Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines

Autoren

Thomas Efferth
Axel Sauerbrey
Marc-Eric Halatsch
Douglas D Ross
Erich Gebhart

DOI

10.1007/s00210-002-0632-0

ISSN

0028-1298

Ausgabe der Veröffentlichung

1

Zeitschrift

Naunyn-Schmiedeberg's Archives of Pharmacology

Sprache

en

Paginierung

56 - 67

Datum der Veröffentlichung

2003

Status

Published

Herausgeber

Springer Science and Business Media LLC

Herausgeber URL

http://dx.doi.org/10.1007/s00210-002-0632-0

Datum der Datenerfassung

2019

Titel

Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines

Ausgabe der Zeitschrift

367

Data source: Crossref

Abstract

Homoharringtonine (HHT) is an ester of cephalotaxine (CET), both of which derive from the Chinese coniferous tree Cephalotaxus hainanensis. HHT inhibited tumor cell growth at molar ranges comparable to established cytostatic drugs, whereas CET was 3-4 orders of magnitude less active. Inhibition concentration 50% (IC50) values of CET and HHT were significantly correlated to doxorubicin, vincristine, methotrexate, cisplatin, or camptothecin in 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute (NCI, Bethesda, Md., USA). We tested both drugs for resistance of cell lines which selectively overexpress the multidrug resistance (MDR)-conferring genes P-glycoprotein/ MDR1 (CEM/ADR5000), MDR-related protein 1 MRP1 (HL60/AR), and breast cancer resistance protein BCRP (MDA-MB-231-BCRP). A threefold and ninefold resistance to HHT and CET, respectively, was found in CEM/ADR5000 cells, while the other MDR cell lines did not show cross-resistance compared to their drug-sensitive counterparts. As the tumor suppressor p53 is another important factor of chemoresistance, we also analyzed the possibility that p53 affects the response of tumor cells to CET and HHT. Comparing the p53 mutational status of the 55 NCI cell lines (http://dtp.nci.nih.gov) with the IC50 values showed a significant correlation. Thus, CET and HHT were more active in cell lines without p53 mutation. We correlated the IC50 values of CET and HHT with the cell doubling times of the 55 NCI cell lines as proliferation parameter and observed that rapidly growing cells were more susceptible than slowly growing cell lines. We conducted a search mining the NCI's database for the mRNA expression of 465 genes in 55 cell lines and correlated the data with the IC50 values for CET and HHT. Of these genes 61 (=13%) correlated with the IC50 values for CET and 122 (=26%) with the IC50 values for HHT indicating the multifactorial mode of action of these drugs in cancer cells. We have chosen one example from these genes to test a causative role for drug response. U-87MG.DeltaEGFR cells transfected with an epidermal growth factor receptor ( EGFR) gene truncated in its extracellular domain through a deletion of exons 2-7 (Delta EGFR) were 14-fold more resistant to HHT than control cells transfected with mock expression vector or non-transfected cells. The present investigation presents a starting point to dissect the genes and molecular pathways involved in the tumor cells' response to CET and HHT in greater detail.

Addresses

Virtual Campus Rhineland-Palatinate, P.O. Box 4380, 55033 Mainz, Germany. efferth@vcrp.de

Autoren

Thomas Efferth
Thomas Efferth
Axel Sauerbrey
Marc-Eric Halatsch
Douglas D Ross
Erich Gebhart

DOI

10.1007/s00210-002-0632-0

eISSN

1432-1912

Externe Identifier

PubMed Identifier: 12616342

Funding acknowledgements

NCI NIH HHS: R01-CA77545

Open access

false

ISSN

0028-1298

Ausgabe der Veröffentlichung

1

Zeitschrift

Naunyn-Schmiedeberg's archives of pharmacology

Schlüsselwörter

HL-60 Cells
Jurkat Cells
Tumor Cells, Cultured
Humans
Cephalotaxus
Harringtonines
Receptors, Vascular Endothelial Growth Factor
Growth Inhibitors
Receptors, Mitogen
Receptors, Growth Factor
Drug Screening Assays, Antitumor
Cluster Analysis
Cell Division
Dose-Response Relationship, Drug
Genes, MDR
Tracheophyta
Homoharringtonine

Sprache

eng

Medium

Print-Electronic

Online publication date

2002

Paginierung

56 - 67

Datum der Veröffentlichung

2003

Status

Published

Datum der Datenerfassung

2003

Titel

Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines.

