The Novel Orally Active Proteasome Inhibitor K-7174 Exerts Anti-myeloma Activity in Vitro and in Vivo by Down-regulating the Expression of Class I Histone Deacetylases

• Published in: The Journal of biological chemistry Vol. 288; no. 35; pp. 25593 - 25602
• Main Authors: Kikuchi, Jiro, Yamada, Satoshi, Koyama, Daisuke, Wada, Taeko, Nobuyoshi, Masaharu, Izumi, Tohru, Akutsu, Miyuki, Kano, Yasuhiko, Furukawa, Yusuke
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.08.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Administration, Oral; Animals; Anisoles - pharmacology; Antineoplastic Agents - pharmacology; Azepines - pharmacology; Boronic Acids - pharmacology; Bortezomib; Cancer; Cell Line, Tumor; Down-Regulation - drug effects; Down-Regulation - genetics; Drug Resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Gene Regulation; Histone Deacetylase; Histone Deacetylase Inhibitors; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - biosynthesis; Histone Deacetylases - genetics; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Proteasome; Pyrazines - pharmacology; Histone Deacetylase Inhibitors; Drug Resistance; Cancer; Histone Deacetylase; Multiple Myeloma; Proteasome
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.480574

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. Background: Orally 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. Conclusion: K-7174 is an orally active proteasome inhibitor with a unique mechanism of action. Significance: K-7174 may compensate for conventional proteasome inhibitors in cancer treatment.