Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Cooperates with Anticancer Drugs to Overcome Chemoresistance in Antiapoptotic Bcl-2 Family Members Expressing Jurkat Cells

Alberto Ballestrero, Alessio Nencioni, Davide Boy, Ilaria Rocco, Anna Garuti, Giuseppe Sandro Mela, Luk Van Parijs, Peter Brossart, Sebastian Wesselborg, Franco Patrone

Research output: Contribution to journalArticle

Abstract

Purpose: Overexpression of antiapoptotic Bcl-2 family members has recently been related to resistance to chemo/radiotherapy in several human malignancies, particularly lymphomas. Hence, innovative approaches bypassing this resistance mechanism are required in the therapeutic approach. This study evaluated whether chemoresistance associated with Bcl-2 and Bcl-xL overexpression would be overcome by activating the death receptor pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the Jurkat cell model Experimental Design: We made use of genetically modified Jurkat cells to evaluate the effect of Bcl-2 or Bcl-xL overexpression on the cytotoxic effect produced by the anticancer drugs doxorubicin, etoposide, and oxaliplatin and TRAIL. Caspase activation was detected by cleavage of caspase-8 and -3. The mitochondrial transmambrane potential was assessed by staining with DiOC6 and flow cytometry. Caspase activity was blocked by the broad-spectrum caspase inhibitor zVAD-fmk. Results: Bcl-2 and Bcl-x L overexpression but not lack of caspase-8 protects the Jurkat cells from the anticancer drug-induced cytolysis. However, Bcl-2/Bcl-xL Jurkat cells retained some susceptibility to TRAIL-induced cytolysis. A highly synergistic cytotoxic effect of the combination of TRAIL with any of the antiblastic used in this study was detected in the chemoresistant cells. This effect was associated with mitochondrial disassemblage and dependent on caspase activation Conclusions: The combination of TRAIL with conventional anticancer drugs may prove to be useful in the treatment of antiapoptotic Bcl-2 family proteins-expressing malignancies.

Original languageEnglish
Pages (from-to)1463-1470
Number of pages8
JournalClinical Cancer Research
Volume10
Issue number4
DOIs
Publication statusPublished - Feb 15 2004

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Jurkat Cells
Caspases
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
oxaliplatin
Caspase 8
Pharmaceutical Preparations
Death Domain Receptors
Caspase Inhibitors
Etoposide
Caspase 3
Doxorubicin
Lymphoma
Neoplasms
Flow Cytometry
Research Design
Radiotherapy
Staining and Labeling
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Cooperates with Anticancer Drugs to Overcome Chemoresistance in Antiapoptotic Bcl-2 Family Members Expressing Jurkat Cells. / Ballestrero, Alberto; Nencioni, Alessio; Boy, Davide; Rocco, Ilaria; Garuti, Anna; Mela, Giuseppe Sandro; Van Parijs, Luk; Brossart, Peter; Wesselborg, Sebastian; Patrone, Franco.

In: Clinical Cancer Research, Vol. 10, No. 4, 15.02.2004, p. 1463-1470.

Research output: Contribution to journalArticle

Ballestrero, Alberto ; Nencioni, Alessio ; Boy, Davide ; Rocco, Ilaria ; Garuti, Anna ; Mela, Giuseppe Sandro ; Van Parijs, Luk ; Brossart, Peter ; Wesselborg, Sebastian ; Patrone, Franco. / Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Cooperates with Anticancer Drugs to Overcome Chemoresistance in Antiapoptotic Bcl-2 Family Members Expressing Jurkat Cells. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 4. pp. 1463-1470.
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abstract = "Purpose: Overexpression of antiapoptotic Bcl-2 family members has recently been related to resistance to chemo/radiotherapy in several human malignancies, particularly lymphomas. Hence, innovative approaches bypassing this resistance mechanism are required in the therapeutic approach. This study evaluated whether chemoresistance associated with Bcl-2 and Bcl-xL overexpression would be overcome by activating the death receptor pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the Jurkat cell model Experimental Design: We made use of genetically modified Jurkat cells to evaluate the effect of Bcl-2 or Bcl-xL overexpression on the cytotoxic effect produced by the anticancer drugs doxorubicin, etoposide, and oxaliplatin and TRAIL. Caspase activation was detected by cleavage of caspase-8 and -3. The mitochondrial transmambrane potential was assessed by staining with DiOC6 and flow cytometry. Caspase activity was blocked by the broad-spectrum caspase inhibitor zVAD-fmk. Results: Bcl-2 and Bcl-x L overexpression but not lack of caspase-8 protects the Jurkat cells from the anticancer drug-induced cytolysis. However, Bcl-2/Bcl-xL Jurkat cells retained some susceptibility to TRAIL-induced cytolysis. A highly synergistic cytotoxic effect of the combination of TRAIL with any of the antiblastic used in this study was detected in the chemoresistant cells. This effect was associated with mitochondrial disassemblage and dependent on caspase activation Conclusions: The combination of TRAIL with conventional anticancer drugs may prove to be useful in the treatment of antiapoptotic Bcl-2 family proteins-expressing malignancies.",
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AU - Ballestrero, Alberto

AU - Nencioni, Alessio

AU - Boy, Davide

AU - Rocco, Ilaria

AU - Garuti, Anna

AU - Mela, Giuseppe Sandro

AU - Van Parijs, Luk

AU - Brossart, Peter

AU - Wesselborg, Sebastian

AU - Patrone, Franco

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AB - Purpose: Overexpression of antiapoptotic Bcl-2 family members has recently been related to resistance to chemo/radiotherapy in several human malignancies, particularly lymphomas. Hence, innovative approaches bypassing this resistance mechanism are required in the therapeutic approach. This study evaluated whether chemoresistance associated with Bcl-2 and Bcl-xL overexpression would be overcome by activating the death receptor pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the Jurkat cell model Experimental Design: We made use of genetically modified Jurkat cells to evaluate the effect of Bcl-2 or Bcl-xL overexpression on the cytotoxic effect produced by the anticancer drugs doxorubicin, etoposide, and oxaliplatin and TRAIL. Caspase activation was detected by cleavage of caspase-8 and -3. The mitochondrial transmambrane potential was assessed by staining with DiOC6 and flow cytometry. Caspase activity was blocked by the broad-spectrum caspase inhibitor zVAD-fmk. Results: Bcl-2 and Bcl-x L overexpression but not lack of caspase-8 protects the Jurkat cells from the anticancer drug-induced cytolysis. However, Bcl-2/Bcl-xL Jurkat cells retained some susceptibility to TRAIL-induced cytolysis. A highly synergistic cytotoxic effect of the combination of TRAIL with any of the antiblastic used in this study was detected in the chemoresistant cells. This effect was associated with mitochondrial disassemblage and dependent on caspase activation Conclusions: The combination of TRAIL with conventional anticancer drugs may prove to be useful in the treatment of antiapoptotic Bcl-2 family proteins-expressing malignancies.

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