Putative molecular determinants mediating sensitivity or resistance towards carnosic acid tumor cell responses

Publication type:
Journal article
Metadata:
Autoren
  • Nuha Mahmoud
  • Mohamed EM Saeed
  • Yoshikazu Sugimoto
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000566511300007&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.phymed.2020.153271
eISSN
1618-095X
Externe Identifier
  • Clarivate Analytics Document Solution ID: NK1PN
  • PubMed Identifier: 32659679
ISSN
0944-7113
Zeitschrift
PHYTOMEDICINE
Schlüsselwörter
  • Chemotherapy
  • Fak
  • Lamiaceae
  • Multidrug resistance
  • Network pharmacology
  • Phytochemicals
Artikelnummer
ARTN 153271
Datum der Veröffentlichung
2020
Status
Published
Titel
Putative molecular determinants mediating sensitivity or resistance towards carnosic acid tumor cell responses
Sub types
  • Article
Ausgabe der Zeitschrift
77

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Nuha Mahmoud
  • Mohamed EM Saeed
  • Yoshikazu Sugimoto
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
DOI
10.1016/j.phymed.2020.153271
ISSN
0944-7113
Zeitschrift
Phytomedicine
Sprache
en
Artikelnummer
153271
Paginierung
153271 - 153271
Datum der Veröffentlichung
2020
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.phymed.2020.153271
Datum der Datenerfassung
2020
Titel
Putative molecular determinants mediating sensitivity or resistance towards carnosic acid tumor cell responses
Ausgabe der Zeitschrift
77

Data source: Crossref

Abstract
<h4>Background</h4>Carnosic acid (CA) is one of the main constituents in rosemary extract. It possesses valuable pharmacological properties, including anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer activities. Numerous in vitro and in vivo studies investigated the anticancer profile of CA and emphasized its potentiality for cancer treatment. Nevertheless, the role of multidrug-resistance (MDR) related mechanisms for CA's anticancer effect is not yet known.<h4>Purpose</h4>We investigated the cytotoxicity of CA against known mechanisms of anticancer drug resistance (P-gp, ABCB5, BCRP, EGFR and p53) and determined novel putative molecular factors associated with cellular response towards CA.<h4>Study design</h4>Cytotoxicity assays, bioinformatic analysis, flow cytometry and western blotting were performed to identify the mode of action of CA towards cancer cells.<h4>Methods</h4>The cytotoxicity to CA was assessed using the resazurin assays in cell lines expressing the mentioned resistance mechanisms. A pharmacogenomic characterization of the NCI 60 cell line panel was applied via COMPARE, hierarchical cluster and network analyses. Flow cytometry was used to detect cellular mode of death and ROS generation. Changes in proteins-related to apoptosis were determined by Western blotting.<h4>Results</h4>Cell lines expressing ABC transporters (P-gp, BCRP or ABCB5), mutant EGFR or p53 were not cross-resistant to CA compared to their parental counterparts. By pharmacogenomic approaches, we identified genes that belong to different functional groups (e.g. signal transduction, regulation of cytoskeleton and developmental regulatory system). These genes were predicted as molecular determinants that mediate CA tumor cellular responses. The top affected biofunctions included cellular development, cellular proliferation and cellular death and survival. The effect of CA-mediated apoptosis in leukemia cells, which were recognized as the most sensitive tumor type, was confirmed via flow cytometry and western blot analysis.<h4>Conclusion</h4>CA may provide a novel treatment option to target refractory tumors and to effectively cooperate with established chemotherapy. Using pharmacogenomic approaches and network pharmacology, the relationship between cancer complexity and multi-target potentials of CA was analyzed and many putative molecular determinants were identified. They could serve as novel targets for CA and further studies are needed to translate the possible implications to clinical cancer treatment.
Addresses
  • Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
  • Nuha Mahmoud
  • Mohamed EM Saeed
  • Yoshikazu Sugimoto
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
DOI
10.1016/j.phymed.2020.153271
eISSN
1618-095X
Externe Identifier
  • PubMed Identifier: 32659679
Funding acknowledgements
  • ABC:
Open access
false
ISSN
0944-7113
Zeitschrift
Phytomedicine : international journal of phytotherapy and phytopharmacology
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Neoplasm Proteins
  • Antineoplastic Agents, Phytogenic
  • Pharmacogenetics
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Tumor Suppressor Protein p53
  • ErbB Receptors
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Abietanes
Sprache
eng
Medium
Print-Electronic
Online publication date
2020
Paginierung
153271
Datum der Veröffentlichung
2020
Status
Published
Datum der Datenerfassung
2020
Titel
Putative molecular determinants mediating sensitivity or resistance towards carnosic acid tumor cell responses.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
77

