Tornatore Laura, Sandomenico Annamaria, Raimondo Domenico, Low Caroline, Rocci Alberto, Tralau-Stewart Cathy, Capece Daria, D'Andrea Daniel, Bua Marco, Boyle Eileen, van Duin Mark, Zoppoli Pietro, Jaxa-Chamiec Albert, Thotakura Anil K, Dyson Julian, Walker Brian A, Leonardi Antonio, Chambery Angela, Driessen Christoph, Sonneveld Pieter, Morgan Gareth, Palumbo Antonio, Tramontano Anna, Rahemtulla Amin, Ruvo Menotti, Franzoso Guido
Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.
Institute of Biostructures and Bioimages, National Research Council and CIRPeB, 80134 Naples, Italy.
Cancer Cell. 2014 Oct 13;26(4):495-508. doi: 10.1016/j.ccr.2014.07.027.
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.
组成型核因子-κB（NF-κB）信号通路促进多发性骨髓瘤（MM）和其他癌症的细胞存活；然而，目前针对NF-κB的靶向策略缺乏癌细胞特异性。在此，我们确定了NF-κB调节的抗凋亡因子生长停滞和DNA损伤诱导蛋白45β（GADD45β）与应激活化蛋白激酶（JNK）激酶MKK7之间的相互作用是MM的一个治疗靶点。我们采用药物发现策略开发了一种D型三肽DTP3，它可破坏GADD45β/MKK7复合物，有效杀死MM细胞，重要的是，对正常细胞无毒。DTP3具有与临床标准药物硼替佐米相似的抗癌效力，但在体外癌细胞特异性方面比硼替佐米高100多倍。值得注意的是，DTP3可消除小鼠体内的骨髓瘤异种移植物，在有效剂量下无明显副作用。因此，对NF-κB通路进行癌症选择性靶向是可行的，至少对骨髓瘤患者而言，有望带来显著益处。
