Abstract
Bortezomib therapy is now indispensable for multiple myeloma, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. The development of orally active proteasome inhibitors with distinct mechanisms of action is therefore eagerly awaited. Previously, we identified homopiperazine derivatives as a novel class of proteasome inhibitors with a different mode of proteasome binding from bortezomib. In this study, we show that K-7174, one of proteasome inhibitory homopiperazine derivatives, exhibits a therapeutic effect, which is stronger when administered orally than intravenously, without obvious side effects in a murine myeloma model. Moreover, K-7174 kills bortezomib-resistant myeloma cells carrying a β5-subunit mutation in vivo and primary cells from a patient resistant to bortezomib. K-7174 induces transcriptional repression of class I histone deacetylases (HDAC1, -2, and -3) via caspase-8-dependent degradation of Sp1, the most potent transactivator of class I HDAC genes. HDAC1 overexpression ameliorates the cytotoxic effect of K-7174 and abrogates histone hyperacetylation without affecting the accumulation of ubiquitinated proteins in K-7174-treated myeloma cells. Conversely, HDAC inhibitors enhance the activity of K-7174 with an increase in histone acetylation. These results suggest that class I HDACs are critical targets of K-7174-induced cytotoxicity. It is highly anticipated that K-7174 increases the tolerability and convenience of patients by oral administration and has the clinical utility in overcoming bortezomib resistance as a single agent or in combination with HDAC inhibitors.
Highlights
Active proteasome inhibitors with novel mechanisms of action are in high clinical demand
K-7174 Inhibits MM Cell Growth in Vitro—Following the demonstration of proteasome inhibitory action [18], we investigated whether K-7174 exerts anti-myeloma activities
CD138-positive cells isolated from bone marrow samples of 6 patients were cultured in the absence or presence of K-7174 for 2 days, followed by annexin-V staining to assess the induction of apoptosis
Summary
Active proteasome inhibitors with novel mechanisms of action are in high clinical demand. Results: K-7174, a homopiperazine derivative with a unique mode of proteasome inhibition, exhibits anti-myeloma effects via transcriptional repression of class I histone deacetylases. We have shown that K-7174 inhibits all three catalytic subunits of 20 S proteasome by direct binding, whereas bortezomib mainly acts on the 5 subunit [18] It is still unclear whether K-7174 has anti-myeloma activity and its underlying mechanism is different from that of bortezomib. We found that the cytotoxic activity of K-7174 largely depends on the expression levels of class I HDACs and the combination of K-7174 and HDAC inhibitors induces additive effects via the reduction of HDAC activity These findings may provide a molecular basis and rationale for the use of K-7174 in myeloma treatment alone or in combination with HDAC inhibitors
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