Data source: Europe PubMed Central

Abstract
BACKGROUND: Carnosic acid (CA) is one of the main constituents in rosemary extract. It possesses valuable pharmacological properties, including anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer activities. Numerous in vitro and in vivo studies investigated the anticancer profile of CA and emphasized its potentiality for cancer treatment. Nevertheless, the role of multidrug-resistance (MDR) related mechanisms for CA's anticancer effect is not yet known. PURPOSE: We investigated the cytotoxicity of CA against known mechanisms of anticancer drug resistance (P-gp, ABCB5, BCRP, EGFR and p53) and determined novel putative molecular factors associated with cellular response towards CA. STUDY DESIGN: Cytotoxicity assays, bioinformatic analysis, flow cytometry and western blotting were performed to identify the mode of action of CA towards cancer cells. METHODS: The cytotoxicity to CA was assessed using the resazurin assays in cell lines expressing the mentioned resistance mechanisms. A pharmacogenomic characterization of the NCI 60 cell line panel was applied via COMPARE, hierarchical cluster and network analyses. Flow cytometry was used to detect cellular mode of death and ROS generation. Changes in proteins-related to apoptosis were determined by Western blotting. RESULTS: Cell lines expressing ABC transporters (P-gp, BCRP or ABCB5), mutant EGFR or p53 were not cross-resistant to CA compared to their parental counterparts. By pharmacogenomic approaches, we identified genes that belong to different functional groups (e.g. signal transduction, regulation of cytoskeleton and developmental regulatory system). These genes were predicted as molecular determinants that mediate CA tumor cellular responses. The top affected biofunctions included cellular development, cellular proliferation and cellular death and survival. The effect of CA-mediated apoptosis in leukemia cells, which were recognized as the most sensitive tumor type, was confirmed via flow cytometry and western blot analysis. CONCLUSION: CA may provide a novel treatment option to target refractory tumors and to effectively cooperate with established chemotherapy. Using pharmacogenomic approaches and network pharmacology, the relationship between cancer complexity and multi-target potentials of CA was analyzed and many putative molecular determinants were identified. They could serve as novel targets for CA and further studies are needed to translate the possible implications to clinical cancer treatment.
Date of acceptance
2020
Autoren
  • Nuha Mahmoud
  • Mohamed EM Saeed
  • Yoshikazu Sugimoto
  • Anette Klinger
  • Edmond Fleischer
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/32659679
DOI
10.1016/j.phymed.2020.153271
eISSN
1618-095X
Zeitschrift
Phytomedicine
Schlüsselwörter
  • Chemotherapy
  • Fak
  • Lamiaceae
  • Multidrug resistance
  • Network pharmacology
  • Phytochemicals
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Abietanes
  • Antineoplastic Agents, Phytogenic
  • Cell Line, Tumor
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • ErbB Receptors
  • Humans
  • Neoplasm Proteins
  • Pharmacogenetics
  • Tumor Suppressor Protein p53
Sprache
eng
Country
Germany
Paginierung
153271
PII
S0944-7113(20)30102-1
Datum der Veröffentlichung
2020
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
Putative molecular determinants mediating sensitivity or resistance towards carnosic acid tumor cell responses.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
77

Data source: PubMed

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