Abstract 4367: Off-Target Effects of the Anticancer Agent Bortezomib (Velcade™) in the Mammalian Heart
Bortezomib (PS-341, Velcade™) is the first proteasome inhibitor approved by FDA for use in patients with relapsed multiple myeloma and mantle cell lymphoma. Recent reports have suggested that bortezomib leads to the development of cardiomyopathy in experimental animals and heart failure in humans. However, the mechanism for the development of cardiomyopathy is unclear. We have shown that sustained cardiac inflammation leads to “proteasome switching” of the 26S proteasome from a proteolytic function to a deubiquitinating (DUB) function that resulting in shortening of the length of the ubiquitin chains of ubiquitin tagged proteins and prevents (“spares”) proteins from degradation by the 20S proteasome. This DUB-induced loss of normal protein quality control mechanisms can lead to the accumulation of toxic proteins in the myocardium, with the subsequent development of a cardiomyopathy. In order to test the hypothesis that inhibition of the 26S proteasome activity with bortezomib leads to increased DUB activity in the heart, bortezomib (1 mg/kg body weight) was administered intravenously to four-month-old wild type FVB mice 2x/week for 4 weeks. Hearts were harvested 1 hour after the last injection and the 26S proteasome purified immediately, followed by determination of 26S proteasome and DUB activity. As expected 26S proteasome activity was decreased significantly (p=0.005) by 80% in mouse hearts treated with bortezomib compared to diluent treated controls. Interestingly, this decrease in protea-some activity was accompanied by a significant (p=0.028) 20% increase in DUB activity in the bortezomib treated mice. Treatment with bortezomib leads to decreased 26S proteasome activity and increased DUB activity, consistent with “proteasome switching”. Whether this off-target effect of bortezomib also leads to the accumulation of toxic proteins in the myocardium that can foster the development of a cardiomyopathy is currently under investigation.