Fas/CD95-mediated apoptosis in human glioblastoma cells

A target for sensitisation to topoisomerase I inhibitors

Emilio Ciusani, Paola Perego, Nives Carenini, Elisabetta Corna, Federica Facchinetti, Amerigo Boiardi, Andrea Salmaggi, Franco Zunino

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The expression of the death receptor Fas/CD95 is cell type-specific and can be modulated by different cytotoxic treatments. In spite of a frequent expression of Fas/CD95 in high-grade gliomas, these tumours are typically refractory to conventional therapy. Using a human glioblastoma cell line (GBM), we explored the possibility of modulating susceptibility to Fas/CD95-mediated apoptosis following cytotoxic treatment. GBM cells were sensitive to the antiproliferative effects of topoisomerase I inhibitors (topotecan and a novel lipophilic analog CPT83) and taxol, less sensitive to cisplatin and, in any case, rather resistant to drug-induced apoptosis. This pattern of cellular response was consistent with p53 mutation. GBM cells expressed low levels of Fas/CD95, which was associated with low susceptibility to antibody-stimulated Fas/CD95-mediated apoptosis. A significant up-regulation of Fas/CD95 expression was detected after exposure to topotecan and CPT83, whereas cisplatin induced a low increase and taxol did not modify Fas/CD95 expression. In addition, after treatment with topoisomerase I inhibitors, the up-regulation of Fas/CD95 resulted in an increased susceptibility of GBM cells to antibody-stimulated Fas/CD95-mediated apoptosis, while no synergistic effects were detected after treatment with cisplatin or taxol. Our data suggest that Fas/CD95 up-regulation can be a common response to DNA damage, whereas sensitisation to Fas/CD95-mediated apoptosis appears to be dependent on the type of DNA damage and on the pathway of cellular response. The observed effects might have important therapeutic implications for the design of novel therapeutic strategies in the treatment of malignant gliomas.

Original languageEnglish
Pages (from-to)881-887
Number of pages7
JournalBiochemical Pharmacology
Volume63
Issue number5
DOIs
Publication statusPublished - Mar 1 2002

Fingerprint

Topoisomerase I Inhibitors
Glioblastoma
Apoptosis
Paclitaxel
Cisplatin
Topotecan
Up-Regulation
Glioma
DNA Damage
Death Domain Receptors
Antibodies
DNA
Refractory materials
Tumors
Therapeutics
Cells
Cell Line
Mutation
Pharmaceutical Preparations
Neoplasms

Keywords

  • Apoptosis
  • DNA damaging agents
  • Fas/CD95
  • Human glioblastoma
  • Taxol
  • Topoisomerase I inhibitors

ASJC Scopus subject areas

  • Pharmacology

Cite this

Fas/CD95-mediated apoptosis in human glioblastoma cells : A target for sensitisation to topoisomerase I inhibitors. / Ciusani, Emilio; Perego, Paola; Carenini, Nives; Corna, Elisabetta; Facchinetti, Federica; Boiardi, Amerigo; Salmaggi, Andrea; Zunino, Franco.

In: Biochemical Pharmacology, Vol. 63, No. 5, 01.03.2002, p. 881-887.

Research output: Contribution to journalArticle

Ciusani, Emilio ; Perego, Paola ; Carenini, Nives ; Corna, Elisabetta ; Facchinetti, Federica ; Boiardi, Amerigo ; Salmaggi, Andrea ; Zunino, Franco. / Fas/CD95-mediated apoptosis in human glioblastoma cells : A target for sensitisation to topoisomerase I inhibitors. In: Biochemical Pharmacology. 2002 ; Vol. 63, No. 5. pp. 881-887.
@article{ea552bc7188145b99ac237b6a0c9e77a,
title = "Fas/CD95-mediated apoptosis in human glioblastoma cells: A target for sensitisation to topoisomerase I inhibitors",
abstract = "The expression of the death receptor Fas/CD95 is cell type-specific and can be modulated by different cytotoxic treatments. In spite of a frequent expression of Fas/CD95 in high-grade gliomas, these tumours are typically refractory to conventional therapy. Using a human glioblastoma cell line (GBM), we explored the possibility of modulating susceptibility to Fas/CD95-mediated apoptosis following cytotoxic treatment. GBM cells were sensitive to the antiproliferative effects of topoisomerase I inhibitors (topotecan and a novel lipophilic analog CPT83) and taxol, less sensitive to cisplatin and, in any case, rather resistant to drug-induced apoptosis. This pattern of cellular response was consistent with p53 mutation. GBM cells expressed low levels of Fas/CD95, which was associated with low susceptibility to antibody-stimulated Fas/CD95-mediated apoptosis. A significant up-regulation of Fas/CD95 expression was detected after exposure to topotecan and CPT83, whereas cisplatin induced a low increase and taxol did not modify Fas/CD95 expression. In addition, after treatment with topoisomerase I inhibitors, the up-regulation of Fas/CD95 resulted in an increased susceptibility of GBM cells to antibody-stimulated Fas/CD95-mediated apoptosis, while no synergistic effects were detected after treatment with cisplatin or taxol. Our data suggest that Fas/CD95 up-regulation can be a common response to DNA damage, whereas sensitisation to Fas/CD95-mediated apoptosis appears to be dependent on the type of DNA damage and on the pathway of cellular response. The observed effects might have important therapeutic implications for the design of novel therapeutic strategies in the treatment of malignant gliomas.",
keywords = "Apoptosis, DNA damaging agents, Fas/CD95, Human glioblastoma, Taxol, Topoisomerase I inhibitors",
author = "Emilio Ciusani and Paola Perego and Nives Carenini and Elisabetta Corna and Federica Facchinetti and Amerigo Boiardi and Andrea Salmaggi and Franco Zunino",
year = "2002",
month = "3",
day = "1",
doi = "10.1016/S0006-2952(01)00837-1",
language = "English",
volume = "63",
pages = "881--887",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - Fas/CD95-mediated apoptosis in human glioblastoma cells

