Roles of c-Rel signalling in inflammation and disease

Fullard, Nicola; Wilson, Caroline; Oakley, Fiona

doi:10.1016/j.biocel.2012.02.017

Cited by 32 publications

(32 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, we have evidence that systemic administration of the c-Rel inhibitor compound discovered by us is feasible, safe, and effective. Furthermore, Rel/NF-κB factors are also known for their roles as proto-oncogenes by contributing to tumor growth, survival, drug resistance, and metastasis of lymphoid malignancies, breast, head, and neck cancers (9, 40). We found in a preliminary experiment that intraperitoneal c-Rel inhibitor compound administration displayed antineoplastic activity in a xenograft model of human diffuse large B-cell lymphoma (data not shown).…”

Section: Discussionmentioning

confidence: 99%

A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity

et al. 2014

View full text Add to dashboard Cite

Preventing unfavorable graft-versus-host disease (GVHD) without inducing broad suppression of the immune system presents a major challenge of allogeneic hematopoietic stem cell transplantation. We developed a novel strategy to ameliorate GVHD while preserving graft-versus-tumor (GVT) activity by small molecule-based inhibition of the NF-κB family member c-Rel. Underlying mechanisms included reduced alloactivation, defective gut homing, and impaired negative feedback on IL-2 production resulting in optimal IL-2 levels, which, in the absence of competition by effector T-cells, translated into expansion of regulatory T-cells. c-Rel activity was dispensable for antigen-specific T-cell receptor activation, allowing c-Rel-deficient T-cells to display normal GVT activity. In addition, inhibition of c-Rel activity reduced alloactivation without compromising antigen-specific cytotoxicity of human T-cells. Finally, we were able to demonstrate feasibility and efficacy of systemic c-Rel inhibitor administration. Our findings validate c-Rel as a promising target for immunomodulatory therapy and demonstrate feasibility and efficacy of pharmaceutical inhibition of c-Rel activity.

show abstract

Section: Discussionmentioning

confidence: 99%

A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Rel/NF-κB proteins can act as oncogenic transcription factors by contributing to tumor growth, survival, drug resistance, and metastasis (1, 7). The combination of c-Rel inhibition and T cell therapy may therefore not only be advantageous in that this immunomodulatory approach allows for the separation of GVHD from GVL activity, but inhibition of c-Rel activity may also display a direct antineoplastic effect.…”

Section: Resultsmentioning

confidence: 99%

“…Amongst its many functions, nuclear factor (NF)-κB plays important roles in immunity (1–6) and oncogenesis (1, 7), indicating that therapeutic targeting of this pathway could be beneficial in a variety of clinical settings; however, an NF-κB-specific inhibitor does not exist in clinical practice to date. One approach toward development of such a compound is small-molecule-mediated direct inhibition of one or several members of the NF-κB family of transcription factors, a network that comprises five structurally related proteins including p50 (NF-κB1), p52 (NF-κB2), p65 (RelA), RelB and c-Rel (8).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses

et al. 2016

View full text Add to dashboard Cite

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 non-discriminatory, anti-lymphoma 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.

show abstract

“…These transcription factors have many roles in both normal and pathologic processes and activate genes related to apoptosis, development, and immune and inflammatory responses (56). Overexpression of c-REL has been linked with mammary tumorigenesis in Michigan Cancer Foundation-7 (MCF7) cells and in primary human breast cancer tissue samples; in addition, the proliferation of B cell lymphoma cell lines was stimulated by c-REL (57)(58)(59).…”

Section: Discussionmentioning

confidence: 99%

A Single Meal Containing Raw, Crushed Garlic Influences Expression of Immunity- and Cancer-Related Genes in Whole Blood of Humans

Charron

Dawson

Albaugh

et al. 2015

The Journal of Nutrition

View full text Add to dashboard Cite

show abstract

Roles of c-Rel signalling in inflammation and disease

Cited by 32 publications

References 100 publications

A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity

A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity

Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses

A Single Meal Containing Raw, Crushed Garlic Influences Expression of Immunity- and Cancer-Related Genes in Whole Blood of Humans

Contact Info

Product

Resources

About