Sub types

Comparative Study
Research Support, U.S. Gov't, P.H.S.
Research Support, U.S. Gov't, Non-P.H.S.
Journal Article

Ausgabe der Zeitschrift

367

Data source: Europe PubMed Central

Abstract

Homoharringtonine (HHT) is an ester of cephalotaxine (CET), both of which derive from the Chinese coniferous tree Cephalotaxus hainanensis. HHT inhibited tumor cell growth at molar ranges comparable to established cytostatic drugs, whereas CET was 3-4 orders of magnitude less active. Inhibition concentration 50% (IC50) values of CET and HHT were significantly correlated to doxorubicin, vincristine, methotrexate, cisplatin, or camptothecin in 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute (NCI, Bethesda, Md., USA). We tested both drugs for resistance of cell lines which selectively overexpress the multidrug resistance (MDR)-conferring genes P-glycoprotein/ MDR1 (CEM/ADR5000), MDR-related protein 1 MRP1 (HL60/AR), and breast cancer resistance protein BCRP (MDA-MB-231-BCRP). A threefold and ninefold resistance to HHT and CET, respectively, was found in CEM/ADR5000 cells, while the other MDR cell lines did not show cross-resistance compared to their drug-sensitive counterparts. As the tumor suppressor p53 is another important factor of chemoresistance, we also analyzed the possibility that p53 affects the response of tumor cells to CET and HHT. Comparing the p53 mutational status of the 55 NCI cell lines (http://dtp.nci.nih.gov) with the IC50 values showed a significant correlation. Thus, CET and HHT were more active in cell lines without p53 mutation. We correlated the IC50 values of CET and HHT with the cell doubling times of the 55 NCI cell lines as proliferation parameter and observed that rapidly growing cells were more susceptible than slowly growing cell lines. We conducted a search mining the NCI's database for the mRNA expression of 465 genes in 55 cell lines and correlated the data with the IC50 values for CET and HHT. Of these genes 61 (=13%) correlated with the IC50 values for CET and 122 (=26%) with the IC50 values for HHT indicating the multifactorial mode of action of these drugs in cancer cells. We have chosen one example from these genes to test a causative role for drug response. U-87MG.DeltaEGFR cells transfected with an epidermal growth factor receptor ( EGFR) gene truncated in its extracellular domain through a deletion of exons 2-7 (Delta EGFR) were 14-fold more resistant to HHT than control cells transfected with mock expression vector or non-transfected cells. The present investigation presents a starting point to dissect the genes and molecular pathways involved in the tumor cells' response to CET and HHT in greater detail.

Date of acceptance

2002

Autoren

Thomas Efferth
Axel Sauerbrey
Marc-Eric Halatsch
Douglas D Ross
Erich Gebhart

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/12616342

DOI

10.1007/s00210-002-0632-0

Funding acknowledgements

NCI NIH HHS: R01-CA77545

ISSN

0028-1298

Ausgabe der Veröffentlichung

1

Zeitschrift

Naunyn Schmiedebergs Arch Pharmacol

Schlüsselwörter

Cell Division
Cephalotaxus
Cluster Analysis
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Genes, MDR
Growth Inhibitors
HL-60 Cells
Harringtonines
Homoharringtonine
Humans
Jurkat Cells
Receptors, Growth Factor
Receptors, Mitogen
Receptors, Vascular Endothelial Growth Factor
Tracheophyta
Tumor Cells, Cultured

Sprache

eng

Country

Germany

Paginierung

56 - 67

Datum der Veröffentlichung

2003

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2003

Titel

Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines.

Sub types

Comparative Study
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Ausgabe der Zeitschrift

367

Data source: PubMed

Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines

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