title: Cell-selective inhibition of NF-κB signaling improves therapeutic index in a melanoma chemotherapy model.
abstract: The transcription factor NF-κB promotes survival of cancer cells exposed to doxorubicin and other chemotherapeutic agents. IκB kinase is essential for chemotherapy-induced NF-κB activation and considered a prime target for anticancer treatment. An IκB kinase inhibitor sensitized human melanoma xenografts in mice to killing by doxorubicin, yet also exacerbated treatment toxicity in the host animals. Using mouse models that simulate cell-selective targeting, we found that impaired NF-κB activation in melanoma and host myeloid cells accounts for the therapeutic and the adverse effects, respectively. Ablation of tumor-intrinsic NF-κB activity resulted in apoptosis-driven tumor regression following doxorubicin treatment. By contrast, chemotherapy in mice with myeloid-specific loss of NF-κB activation led to a massive intratumoral recruitment of interleukin-1β-producing neutrophils and necrotic tumor lesions, a condition associated with increased host mortality but not accompanied by tumor regression. Therefore, a molecular target-based therapy may be steered toward different clinical outcomes depending on the drug's cell-specific effects.
  
  
  CONCLUSIONS
  Our findings show that the IκB kinase–NF-κB signaling pathway is important for both promoting treatment resistance and preventing host toxicity in cancer chemotherapy; however, the two functions are exerted by distinct cell type–specific mechanisms and can therefore be selectively targeted to achieve an improved therapeutic outcome.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Enzler
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Sano
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Choo
authors.forename: Howard B
authors.initials: HB
authors.lastname: Cottam
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D007093:Imidazoles; D053583:Interleukin-1beta; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D004317:Doxorubicin; D051550:I-kappa B Kinase