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1.
Cell Rep ; 24(8): 2155-2166, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30134175

RESUMO

The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase ß (GSK3ß) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma. In a high-throughput combinatorial drug screening experiment, BETi enhance the antiproliferative effects of PI3K inhibitors in a panel of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma cell lines. BETi or MYC silencing upregulates several PI3K pathway genes and induces GSK3ß S9 inhibitory phosphorylation, resulting in increased ß-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3ß S9 phosphorylation levels and ß-catenin protein abundance through downregulating the E2 ubiquitin conjugating enzymes UBE2C and UBE2T. In a mouse xenograft DLBCL model, BETi decrease MYC, UBE2C, and UBE2T and increase phospho-GSK3ß S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3ß regulation, providing a mechanistic rationale for combination strategies.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Linfoma Difuso de Grandes Células B/genética , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Animais , Humanos , Camundongos
2.
Cancer Res ; 76(2): 377-89, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26744524

RESUMO

NF-κB plays a variety of roles in oncogenesis and immunity that may be beneficial for therapeutic targeting, but strategies to selectively inhibit NF-κB to exert antitumor activity have been elusive. Here, we describe IT-901, a bioactive naphthalenethiobarbiturate derivative that potently inhibits the NF-κB subunit c-Rel. IT-901 suppressed graft-versus-host disease while preserving graft-versus-lymphoma activity during allogeneic transplantation. Further preclinical assessment of IT-901 for the treatment of human B-cell lymphoma revealed antitumor properties in vitro and in vivo without restriction to NF-κB-dependent lymphoma. This nondiscriminatory, antilymphoma effect was attributed to modulation of the redox homeostasis in lymphoma cells resulting in oxidative stress. Moreover, NF-κB inhibition by IT-901 resulted in reduced stimulation of the oxidative stress response gene heme oxygenase-1, and we demonstrated that NF-κB inhibition exacerbated oxidative stress induction to inhibit growth of lymphoma cells. Notably, IT-901 did not elicit increased levels of reactive oxygen species in normal leukocytes, illustrating its cancer selective properties. Taken together, our results provide mechanistic insight and preclinical proof of concept for IT-901 as a novel therapeutic agent to treat human lymphoid tumors and ameliorate graft-versus-host disease.


Assuntos
NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-rel/antagonistas & inibidores , Animais , Feminino , Neoplasias Hematológicas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-rel/genética , Proteínas Proto-Oncogênicas c-rel/metabolismo , Espécies Reativas de Oxigênio , Transdução de Sinais
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