Identification of cellular and molecular factors determining the response of cancer cells to six ergot alkaloids
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Marco Mrusek
- Ean-Jeong Seo
- Henry Johannes Greten
- Michael Simon
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000347949400004&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1007/s10637-014-0168-4
- eISSN
- 1573-0646
- Externe Identifier
- Clarivate Analytics Document Solution ID: AZ0QI
- PubMed Identifier: 25342140
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- INVESTIGATIONAL NEW DRUGS
- Schlüsselwörter
- Alkaloids
- Cancer
- Claviceps purpurea
- Clavicipitaceae
- Microarrays
- Pharmacogenomics
- Paginierung
- 32 - 44
- Datum der Veröffentlichung
- 2015
- Status
- Published
- Titel
- Identification of cellular and molecular factors determining the response of cancer cells to six ergot alkaloids
- Sub types
- Article
- Ausgabe der Zeitschrift
- 33
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Marco Mrusek
- Ean-Jeong Seo
- Henry Johannes Greten
- Michael Simon
- Thomas Efferth
- DOI
- 10.1007/s10637-014-0168-4
- eISSN
- 1573-0646
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Investigational New Drugs
- Sprache
- en
- Online publication date
- 2014
- Paginierung
- 32 - 44
- Datum der Veröffentlichung
- 2015
- Status
- Published
- Herausgeber
- Springer Science and Business Media LLC
- Herausgeber URL
- http://dx.doi.org/10.1007/s10637-014-0168-4
- Datum der Datenerfassung
- 2023
- Titel
- Identification of cellular and molecular factors determining the response of cancer cells to six ergot alkaloids
- Ausgabe der Zeitschrift
- 33
Data source: Crossref
- Abstract
- Ergot alkaloids are psychoactive and vasoconstricting agents of the fungus Claviceps purpurea causing poisoning such as ergotism in medieval times (St. Anthony's Fire). This class of substances also inhibits tumor growth in vitro and in vivo, though the underlying mechanisms are unclear as yet. We investigated six ergot alkaloids (agroclavine, ergosterol, ergocornin E, ergotamine, dihydroergocristine, and 1-propylagroclavine tartrate) for their cytotoxicity towards tumor cell lines of the National Cancer Institute, USA. 1-Propylagroclavine tartrate (1-PAT) revealed the strongest cytotoxicity. Out of 76 clinically established anticancer drugs, cross-resistance was found between the ergot alkaloids and 6/7 anti-hormonal drugs (=85.7 %) and 5/15 DNA-alkylating drugs (=33.3 %). The IC50 values for the six alkaloids were not correlated to well-known determinants of drug resistance, such as proliferative activity (as measured by cell doubling times, PCNA expression, and cell cycle distribution), the multidrug resistance-mediating P-glycoprotein/MDR1 and expression or mutations of oncogenes and tumor suppressor genes (EGFR, RAS, TP53). While resistance of control drugs (daunorubicin, cisplatin, erlotinib) correlated with these classical resistance mechanisms, ergot alkaloids did not. Furthermore, COMPARE and hierarchical cluster analyses were performed of mRNA microarray data to identify genes correlating with sensitivity or resistance to 1-PAT. Twenty-three genes were found with different biological functions (signal transducers, RNA metabolism, ribosome constituents, cell cycle and apoptosis regulators etc.). The expression of only 3/66 neuroreceptor genes correlated with the IC50 values for 1-PAT, suggesting that the psychoactive effects of ergot alkaloids may not play a major role for the cytotoxic activity against cancer cells. In conclusion, the cytotoxicity of ergot alkaloids is not involved in classical mechanisms of drug resistance opening the possibility to bypass resistance and to treat otherwise drug-resistant and refractory tumors. The modes of action are multifactorial, which is a typical feature of many natural compounds.
- Addresses
- Institute of Cultural Anthropology, Johannes Gutenberg University, Mainz, Germany.
