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

• Published in: Clinical cancer research 2004-02, Vol.10 (4), p.1463-1470
• Main Authors: BALLESTRERO, Alberto, NENCIONI, Alessio, BOY, Davide, ROCCO, Ilaria, GARUTI, Anna, SANDRO MELA, Giuseppe, VAN PARIJS, Luk, BROSSART, Peter, WESSELBORG, Sebastian, PATRONE, Franco
• Format: Article
• Language: English
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis Regulatory Proteins; bcl-X Protein; Biological and medical sciences; Caspase 3; Caspase 8; Caspases - metabolism; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; Enzyme Activation; Etoposide - pharmacology; Flow Cytometry; Humans; Immunoblotting; Jurkat Cells; Ligands; Lymphoma - metabolism; Medical sciences; Membrane Glycoproteins - metabolism; Membrane Potentials; Organoplatinum Compounds - pharmacology; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-bcl-2 - metabolism; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha - metabolism; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-1365-02

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-x L 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-x L 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 DiOC 6 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-x L 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.