Constitutive NF-?B signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-?B-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-?B-regulated antiapoptotic factor GADD45? 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 GADD45?/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-?B pathway is possible and, at least for myeloma patients, promises a profound benefit.
Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta/MKK7 Inhibitors (vol 26, pg 495, 2014)
Sandomenico Annamaria;Ruvo Menotti;
2014
Abstract
Constitutive NF-?B signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-?B-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-?B-regulated antiapoptotic factor GADD45? 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 GADD45?/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-?B pathway is possible and, at least for myeloma patients, promises a profound benefit.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
