PT  - JOURNAL ARTICLE
AU  - Enzler, Thomas
AU  - Sano, Yasuyo
AU  - Choo, Min-Kyung
AU  - Cottam, Howard B.
AU  - Karin, Michael
AU  - Tsao, Hensin
AU  - Park, Jin Mo
TI  - Cell-Selective Inhibition of NF-κB Signaling Improves Therapeutic Index in a Melanoma Chemotherapy Model
AID  - 10.1158/2159-8290.CD-11-0143
DP  - 2011 Nov 01
TA  - Cancer Discovery
PG  - 496--507
VI  - 1
IP  - 6
4099  - http://cancerdiscovery.aacrjournals.org/content/1/6/496.short
4100  - http://cancerdiscovery.aacrjournals.org/content/1/6/496.full
SO  - CANCER DISCOVERY2011 Nov 01; 1
AB  - The transcription factor NF-κB promotes the 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. By using mouse models that simulate cell-selective targeting, we found that impaired NF-κB activation in melanoma and host myeloid cells accounts for therapeutic and adverse effects, respectively. Ablation of tumor-intrinsic NF-κB activity resulted in apoptosis-driven tumor regression after treatment with doxorubicin. 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. Significance: 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. Cancer Discovery; 1(6); 496–507. ©2011 AACR. Read the Commentary on this article by Aggarwal and Sung, p. 469 This article is highlighted in the In This Issue feature, p. 457