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2.
Blood ; 117(12): 3363-9, 2011 Mar 24.
Article in English | MEDLINE | ID: mdl-21212284

ABSTRACT

The human T-lymphotropic virus type I (HTLV-I) causes a chronic inflammatory disorder of the central nervous system termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-I encodes a protein known to activate several host-signaling pathways involved in inflammation, such as the nuclear factor-κB (NF-κB). The contribution of the NF-κB pathway to the pathogenesis of HAM/TSP, however, has not been fully defined. We show evidence of canonical NF-κB activation in short-term cultures of peripheral blood mononuclear cells (PBMCs) from subjects with HAM/TSP. NF-κB activation was closely linked to HTLV-I viral protein expression. The NF-κB activation in HAM/TSP PBMCs was reversed by a novel small-molecule inhibitor that demonstrates potent and selective NF-κB antagonist activity. Inhibition of NF-κB activation led to a reduction in the expression of lymphocyte activation markers and resulted in reduced cytokine signaling in HAM/TSP PBMCs. Furthermore, NF-κB inhibition led to a reduction in spontaneous lymphoproliferation, a key ex vivo correlate of the immune activation associated with HAM/TSP. These results indicate that NF-κB activation plays a critical upstream role in the immune activation of HAM/TSP, and identify the NF-κB pathway as a potential target for immunomodulation in HAM/TSP.


Subject(s)
Human T-lymphotropic virus 1/physiology , Immunologic Factors/pharmacology , Lymphocyte Activation/drug effects , NF-kappa B/antagonists & inhibitors , Paraparesis, Tropical Spastic/immunology , Benzamides/pharmacology , Cell Proliferation/drug effects , Cells, Cultured , Cyclohexanones/pharmacology , Drug Evaluation, Preclinical , HeLa Cells , Human T-lymphotropic virus 1/drug effects , Human T-lymphotropic virus 1/immunology , Humans , Immunologic Factors/therapeutic use , Immunotherapy/methods , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/physiology , NF-kappa B/metabolism , Paraparesis, Tropical Spastic/blood , Paraparesis, Tropical Spastic/drug therapy , Paraparesis, Tropical Spastic/pathology , Signal Transduction/drug effects , Signal Transduction/physiology , Viral Load/drug effects
3.
Cell Rep ; 11(1): 98-110, 2015 Apr 07.
Article in English | MEDLINE | ID: mdl-25843712

ABSTRACT

Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR mutant lung adenocarcinoma, we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses.


Subject(s)
Adenocarcinoma/genetics , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , Lung Neoplasms/genetics , NF-kappa B/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adenocarcinoma of Lung , Antineoplastic Agents/administration & dosage , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cyclohexanones/administration & dosage , Epoxy Compounds/administration & dosage , ErbB Receptors/antagonists & inhibitors , Gene Expression Regulation, Neoplastic/drug effects , Humans , I-kappa B Kinase/genetics , I-kappa B Kinase/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Molecular Targeted Therapy , NF-kappa B/antagonists & inhibitors , Nuclear Pore Complex Proteins/genetics , Nuclear Pore Complex Proteins/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Signal Transduction/drug effects , TNF Receptor-Associated Factor 2/genetics , TNF Receptor-Associated Factor 2/metabolism
5.
Clin Cancer Res ; 18(17): 4669-81, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22806876

ABSTRACT

PURPOSE: NF-κB transcription factor plays a key role in the pathogenesis of multiple myeloma in the context of the bone marrow microenvironment. Both canonical and noncanonical pathways contribute to total NF-κB activity. Recent studies have shown a critical role for the noncanonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the noncanonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity. EXPERIMENTAL DESIGN: Multiple myeloma cell lines, primary patient cells, and the human multiple myeloma xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and noncanonical NF-κB pathways. RESULTS: We show that PBS-1086 induces potent cytotoxicity in multiple myeloma cells but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and antiapoptotic effects of the bone marrow milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant multiple myeloma cell lines and patient multiple myeloma cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANK ligand (RANKL)-induced NF-κB activation. Finally, in a xenograft model of human multiple myeloma in the bone marrow milieu, PBS-1086 shows significant in vivo anti-multiple myeloma activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells. CONCLUSIONS: Our data show that PBS-1086 is a promising dual inhibitor of the canonical and noncanonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of multiple myeloma and related bone lesions.


Subject(s)
Cyclohexanones/administration & dosage , Epoxy Compounds/administration & dosage , Multiple Myeloma , NF-kappa B/antagonists & inhibitors , Signal Transduction/drug effects , Amino Acid Chloromethyl Ketones/administration & dosage , Animals , Apoptosis/drug effects , Boronic Acids/administration & dosage , Bortezomib , Cell Differentiation/drug effects , Cell Line, Tumor , Doxorubicin/administration & dosage , Humans , Leukocytes, Mononuclear/drug effects , Mice , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , NF-kappa B/metabolism , Osteoclasts/cytology , Osteoclasts/drug effects , Osteoclasts/metabolism , Pyrazines/administration & dosage , RANK Ligand/metabolism , Transplantation, Heterologous
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