T2 - A target for sensitisation to topoisomerase I inhibitors

AU - Ciusani, Emilio

AU - Perego, Paola

AU - Carenini, Nives

AU - Corna, Elisabetta

AU - Facchinetti, Federica

AU - Boiardi, Amerigo

AU - Salmaggi, Andrea

AU - Zunino, Franco

PY - 2002/3/1

Y1 - 2002/3/1

N2 - The expression of the death receptor Fas/CD95 is cell type-specific and can be modulated by different cytotoxic treatments. In spite of a frequent expression of Fas/CD95 in high-grade gliomas, these tumours are typically refractory to conventional therapy. Using a human glioblastoma cell line (GBM), we explored the possibility of modulating susceptibility to Fas/CD95-mediated apoptosis following cytotoxic treatment. GBM cells were sensitive to the antiproliferative effects of topoisomerase I inhibitors (topotecan and a novel lipophilic analog CPT83) and taxol, less sensitive to cisplatin and, in any case, rather resistant to drug-induced apoptosis. This pattern of cellular response was consistent with p53 mutation. GBM cells expressed low levels of Fas/CD95, which was associated with low susceptibility to antibody-stimulated Fas/CD95-mediated apoptosis. A significant up-regulation of Fas/CD95 expression was detected after exposure to topotecan and CPT83, whereas cisplatin induced a low increase and taxol did not modify Fas/CD95 expression. In addition, after treatment with topoisomerase I inhibitors, the up-regulation of Fas/CD95 resulted in an increased susceptibility of GBM cells to antibody-stimulated Fas/CD95-mediated apoptosis, while no synergistic effects were detected after treatment with cisplatin or taxol. Our data suggest that Fas/CD95 up-regulation can be a common response to DNA damage, whereas sensitisation to Fas/CD95-mediated apoptosis appears to be dependent on the type of DNA damage and on the pathway of cellular response. The observed effects might have important therapeutic implications for the design of novel therapeutic strategies in the treatment of malignant gliomas.

AB - The expression of the death receptor Fas/CD95 is cell type-specific and can be modulated by different cytotoxic treatments. In spite of a frequent expression of Fas/CD95 in high-grade gliomas, these tumours are typically refractory to conventional therapy. Using a human glioblastoma cell line (GBM), we explored the possibility of modulating susceptibility to Fas/CD95-mediated apoptosis following cytotoxic treatment. GBM cells were sensitive to the antiproliferative effects of topoisomerase I inhibitors (topotecan and a novel lipophilic analog CPT83) and taxol, less sensitive to cisplatin and, in any case, rather resistant to drug-induced apoptosis. This pattern of cellular response was consistent with p53 mutation. GBM cells expressed low levels of Fas/CD95, which was associated with low susceptibility to antibody-stimulated Fas/CD95-mediated apoptosis. A significant up-regulation of Fas/CD95 expression was detected after exposure to topotecan and CPT83, whereas cisplatin induced a low increase and taxol did not modify Fas/CD95 expression. In addition, after treatment with topoisomerase I inhibitors, the up-regulation of Fas/CD95 resulted in an increased susceptibility of GBM cells to antibody-stimulated Fas/CD95-mediated apoptosis, while no synergistic effects were detected after treatment with cisplatin or taxol. Our data suggest that Fas/CD95 up-regulation can be a common response to DNA damage, whereas sensitisation to Fas/CD95-mediated apoptosis appears to be dependent on the type of DNA damage and on the pathway of cellular response. The observed effects might have important therapeutic implications for the design of novel therapeutic strategies in the treatment of malignant gliomas.

KW - Apoptosis

KW - DNA damaging agents

KW - Fas/CD95

KW - Human glioblastoma

KW - Taxol

KW - Topoisomerase I inhibitors

UR - http://www.scopus.com/inward/record.url?scp=0036496550&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036496550&partnerID=8YFLogxK

U2 - 10.1016/S0006-2952(01)00837-1

DO - 10.1016/S0006-2952(01)00837-1

M3 - Article

VL - 63

SP - 881

EP - 887

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 5

ER -