| Pentoxifylline augments TRAIL/Apo2L mediated apoptosis in cutaneous T cell lymphoma (HuT-78 and MyLa) by modulating the expression of antiapoptotic proteins and death receptors. | |
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MedLine Citation:
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PMID: 20804743 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising anticancer agent but cutaneous T lymphoma cells (CTCL) are less sensitive to TRAIL-induced apoptosis. Here, we report that pentoxifylline (PTX), a phosphodiesterase inhibitor, augments TRAIL-mediated apoptosis in HuT-78 and MyLa cells through modulating extrinsic death receptors and intrinsic mitochondria dependent pathways. Our results clearly show that PTX augments TRAIL-mediated activation of caspase-8 and induces cleavage of Bid, although PTX alone cannot activate caspase-8. This is followed by cytochrome c release and subsequent, activation of caspase-9 and caspase-3 and cleavage of poly (ADP ribose) polymerase (PARP). Combined treatment downregulates the expression of various antiapoptotic proteins including c-FLIP, Bcl-xl, cIAP-1, cIAP-2 and XIAP. PTX induces the expression of death receptors DR4 and DR5 on cell surface of both the cell types where c-Jun NH2-terminal kinase (JNK) pathway plays an important role. Moreover, combined silencing of DR4 and DR5 by small interfering RNA abrogates the ability of PTX to induce TRAIL-mediated apoptosis. Thus, this is the first demonstration that PTX can potentiate TRAIL-mediated apoptosis through downregulation of cell survival gene products and upregulation of death receptors. |
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Authors:
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Satindra Gahlot; Mohammad Aslam Khan; Loveena Rishi; Sekhar Majumdar |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-08 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 80 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-10-18 Completed Date: 2010-11-05 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1650-61 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adjuvants, Pharmaceutic
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pharmacology* Apoptosis / drug effects, physiology* Apoptosis Regulatory Proteins / biosynthesis*, physiology Cell Line, Tumor Drug Synergism Gene Expression Regulation, Neoplastic / drug effects*, physiology Humans Lymphoma, T-Cell, Cutaneous / metabolism, pathology* Pentoxifylline / pharmacology* Receptors, Death Domain / biosynthesis*, physiology TNF-Related Apoptosis-Inducing Ligand / physiology* |
| Chemical | |
Reg. No./Substance:
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0/Adjuvants, Pharmaceutic; 0/Apoptosis Regulatory Proteins; 0/Receptors, Death Domain; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; 6493-05-6/Pentoxifylline |
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