Mantle cell lymphoma (MCL) remains incurable due to its inevitable pattern of relapse
after treatment with current existing
therapies. However, the promise of a cure for MCL lies in the burgeoning area of novel agents. In this study, we elucidated the
therapeutic effect and mechanism of
carfilzomib, a novel long-acting second-generation
proteasome inhibitor, in MCL cells. We found that
carfilzomib induced growth inhibition and apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast,
carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The
carfilzomib-induced apoptosis of MCL cells was mediated by the activation of JNK, Bcl-2, and mitochondria-related pathways. In addition,
carfilzomib inhibited the growth and survival signaling pathways NF-κB and STAT3. Interestingly, we discovered that expression of immunoproteasome (i-
proteasome) subunits is required for the anti-MCL activity of
carfilzomib in MCL cells. In MCL-bearing SCID mice/primary MCL-bearing SCID-hu mice,
intravenous administration of 5 mg/kg
carfilzomib on days 1 and 2 for 5 weeks slowed/abrogated
tumor growth and significantly prolonged survival. Our preclinical data show that
carfilzomib is a promising, potentially less toxic treatment for MCL. Furthermore, an intact i-
proteasome, especially LMP2, appears to be necessary for its anti-MCL activity, suggesting that i-
proteasome could serve as a
biomarker for identifying patients who will benefit from
carfilzomib.