Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors.
Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors.
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DOI：
10.1016/j.ccr.2014.07.027
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发表时间：
2014-10-13
期刊：
影响因子：
50.3
通讯作者：
Franzoso G
中科院分区：
文献类型：
--
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
组成型NF-κB信号传导促进多发性骨髓瘤（MM）和其他癌症的生存;然而，目前的NF-κ B靶向策略缺乏癌细胞特异性。在这里，我们确定了NF-κ B调节的抗凋亡因子GADD 45 β和JNK激酶MKK 7之间的相互作用作为MM的治疗靶点。使用药物发现策略，我们开发了DTP 3，一种D-三肽，它破坏GADD 45 β/MKK 7复合物，有效地杀死MM细胞，重要的是，对正常细胞没有毒性。DTP 3具有与临床标准硼替佐米相似的抗癌效力，但在体外的癌细胞特异性高出100倍以上。值得注意的是，在有效剂量下，DTP 3消融小鼠中的骨髓瘤异种移植物而没有明显的副作用。因此，NF-κB通路的癌症选择性靶向是可能的，并且至少对于骨髓瘤患者而言，有望带来深远的益处。GADD 45 β是MM中NF-κB抗凋亡功能的关键介质GADD 45 β与MKK 7结合并通过阻断MKK 7/JNK信号传导促进MM细胞存活GADD 45 β/MKK 7抑制剂显示出有效的抗MM活性，在体外和体内GADD 45 β/MKK 7抑制剂比IKK/NF-κB抑制剂具有更高的癌症选择性NF-κB与MM和其他恶性肿瘤有关，但仅在病变细胞中阻断NF-κB是具有挑战性的。Tornatore等人确定MKK 7和NF-κ B调节的GADD 45 β之间的相互作用作为治疗靶点，并开发一种破坏复合物并选择性杀死MM细胞的肽。
Constitutive NF-κB signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-κB-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-κB-regulated antiapoptotic factor GADD45β and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45β/MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher cancer cell specificity in vitro. Notably, DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit. GADD45β is a critical mediator of the NF-κB antiapoptotic function in MM GADD45β binds to MKK7 and promotes MM cell survival by blocking MKK7/JNK signaling GADD45β/MKK7 inhibitors display potent activity against MM, in vitro and in vivo GADD45β/MKK7 inhibitors are far more cancer selective than IKK/NF-κB inhibitors NF-κB is implicated in MM and other malignancies, but it is challenging to block NF-κB only in diseased cells. Tornatore et al. identify an interaction between MKK7 and NF-κB-regulated GADD45β as a therapeutic target and develop a peptide that disrupts the complex and selectively kills MM cells.
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影响因子：
21.3
作者：
Papa, S;Zazzeroni, F;Franzoso, G
通讯作者：
Franzoso, G
DOI：
10.1158/1078-0432.ccr-09-2831
发表时间：
2010-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dickens NJ;Walker BA;Leone PE;Johnson DC;Brito JL;Zeisig A;Jenner MW;Boyd KD;Gonzalez D;Gregory WM;Ross FM;Davies FE;Morgan GJ
通讯作者：
Morgan GJ
影响因子：
4.8
作者：
Bjorklund, Chad C.;Ma, Wencai;Orlowski, Robert Z.
通讯作者：
Orlowski, Robert Z.
影响因子：
15.9
作者：
Papa, Salvatore;Zazzeroni, Francesca;Franzosol, Guido
通讯作者：
Franzosol, Guido
DOI：
10.1016/j.bbapap.2009.12.004
发表时间：
2010-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Nickl CK;Raidas SK;Zhao H;Sausbier M;Ruth P;Tegge W;Brayden JE;Dostmann WR
通讯作者：
Dostmann WR