibition
targeted chemotherapy

Artikelnummer

ARTN 267

Datum der Veröffentlichung

2015

Status

Published

Titel

Cytotoxicity of the Sesquiterpene Lactones Neoambrosin and Damsin from <i>Ambrosia maritima</i> Against Multidrug-Resistant Cancer Cells

Sub types

Article

Ausgabe der Zeitschrift

6

Datenquelle: Web of Science (Lite)

Autoren

Mohamed Saeed
Stefan Jacob
Louis P Sandjo
Yoshikazu Sugimoto
Hassan E Khalid
Till Opatz
Eckhard Thines
Thomas Efferth

DOI

10.3389/fphar.2015.00267

eISSN

1663-9812

Zeitschrift

Frontiers in Pharmacology

Online publication date

2015

Status

Published online

Herausgeber

Frontiers Media SA

Herausgeber URL

http://dx.doi.org/10.3389/fphar.2015.00267

Datum der Datenerfassung

2015

Titel

Cytotoxicity of the Sesquiterpene Lactones Neoambrosin and Damsin from Ambrosia maritima Against Multidrug-Resistant Cancer Cells

Ausgabe der Zeitschrift

6

Datenquelle: Crossref

Abstract

Multidrug resistance is a prevailing phenomenon leading to chemotherapy treatment failure in cancer patients. In the current study two known cytotoxic pseudoguaianolide sesquiterpene lactones; neoambrosin (1) and damsin (2) that circumvent MDR were identified. The two cytotoxic compounds were isolated using column chromatography, characterized using 1D and 2D NMR, MS, and compared with literature values. The isolated compounds were investigated for their cytotoxic potential using resazurin assays and thereafter confirmed with immunoblotting and in silico studies. MDR cells overexpressing ABC transporters (P-glycoprotein, BCRP, ABCB5) did not confer cross-resistance toward (1) and (2), indicating that these compounds are not appropriate substrates for any of the three ABC transporters analyzed. Resistance mechanisms investigated also included; the loss of the functions of the TP53 and the mutated EGFR. The HCT116 p53(-/-) cells were sensitive to 1 but resistant to 2. It was interesting to note that resistant cells transfected with oncogenic ΔEGFR exhibited hypersensitivity CS toward (1) and (2) (degrees of resistances were 0.18 and 0.15 for (1) and (2), respectively). Immunoblotting and in silico analyses revealed that 1 and 2 silenced c-Src kinase activity. It was hypothesized that inhibition of c-Src kinase activity may explain CS in EGFR-transfected cells. In conclusion, the significant cytotoxicity of 1 and 2 against different drug-resistant tumor cell lines indicate that they may be promising candidates to treat refractory tumors.

Addresses

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz Mainz, Germany.

Autoren

Mohamed Saeed
Stefan Jacob
Louis P Sandjo
Yoshikazu Sugimoto
Hassan E Khalid
Till Opatz
Eckhard Thines
Thomas Efferth
Thomas Efferth

DOI

10.3389/fphar.2015.00267

eISSN

1663-9812

Externe Identifier

PubMed Identifier: 26617519
PubMed Central ID: PMC4637410

Open access

true

ISSN

1663-9812

Zeitschrift

Frontiers in pharmacology

Sprache

eng

Medium

Electronic-eCollection

Online publication date

2015

Open access status

Open Access

Paginierung

267

Datum der Veröffentlichung

2015

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2015

Titel

Cytotoxicity of the Sesquiterpene Lactones Neoambrosin and Damsin from Ambrosia maritima Against Multidrug-Resistant Cancer Cells.

