التفاصيل البيبلوغرافية
العنوان:
In vitro and in vivo interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib in non-Hodgkin lymphoma cells
المؤلفون:
Hiral Patel , Johnathan Friedberg , Simon S. Jones , Steven N. Quayle , Girija Dasmahapatra , Steven Grant
المصدر:
Molecular cancer therapeutics . 13(12)
سنة النشر:
2014
مصطلحات موضوعية:
Cancer Research , Programmed cell death , Cell cycle checkpoint , DNA damage , Apoptosis , Biology , Histone Deacetylase 6 , Hydroxamic Acids , Histone Deacetylases , Article , chemistry.chemical_compound , immune system diseases , hemic and lymphatic diseases , Cell Line, Tumor , medicine , Animals , Humans , Drug Interactions , RNA, Small Interfering , Lymphoma, Non-Hodgkin , Drug Synergism , Cell Cycle Checkpoints , medicine.disease , Carfilzomib , Xenograft Model Antitumor Assays , Lymphoma , Tumor Burden , DNA-Binding Proteins , Histone Deacetylase Inhibitors , Disease Models, Animal , Oxidative Stress , DNA Repair Enzymes , Pyrimidines , Oncology , chemistry , Gene Knockdown Techniques , Immunology , Proteasome inhibitor , Cancer research , Mantle cell lymphoma , Female , Reactive Oxygen Species , Oligopeptides , Proteasome Inhibitors , medicine.drug , Signal Transduction
الوصف:
Interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib were examined in non-Hodgkin lymphoma (NHL) models, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and double-hit lymphoma cells. Marked in vitro synergism was observed in multiple cell types associated with activation of cellular stress pathways (e.g., JNK1/2, ERK1/2, and p38) accompanied by increases in DNA damage (γH2A.X), G2–M arrest, and the pronounced induction of mitochondrial injury and apoptosis. Combination treatment with carfilzomib and ricolinostat increased reactive oxygen species (ROS), whereas the antioxidant TBAP attenuated DNA damage, JNK activation, and cell death. Similar interactions occurred in bortezomib-resistant and double-hit DLBCL, MCL, and primary DLBCL cells, but not in normal CD34+ cells. However, ricolinostat did not potentiate inhibition of chymotryptic activity by carfilzomib. shRNA knockdown of JNK1 (but not MEK1/2), or pharmacologic inhibition of p38, significantly reduced carfilzomib–ricolinostat lethality, indicating a functional contribution of these stress pathways to apoptosis. Combined exposure to carfilzomib and ricolinostat also markedly downregulated the cargo-loading protein HR23B. Moreover, HR23B knockdown significantly increased carfilzomib- and ricolinostat-mediated lethality, suggesting a role for this event in cell death. Finally, combined in vivo treatment with carfilzomib and ricolinostat was well tolerated and significantly suppressed tumor growth and increased survival in an MCL xenograft model. Collectively, these findings indicate that carfilzomib and ricolinostat interact synergistically in NHL cells through multiple stress-related mechanisms, and suggest that this strategy warrants further consideration in NHL. Mol Cancer Ther; 13(12); 2886–97. ©2014 AACR.
تدمد:
1538-8514
الوصول الحر:
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f8c435023b69a37098187b5728036d0Test https://pubmed.ncbi.nlm.nih.gov/31160511Test
حقوق:
OPEN
رقم الانضمام:
edsair.doi.dedup.....0f8c435023b69a37098187b5728036d0
قاعدة البيانات:
OpenAIRE
