NF-κB in the crosshairs: Rethinking an old riddle.
NF-κB in the crosshairs: Rethinking an old riddle.
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DOI：
10.1016/j.biocel.2017.12.020
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Franzoso G
中科院分区：
文献类型：
--
作者：
Bennett J;Capece D;Begalli F;Verzella D;D'Andrea D;Tornatore L;Franzoso G
NF-κB 转录因子是免疫、炎症和细胞存活的中心协调调节因子。 NF-κB 通路在癌症中异常且稳定地激活。 NF-κB 二聚体的普遍存在和多效性生理作用迄今为止阻碍了任何临床上有用的 NF-κB 抑制剂的开发。新兴的治疗方法旨在实现 NF-κB 通路的癌症选择性抑制，以此克服传统 IKKβ/NF-κB 靶向药物的独特毒性。组成型 NF-κB 信号传导与大多数人类恶性肿瘤和几乎所有非恶性病理的发病机制有关。因此，NF-κB 通路已被积极地作为药物发现的有吸引力的治疗靶标。然而，迄今为止，与全身性 NF-κB 抑制相关的严重靶向毒性阻碍了临床上有用的 NF-κB 靶向药物的开发，作为治疗肿瘤或非肿瘤疾病患者的方法。这篇小综述讨论了目前正在开发的一些更有前景的方法，通过选择性地靶向癌症中的致病性 NF-κB 信号传导，同时保留 NF-κB 在宿主防御反应和组织稳态中的多种生理功能，来规避全球 NF-κB 阻断的排除性安全责任。
NF-κB transcription factors are central coordinating regulators of immunity, inflammation and cell survival. NF-κB pathway is aberrantly and stably activated in cancer. The ubiquitous presence and pleiotropic physiological role of NF-κB dimers have thus far prevented the development of any clinically useful NF-κB inhibitor. Emerging therapeutic approaches aim to achieve the cancer-selective inhibition of the NF-κB pathway as a way to overcome the preclusive toxicities of conventional IKKβ/NF-κB-targeting drugs. Constitutive NF-κB signalling has been implicated in the pathogenesis of most human malignancies and virtually all non-malignant pathologies. Accordingly, the NF-κB pathway has been aggressively pursued as an attractive therapeutic target for drug discovery. However, the severe on-target toxicities associated with systemic NF-κB inhibition have thus far precluded the development of a clinically useful, NF-κB-targeting medicine as a way to treat patients with either oncological or non-oncological diseases. This minireview discusses some of the more promising approaches currently being developed to circumvent the preclusive safety liabilities of global NF-κB blockade by selectively targeting pathogenic NF-κB signalling in cancer, while preserving the multiple physiological functions of NF-κB in host defence responses and tissue homeostasis.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
21.3
作者：
Papa, S;Zazzeroni, F;Franzoso, G
通讯作者：
Franzoso, G
影响因子：
30.5
作者：
Lu, BF;Ferrandino, AF;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
4.7
作者：
Begalli F;Bennett J;Capece D;Verzella D;D'Andrea D;Tornatore L;Franzoso G
通讯作者：
Franzoso G
影响因子：
50.3
作者：
Tornatore L;Sandomenico A;Raimondo D;Low C;Rocci A;Tralau-Stewart C;Capece D;D'Andrea D;Bua M;Boyle E;van Duin M;Zoppoli P;Jaxa-Chamiec A;Thotakura AK;Dyson J;Walker BA;Leonardi A;Chambery A;Driessen C;Sonneveld P;Morgan G;Palumbo A;Tramontano A;Rahemtulla A;Ruvo M;Franzoso G
通讯作者：
Franzoso G