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 invitro. 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.
Cancer-Selective Targeting of the Nf-ΚB Survival Pathway With Gadd45Β/Mkk7 Inhibitors / L., T., A., S., Raimondo, D., C., L., A., R., C., T.S., D., C., D'Andrea, D., M., B., E., B., M., V.D., P., Z., A., J.C., A. K., T., J., D., B. A., W., A., L., A., C., C., D., P., S., et al.. - In: CANCER CELL. - ISSN 1535-6108. - STAMPA. - 26:4(2014), pp. 495-508. [10.1016/j.ccr.2014.07.027]
Cancer-Selective Targeting of the Nf-ΚB Survival Pathway With Gadd45Β/Mkk7 Inhibitors
RAIMONDO, Domenico;D'ANDREA, DANIEL;TRAMONTANO, ANNA;
2014
Abstract
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 invitro. 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