Sub types

research-article
Journal Article

Ausgabe der Zeitschrift

6

Files

https://www.frontiersin.org/articles/10.3389/fphar.2015.00267/pdf https://europepmc.org/articles/PMC4637410?pdf=render

Datenquelle: Europe PubMed Central

Abstract

Multidrug resistance is a prevailing phenomenon leading to chemotherapy treatment failure in cancer patients. In the current study two known cytotoxic pseudoguaianolide sesquiterpene lactones; neoambrosin (1) and damsin (2) that circumvent MDR were identified. The two cytotoxic compounds were isolated using column chromatography, characterized using 1D and 2D NMR, MS, and compared with literature values. The isolated compounds were investigated for their cytotoxic potential using resazurin assays and thereafter confirmed with immunoblotting and in silico studies. MDR cells overexpressing ABC transporters (P-glycoprotein, BCRP, ABCB5) did not confer cross-resistance toward (1) and (2), indicating that these compounds are not appropriate substrates for any of the three ABC transporters analyzed. Resistance mechanisms investigated also included; the loss of the functions of the TP53 and the mutated EGFR. The HCT116 p53(-/-) cells were sensitive to 1 but resistant to 2. It was interesting to note that resistant cells transfected with oncogenic ΔEGFR exhibited hypersensitivity CS toward (1) and (2) (degrees of resistances were 0.18 and 0.15 for (1) and (2), respectively). Immunoblotting and in silico analyses revealed that 1 and 2 silenced c-Src kinase activity. It was hypothesized that inhibition of c-Src kinase activity may explain CS in EGFR-transfected cells. In conclusion, the significant cytotoxicity of 1 and 2 against different drug-resistant tumor cell lines indicate that they may be promising candidates to treat refractory tumors.

Date of acceptance

2015

Autoren

Mohamed Saeed
Stefan Jacob
Louis P Sandjo
Yoshikazu Sugimoto
Hassan E Khalid
Till Opatz
Eckhard Thines
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/26617519

DOI

10.3389/fphar.2015.00267

Externe Identifier

PubMed Central ID: PMC4637410

ISSN

1663-9812

Zeitschrift

Front Pharmacol

Schlüsselwörter

ABC-transporters
Asteraceae
EGFR
Src inhibition
p53
targeted chemotherapy

Sprache

eng

Country

Switzerland

Paginierung

267

Datum der Veröffentlichung

2015

Status

Published online

Datum, an dem der Datensatz öffentlich gemacht wurde

2015

Titel

Cytotoxicity of the Sesquiterpene Lactones Neoambrosin and Damsin from Ambrosia maritima Against Multidrug-Resistant Cancer Cells.

Sub types

Journal Article

Ausgabe der Zeitschrift

6

Datenquelle: PubMed

Author's licence

CC-BY

Autoren

Mohamed Saaed
Stefan Jacob
Louis P Sandjo
Yoshikazu Sugimoto
Hassan E Khalid
Till Opatz
Eckhard Thines
Thomas Efferth

Hosting institution

Universitätsbibliothek Mainz

Sammlungen

DFG-OA-Publizieren (2012 - 2017)

Resource version

Published version

DOI

10.3389/fphar.2015.00267

Funding acknowledgements

DFG, Open Access-Publizieren Universität Mainz / Universitätsmedizin

File(s) embargoed

false

Open access

true

ISSN

1663-9812

Zeitschrift

Frontiers in pharmacology

Schlüsselwörter

570 Biowissenschaften
570 Life sciences

Sprache

eng

Open access status

Open Access

Paginierung

Art. 267

Datum der Veröffentlichung

2015

Public URL

https://openscience.ub.uni-mainz.de/handle/20.500.12030/8065

Herausgeber

Frontiers Media

Herausgeber URL

http://dx.doi.org/10.3389/fphar.2015.00267

Datum der Datenerfassung

2022

Datum, an dem der Datensatz öffentlich gemacht wurde

2022

Zugang

Public

Titel

Cytotoxicity of the sesquiterpene lactones neoambrosin and damsin from ambrosia maritima against multidrug-resistant cancer cells

Ausgabe der Zeitschrift

6

Files

cytotoxicity_of_the_sesquiter-20220925164201931.pdf

Datenquelle: OPENSCIENCE.UB

Cytotoxicity of the sesquiterpene lactones neoambrosin and damsin from ambrosia maritima against multidrug-resistant cancer cells

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Files

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