Characterization of a c-Rel inhibitor that mediates anticancer properties in hematologic malignancies by blocking NF-κB-controlled oxidative stress responses Journal Article

   

Authors:	Shono, Y.; Tuckett, A. Z.; Liou, H. C.; Doubrovina, E.; Derenzini, E.; Ouk, S.; Tsai, J. J.; Smith, O. M.; Levy, E. R.; Kreines, F. M.; Ziegler, C. G. K.; Scallion, M. I.; Doubrovin, M.; Heller, G.; Younes, A.; O'Reilly, R. J.; Van Den Brink, M. R. M.; Zakrzewski, J. L.
Article Title:	Characterization of a c-Rel inhibitor that mediates anticancer properties in hematologic malignancies by blocking NF-κB-controlled oxidative stress responses
Abstract:	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. © 2016 American Association for Cancer Research.
Journal Title:	Cancer Research
Volume:	76
Issue:	2
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2016-01-15
Start Page:	377
End Page:	389
Language:	English
DOI:	10.1158/0008-5472.can-14-2814
PROVIDER:	scopus
PMCID:	PMC4715937
PUBMED:	26744524
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84959020681&partnerID=40&md5=2759fcce8c6f73e81cdb43a52acc73a6
Notes:	Article -- Export Date: 4 April 2016 -- Source: Scopus