Molecular determinants of cancer cell sensitivity and resistance towards the sesquiterpene farnesol

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000334260300022&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1691/ph.2013.6503
Externe Identifier
  • Clarivate Analytics Document Solution ID: AE8OD
  • PubMed Identifier: 23923645
ISSN
0031-7144
Ausgabe der Veröffentlichung
7
Zeitschrift
PHARMAZIE
Paginierung
608 - 615
Datum der Veröffentlichung
2013
Status
Published
Titel
Molecular determinants of cancer cell sensitivity and resistance towards the sesquiterpene farnesol
Sub types
  • Article
Ausgabe der Zeitschrift
68

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Abstract
Farnesol is a non-cyclic sesquiterpene (isoprenoid) found in the essential oils of many plants. In cancer biology, farnesylation of mutated Ras oncoproteins allows the proteins to dock to the membrane and be functionalized. Therefore, farnesyltransferase is a target for drug development to inhibit Ras. Farnesol exhibits cytotoxic activity against tumor cells in vitro and in vivo, implying that novel treatment strategies may be devised independent of Ras farnesylation. Tumors frequently develop resistance towards standard chemotherapies, and thus novel agents are urgently required that bypass the cross-resistance evoked by established anticancer drugs. We investigated whether classical mechanisms of drug resistance such as ATP-binding cassette transporters (P-glycoprotein/MDR1, MRP1, BCRP), the tumor suppressor gene TP53, and the oncogene EGFR play a role in the response of tumor cells to farnesol. Remarkably, none of these genes conferred resistance to farnesol, indicating that this compound may be useful for the treatment of otherwise drug-resistant and refractory tumors expressing these mechanisms of resistance. Furthermore, we applied a pharmacogenomic approach to explore molecular determinants of sensitivity and resistance to farnesol. Among the candidates were genes involved in apoptosis (STAB2, NUMBL), regulation of transcription (CDYL, FOXA2) and diverse other functional groups (INE1, CTRL, MRS2, NEB, LMO7, C9orf3, EHBP1). The fact that these genes are not associated with resistance to traditional anticancer drugs suggests farnesol may possess a novel mechanism of action, and consequently might bypass drug resistance to established chemotherapeutics.
Addresses
  • Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
Autoren
Externe Identifier
  • PubMed Identifier: 23923645
Open access
false
ISSN
0031-7144
Ausgabe der Veröffentlichung
7
Zeitschrift
Die Pharmazie
Schlüsselwörter
  • Cell Line, Tumor
  • HL-60 Cells
  • Humans
  • Neoplasms
  • Farnesol
  • Oxazines
  • Xanthenes
  • Doxorubicin
  • ATP-Binding Cassette Transporters
  • RNA, Messenger
  • Antibiotics, Antineoplastic
  • Microarray Analysis
  • Cluster Analysis
  • Transfection
  • Cell Division
  • Drug Resistance, Neoplasm
  • Genes, p53
  • Genes, erbB-1
Sprache
eng
Medium
Print
Paginierung
608 - 615
Datum der Veröffentlichung
2013
Status
Published
Datum der Datenerfassung
2013
Titel
Molecular determinants of cancer cell sensitivity and resistance towards the sesquiterpene farnesol.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
68

Datenquelle: Europe PubMed Central

Abstract
Farnesol is a non-cyclic sesquiterpene (isoprenoid) found in the essential oils of many plants. In cancer biology, farnesylation of mutated Ras oncoproteins allows the proteins to dock to the membrane and be functionalized. Therefore, farnesyltransferase is a target for drug development to inhibit Ras. Farnesol exhibits cytotoxic activity against tumor cells in vitro and in vivo, implying that novel treatment strategies may be devised independent of Ras farnesylation. Tumors frequently develop resistance towards standard chemotherapies, and thus novel agents are urgently required that bypass the cross-resistance evoked by established anticancer drugs. We investigated whether classical mechanisms of drug resistance such as ATP-binding cassette transporters (P-glycoprotein/MDR1, MRP1, BCRP), the tumor suppressor gene TP53, and the oncogene EGFR play a role in the response of tumor cells to farnesol. Remarkably, none of these genes conferred resistance to farnesol, indicating that this compound may be useful for the treatment of otherwise drug-resistant and refractory tumors expressing these mechanisms of resistance. Furthermore, we applied a pharmacogenomic approach to explore molecular determinants of sensitivity and resistance to farnesol. Among the candidates were genes involved in apoptosis (STAB2, NUMBL), regulation of transcription (CDYL, FOXA2) and diverse other functional groups (INE1, CTRL, MRS2, NEB, LMO7, C9orf3, EHBP1). The fact that these genes are not associated with resistance to traditional anticancer drugs suggests farnesol may possess a novel mechanism of action, and consequently might bypass drug resistance to established chemotherapeutics.
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/23923645
ISSN
0031-7144
Ausgabe der Veröffentlichung
7
Zeitschrift
Pharmazie
Schlüsselwörter
  • ATP-Binding Cassette Transporters
  • Antibiotics, Antineoplastic
  • Cell Division
  • Cell Line, Tumor
  • Cluster Analysis
  • Doxorubicin
  • Drug Resistance, Neoplasm
  • Farnesol
  • Genes, erbB-1
  • Genes, p53
  • HL-60 Cells
  • Humans
  • Microarray Analysis
  • Neoplasms
  • Oxazines
  • RNA, Messenger
  • Transfection
  • Xanthenes
Sprache
eng
Country
Germany
Paginierung
608 - 615
Datum der Veröffentlichung
2013
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2013
Titel
Molecular determinants of cancer cell sensitivity and resistance towards the sesquiterpene farnesol.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
68

Datenquelle: PubMed

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