Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma.
Blood. 2007 Nov 15
Chauhan D, Singh A, Brahmandam M, Podar K, Hideshima T, Richardson P, Munshi N, Palladino MA, Anderson KC.
Department of Medical Oncology, the LeBow Institute for Myeloma Therapeutics, and Jerome Lipper Center for Myeloma Research, Dana Farber Cancer Institute, Boston, MA, United States.
Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells; and importantly, is distinct from bortezomib (Velcade(TM)) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138+ MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 + bortezomib-induced synergistic apoptosis is associated with: 1) activation of caspase-8, caspase-9, caspase-3, and PARP; 2) induction of ER-stress response and JNK; 3) inhibition of migration of MM cells and angiogenesis; 4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L) and trypsin-like (T-L) proteolytic activities; and 5) blockade of NF-kappaB signaling. Studies in a xenograft model show that low dose combinations of NPI-0052 and bortezomib is well tolerated, triggers synergistic inhibition of tumor growth, and CT-L, C-L and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 + bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM. |
