A model of sensitivity and resistance to histone deacetylase inhibitors in diffuse large B cell lymphoma
| العنوان: | A model of sensitivity and resistance to histone deacetylase inhibitors in diffuse large B cell lymphoma |
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| المؤلفون: | Lisa M. Rimsza, Betty Glinsmann-Gibson, Catharine L. Smith, Samantha R Doctor, Aaron P. Havas, Ana A. Tula-Sanchez, William Pinkston, Peter J Alonge, Mary E. Klein |
| المصدر: | Cancer Biology & Therapy. 14:949-961 |
| بيانات النشر: | Informa UK Limited, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Pharmacology, Cancer Research, Cyclin E, biology, Cell growth, medicine.drug_class, Cyclin-dependent kinase 2, Histone deacetylase inhibitor, Retinoblastoma protein, Cell cycle, medicine.disease, 3. Good health, Oncology, immune system diseases, hemic and lymphatic diseases, medicine, Cancer research, biology.protein, Molecular Medicine, Histone deacetylase, Diffuse large B-cell lymphoma |
| الوصف: | Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma. While the initial treatment strategy is highly effective, relapse occurs in 40% of cases. Histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs but their single agent efficacy against relapsed DLBCL has been variable, ranging from few complete/partial responses to some stable disease. However, most patients showed no response to HDACi monotherapy for unknown reasons. Here we show that sensitivity and resistance to the hydroxamate HDACi, PXD101, can be modeled in DLBCL cell lines. Sensitivity is characterized by G 2/M arrest and apoptosis and resistance by reversible G 1 growth arrest. These responses to PXD101 are independent of several negative prognostic indicators such as DLBCL subtype, BCL2 and MYC co-expression, and p53 mutation, suggesting that HDACi might be used effectively against highly aggressive DLBCL tumors if they are combined with other therapeutics that overcome HDACi resistance. Our investigation of mechanisms underlying HDACi resistance showed that cyclin-dependent kinase inhibitors (CKIs), p21 and p27, are upregulated by PXD101 in a sustained fashion in resistant cell lines concomitant with decreased activity of the cyclin E/cdk2 complex and decreased Rb phosphorylation. PXD101 treatment results in increased association of CKI with the cyclin E/cdk2 complex in resistant cell lines but not in a sensitive line, indicating that the CKIs play a key role in G 1 arrest. The results suggest several treatment strategies that might increase the efficacy of HDACi against aggressive DLBCL. |
| تدمد: | 1555-8576 1538-4047 |
| DOI: | 10.4161/cbt.25941 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::49b308056d06daf9cd7c842e684fd4d6 https://doi.org/10.4161/cbt.25941 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi...........49b308056d06daf9cd7c842e684fd4d6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15558576 15384047 |
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| DOI: | 10.4161/cbt.25941 |