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Start Over Descriptor "TRAIL/Apo-2L" Publisher elsevier
2 results on '"TRAIL/Apo-2L"'

1. Interactive Effects of HDAC Inhibitors and TRAIL on Apoptosis Are Associated with Changes in Mitochondrial Functions and Expressions of Cell Cycle Regulatory Genes in Multiple Myeloma

Author

Tamer E. Fandy, Sharmila Shankar, Douglas D. Ross, Edward Sausville, and Rakesh K. Srivastava

Subjects
TRAIL/Apo-2L, apoptosis, histone deacetylase inhibitor, multiple myeloma, death receptors, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

In this study, we have evaluated the cytotoxic effect of combining two HDAC inhibitors, SAHA and TSA, with TRAIL in human multiple myeloma cell lines. Low doses of SAHA or TSA enhanced the cytotoxic and apoptotic effects of TRAIL and upregulated the surface expression of TRAIL death receptors (DR4 and/or DR5). SAHA and TSA induced G1 phase cell cycle growth arrest by upregulating p21WAF1 and p27KiP1 expression and by inhibiting E2F transcriptional activity. The enhanced TRAIL effect after pretreatment with HDAC inhibitors was consistent with the upregulation of the proapoptotic Bcl-2 family members (Bim, Bak, Bax, Noxa, PUMA), the downregulation of the antiapoptotic members of the Bcl-2 family (Bcl-2 and Bcl-XL), IAPs. SAHA and TSA dissipated the mitochondrial membrane potential and enhanced the release of Omi/HtrA2 and AIF from the mitochondria to the cytosol. The cytotoxic effect of both SAHA and TSA was caspase- and calpain-independent. Inhibition of NFΚB activation by the proteasome inhibitor, MG132, enhanced the apoptotic effect of TSA. Our study demonstrated the enhancing effects of HDAC inhibitors on apoptosis when combined with TRAIL and, for the first time, emphasized the role of AIF in mediating the cytotoxic effects of HDAC inhibitors.

Published
2005
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2. Interactive Effects of HDAC Inhibitors and TRAIL on Apoptosis Are Associated with Changes in Mitochondrial Functions and Expressions of Cell Cycle Regulatory Genes in Multiple Myeloma

Author

Sharmila Shankar, Douglas D. Ross, Tamer E. Fandy, Edward A. Sausville, and Rakesh K. Srivastava

Subjects
Cancer Research, Time Factors, Leupeptins, Cell Cycle Proteins, Amino Acid Chloromethyl Ketones, Membrane Potentials, Histones, TNF-Related Apoptosis-Inducing Ligand, chemistry.chemical_compound, MG132, Annexin A5, Enzyme Inhibitors, Phosphorylation, Luciferases, Membrane Glycoproteins, Calpain, Cell Cycle, Histone deacetylase inhibitor, NF-kappa B, apoptosis, Cell cycle, Flow Cytometry, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Mitochondria, Up-Regulation, Cell biology, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, multiple myeloma, Caspases, Apoptosis-inducing factor, biological phenomena, cell phenomena, and immunity, Cyclin-Dependent Kinase Inhibitor p27, Propidium, Protein Binding, Subcellular Fractions, Research Article, medicine.drug, medicine.drug_class, Immunoblotting, Down-Regulation, Biology, lcsh:RC254-282, Inhibitory Concentration 50, Ribonucleases, Cell Line, Tumor, death receptors, medicine, Humans, neoplasms, histone deacetylase inhibitor, Cell Proliferation, Dose-Response Relationship, Drug, Tumor Necrosis Factor-alpha, Cell growth, Tumor Suppressor Proteins, G1 Phase, E2F Transcription Factors, Histone Deacetylase Inhibitors, Trichostatin A, Microscopy, Fluorescence, chemistry, Apoptosis, Proteasome inhibitor, TRAIL/Apo-2L, Apoptosis Regulatory Proteins, Transcription Factors
Abstract

In this study, we have evaluated the cytotoxic effect of combining two HDAC inhibitors, SAHA and TSA, with TRAIL in human multiple myeloma cell lines. Low doses of SAHA or TSA enhanced the cytotoxic and apoptotic effects of TRAIL and upregulated the surface expression of TRAIL death receptors (DR4 and/or DR5). SAHA and TSA induced G1 phase cell cycle growth arrest by upregulating p21(WAF1) and p27(Kip1) expression and by inhibiting E2F transcriptional activity. The enhanced TRAIL effect after pretreatment with HDAC inhibitors was consistent with the upregulation of the proapoptotic Bcl-2 family members (Bim, Bak, Bax, Noxa, and PUMA), the downregulation of the anti-apoptotic members of the Bcl-2 family (Bcl-2 and Bcl-X(L)), and IAPs. SAHA and TSA dissipated the mitochondrial membrane potential and enhanced the release of Omi/HtrA2 and AIF from the mitochondria to the cytosol. The cytotoxic effect of both SAHA and TSA was caspase- and calpain-independent. Inhibition of NF(kappa)B activation by the proteasome inhibitor, MG132, enhanced the apoptotic effect of TSA. Our study demonstrated the enhancing effects of HDAC inhibitors on apoptosis when combined with TRAIL and, for the first time, emphasized the role of AIF in mediating the cytotoxic effects of HDAC inhibitors.

Published
2005

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