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.
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shono
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Andrea Z
authors.initials: AZ
authors.lastname: Tuckett
authors.affiliation: ImmuneTarget Inc., San Diego, California.
authors.forename: Hsiou-Chi
authors.initials: HC
authors.lastname: Liou
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Doubrovina
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Enrico
authors.initials: E
authors.lastname: Derenzini
authors.affiliation: ImmuneTarget Inc., San Diego, California.
authors.forename: Samedy
authors.initials: S
authors.lastname: Ouk
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Tsai
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Levy
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Fabiana M
authors.initials: FM
authors.lastname: Kreines
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Carly G K
authors.initials: CG
authors.lastname: Ziegler
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Mary I
authors.initials: MI
authors.lastname: Scallion
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Doubrovin
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: O'Reilly
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York. ZakrzewJ@mskcc.org.
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Zakrzewski
mesh_terms: D000818:Animals; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D020569:Proto-Oncogene Proteins c-rel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D017382:Reactive Oxygen Species