Sanguinarine-Dependent Induction of Apoptosis in Primary Effusion Lymphoma Cells
| Autor: | Pulicat S. Manogaran, Khalid Al-Hussein, Azhar R. Hussain, Khawla S. Al-Kuraya, Leonidas C. Platanias, Jehad Abubaker, Shahab Uddin, Abdul K. Siraj, Naif A. Al-Jomah |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Programmed cell death Lymphoma B-Cell Poly ADP ribose polymerase Molecular Conformation Apoptosis Cell Growth Processes Collagen Type XI Inhibitor of apoptosis chemistry.chemical_compound Alkaloids Bcl-2-associated X protein Cell Line Tumor Humans Sanguinarine Caspase bcl-2-Associated X Protein Benzophenanthridines Membrane Potential Mitochondrial Dose-Response Relationship Drug biology Cytochrome c Cytochromes c Exudates and Transudates Isoquinolines Virology Mitochondria Up-Regulation Enzyme Activation Isoenzymes Receptors TNF-Related Apoptosis-Inducing Ligand Oncology chemistry Caspases biology.protein Cancer research Reactive Oxygen Species BH3 Interacting Domain Death Agonist Protein Signal Transduction |
| Zdroj: | Cancer Research. 67:3888-3897 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-06-3764 |
| Popis: | Primary effusion lymphoma (PEL) is an incurable, aggressive B-cell malignancy that develops rapid resistance to conventional chemotherapy. In efforts to identify novel approaches to block proliferation of PEL cells, we found that sanguinarine, a natural compound isolated from the root plant Sanguinaria canadendid, inhibits cell proliferation and induces apoptosis in a dose-dependent manner in several PEL cell lines. Our data show that sanguinarine treatment of PEL cells results in up-regulation of death receptor 5 (DR5) expression via generation of reactive oxygen species (ROS) and causes activation of caspase-8 and truncation of Bid (tBid). Subsequently, tBid translocates to the mitochondria causing conformational changes in Bax, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. Sanguinarine-induced release of cytochrome c results in activation of caspase-9 and caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, leading to induction of caspase-dependent apoptosis. In addition, we show that pretreatment of PEL cells with carbobenzoxy-Val-Ala-Asp-fluoromethylketone, a universal inhibitor of caspases, abrogates caspase and PARP activation and prevents cell death induced by sanguinarine. Moreover, treatment of PEL cells with sanguinarine down-regulates expression of inhibitor of apoptosis proteins (IAP). Finally, N-acetylcysteine, an inhibitor of ROS, inhibits sanguinarine-induced generation of ROS, up-regulation of DR5, Bax conformational changes, activation of caspase-3, and down-regulation of IAPs. Taken together, our findings suggest that sanguinarine is a potent inducer of apoptosis of PEL cells via up-regulation of DR5 and raise the possibility that this agent may be of value in the development of novel therapeutic approaches for the treatment of PEL. [Cancer Res 2007;67(8):3888–97] |
| Databáze: | OpenAIRE |
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