Proteasome inhibition by Carfilzomib, but not by Bortezomib, induces a specific, proteasome subunit-dependent impairment in cardiac contractility.

Abstract

All approved proteasome inhibitors (PI), Bortezomib (BTZ), Ixazomib (IXA) and Carfilzomib (CFZ), by design target the rate-limiting B5 proteasome subunit. Only CFZ at higher doses shows co-inhibition of B5/B2. The CFZ-type B5/B2 co-inhibition induces increased proteotoxic stress and higher cytotoxicity in MM than the BTZ-type, B5/B1 inhibition, consistent with increased survival of relapsed/refractory MM patients. However, higher doses of CFZ produce acute heart failure not commonly seen with the first-generation PI, which is mechanistically poorly understood.