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KINK-1, a novel small-molecule inhibitor of IKKbeta, enhances susceptibility of melanoma cells to antitumoral treatment

ABSTRACT: Interference with chemoresistance to enhance the efficacy of chemotherapeutics may be of great utility for cancer therapy. We have identified KINK-1 (Kinase Inhibitor of NF-kappaB-1), a highly selective small-molecule IKKkappa inhibitor, as a potent suppressor of both constitutive and induced NF-kappaB activity in melanoma cells. While KINK-1 profoundly diminished various NF-kappaB-dependent gene products regulating proliferation, cytokine production or anti-apoptotic responses, the compound by itself showed little antiproliferative or pro-apoptotic activity on the cellular level. However, its combination with some cytostatics markedly enhanced their antitumoral activities in vitro, and doxorubicin-induced NF-kappaB activation, a mechanism implicated in chemoresistance, was abrogated by KINK-1. In addition, when KINK-1 was combined with doxorubicin in an in vivo melanoma model, experimental metastasis was significantly diminished as compared to either treatment alone. Induction of chemoresistance by KINK-1 in vivo was not observed. Thus, KINK-1 or related substances might increase the susceptibility of tumors to chemotherapy. Keywords: time-course

ORGANISM(S): Homo sapiens

PROVIDER: GSE8772 | GEO | 2008/08/09

SECONDARY ACCESSION(S): PRJNA102059

REPOSITORIES: GEO

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Transcription profiling of human melanoma cells reveals KINK-1 a novel small-molecule inhibitor of IKK, enhances susceptibility of melanoma cells to antitumoral treatment

Project description:Interference with chemoresistance to enhance the efficacy of chemotherapeutics may be of great utility for cancer therapy. We have identified KINK-1 (Kinase Inhibitor of NF-ï«B-1), a highly selective small-molecule IKKï¢ inhibitor, as a potent suppressor of both constitutive and induced NF-ï«B activity in melanoma cells. While KINK-1 profoundly diminished various NF-ï«B-dependent gene products regulating proliferation, cytokine production or anti-apoptotic responses, the compound by itself showed little antiproliferative or pro-apoptotic activity on the cellular level. However, its combination with some cytostatics markedly enhanced their antitumoral activities in vitro, and doxorubicin-induced NF-ï«B activation, a mechanism implicated in chemoresistance, was abrogated by KINK-1. In addition, when KINK-1 was combined with doxorubicin in an in vivo melanoma model, experimental metastasis was significantly diminished as compared to either treatment alone. Induction of chemoresistance by KINK-1 in vivo was not observed. Thus, KINK-1 or related substances might increase the susceptibility of tumors to chemotherapy. Experiment Overall Design: one control and two time point (12hrs and 24hrs) are analyzed, with one replicate each (6 arrays total)

2008-10-18 | E-GEOD-8772 | biostudies-arrayexpress

p65-HaloTag copurifying proteins in human 293T cells

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Project description:Aspirin antitumoral effect on pituitary adenoma

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NFkB in multiple myeloma - L363 IKK inhibitor

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Deficiency in tumor suppressor p53 is required for doxorubicin induced transcriptional upregulation of NF-kB target genes in human breast cancer

2013-12-31 | GSE47013 | GEO

Mepazine inhibitor effects DLBCL cell line HBL1

Project description:The medicinal active phenothiazine mepazine acts as a small molecule inhibitor of the MALT1 protease. Mepazine selectively inhibits cleavage activity of recombinant and cellular MALT1 by a noncompetitive mechanism. MALT1 activity is required for NF-kappaB signaling and survival of aggressive lymphoma belonging to the ABC-DLBCL (activated B-cell-type of diffuse large B-cell lymphoma) entity. Gene expression profiling was carried out in the ABC-DLBCL cell line HBL1 after treatment with mepazine (20 microM) for 6, 12, and 24 hr. Mepazine inhibits anti-apoptotic NF-kB signaling and thereby survival of these cells. Using Agilent 2-color gene expression microarrays (GPL10332) mepazine-treated HBL1 cells were compared with DMSO in the control channels.

2012-07-31 | E-GEOD-39741 | biostudies-arrayexpress

TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma

Project description:Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas. It is characterized by the presence of rare Hodgkin and Reed/Sternberg (HRS) cells embedded in an extensive inflammatory infiltrate. Constitutive activation of nuclear factor-kappaB (NF-kappaB) in HRS cells which transcriptionally regulates expression of multiple anti-apoptotic factors and pro-inflammatory cytokines plays a central role in the pathogenesis of cHL (1, 2). In non-stimulated condition, NF-kappaB proteins are rendered inactive by binding to their inhibitors (IkappaB s), which sequester them in the cytoplasm. Stimulation of multiple receptors activates the IkappaB kinase (IKK) complex that phosphorylates IkappaB at two specific serine residues, followed by its ubiquitination and proteasomal degradation, thereby releasing NF-kappaB proteins and allowing their nuclear translocation (3). Recently, two studies provided further insights into the molecular mechanisms of IKK activation upon TNF stimulation (4, 5). Activation of the IKK complex and subsequent NF-kappaB activation requires Lys63 polyubiquitination of RIP1, a kinase which is recruited to the receptor upon TNF stimulation. IKK-gamma (NEMO), the regulatory subunit of the IKK complex, specifically recognizes these Lys63-linked polyubiquitins attached to RIP1 and thereby activates IKK and NF-kappaB (4, 5). A20 is an ubiquitin-modifying enzyme that inhibits NF-kappaB activation in succession of tumor necrosis factor (TNF) receptor and Toll-like receptor induced signals (6-8). This enzyme removes Lys63 linked ubiquitin chains from RIP1 and adds Lys48 polyubiquitins to RIP1, thereby targeting this factor for proteasomal degradation, thus explaining the molecular mechanism of NF-kappaB inhibition by A20 (6). A20 likely inhibits NF-kappaB acitivity also by additional means, including interaction with TRAF1 and TRAF2 (9).

2009-03-24 | GSE15264 | GEO

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