| RRC ID |
35724
|
| 著者 |
Kikuchi J, Yamada S, Koyama D, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Furukawa Y.
|
| タイトル |
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.
|
| ジャーナル |
J Biol Chem
|
| 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.
|
| 巻・号 |
288(35)
|
| ページ |
25593-25602
|
| 公開日 |
2013-8-30
|
| DOI |
10.1074/jbc.M113.480574
|
| PII |
S0021-9258(20)49162-8
|
| PMID |
23878197
|
| PMC |
PMC3757220
|
| MeSH |
Administration, Oral
Animals
Anisoles / pharmacology*
Antineoplastic Agents / pharmacology
Azepines / pharmacology*
Boronic Acids / pharmacology
Bortezomib
Cell Line, Tumor
Down-Regulation / drug effects*
Down-Regulation / genetics
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
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylases / biosynthesis*
Histone Deacetylases / genetics
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
Multiple Myeloma / drug therapy*
Multiple Myeloma / enzymology
Multiple Myeloma / genetics
Multiple Myeloma / pathology
Pyrazines / pharmacology
|
| IF |
4.238
|
| 引用数 |
15
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| 遺伝子材料 |
CSII-CMV-MCS-IRES2-Venus (RDB04383) |