- Autoren
- Marco Mrusek
- Ean-Jeong Seo
- Henry Johannes Greten
- Michael Simon
- Thomas Efferth
- Thomas Efferth
- DOI
- 10.1007/s10637-014-0168-4
- eISSN
- 1573-0646
- Externe Identifier
- PubMed Identifier: 25342140
- Open access
- false
- ISSN
- 0167-6997
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Investigational new drugs
- Schlüsselwörter
- Cell Line, Tumor
- Humans
- Neoplasms
- Ergot Alkaloids
- RNA, Messenger
- Antineoplastic Agents
- Microarray Analysis
- Cell Survival
- Gene Expression Regulation, Neoplastic
- Drug Resistance, Neoplasm
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2014
- Paginierung
- 32 - 44
- Datum der Veröffentlichung
- 2015
- Status
- Published
- Datum der Datenerfassung
- 2014
- Titel
- Identification of cellular and molecular factors determining the response of cancer cells to six ergot alkaloids.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 33
Data source: Europe PubMed Central
- Abstract
- Ergot alkaloids are psychoactive and vasoconstricting agents of the fungus Claviceps purpurea causing poisoning such as ergotism in medieval times (St. Anthony's Fire). This class of substances also inhibits tumor growth in vitro and in vivo, though the underlying mechanisms are unclear as yet. We investigated six ergot alkaloids (agroclavine, ergosterol, ergocornin E, ergotamine, dihydroergocristine, and 1-propylagroclavine tartrate) for their cytotoxicity towards tumor cell lines of the National Cancer Institute, USA. 1-Propylagroclavine tartrate (1-PAT) revealed the strongest cytotoxicity. Out of 76 clinically established anticancer drugs, cross-resistance was found between the ergot alkaloids and 6/7 anti-hormonal drugs (=85.7 %) and 5/15 DNA-alkylating drugs (=33.3 %). The IC50 values for the six alkaloids were not correlated to well-known determinants of drug resistance, such as proliferative activity (as measured by cell doubling times, PCNA expression, and cell cycle distribution), the multidrug resistance-mediating P-glycoprotein/MDR1 and expression or mutations of oncogenes and tumor suppressor genes (EGFR, RAS, TP53). While resistance of control drugs (daunorubicin, cisplatin, erlotinib) correlated with these classical resistance mechanisms, ergot alkaloids did not. Furthermore, COMPARE and hierarchical cluster analyses were performed of mRNA microarray data to identify genes correlating with sensitivity or resistance to 1-PAT. Twenty-three genes were found with different biological functions (signal transducers, RNA metabolism, ribosome constituents, cell cycle and apoptosis regulators etc.). The expression of only 3/66 neuroreceptor genes correlated with the IC50 values for 1-PAT, suggesting that the psychoactive effects of ergot alkaloids may not play a major role for the cytotoxic activity against cancer cells. In conclusion, the cytotoxicity of ergot alkaloids is not involved in classical mechanisms of drug resistance opening the possibility to bypass resistance and to treat otherwise drug-resistant and refractory tumors. The modes of action are multifactorial, which is a typical feature of many natural compounds.
- Date of acceptance
- 2014
- Autoren
- Marco Mrusek
- Ean-Jeong Seo
- Henry Johannes Greten
- Michael Simon
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/25342140
- DOI
- 10.1007/s10637-014-0168-4
- eISSN
- 1573-0646
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Invest New Drugs
- Schlüsselwörter
- Antineoplastic Agents
- Cell Line, Tumor
- Cell Survival
- Drug Resistance, Neoplasm
- Ergot Alkaloids
- Gene Expression Regulation, Neoplastic
- Humans
- Microarray Analysis
- Neoplasms
- RNA, Messenger
- Sprache
- eng
- Country
- United States
- Paginierung
- 32 - 44
- Datum der Veröffentlichung
- 2015
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2015
- Titel
- Identification of cellular and molecular factors determining the response of cancer cells to six ergot alkaloids.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 33
Data source: PubMed
- Beziehungen:
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