Development of intracellular proteolytic pathways targeted therapies for the treatment of multiple myeloma

2015 Fiscal Year Final Research Report

• Project/Area Number: 25860398
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Tokyo Medical University
• Principal Investigator: Moriya Shota 東京医科大学, 医学部, 助教 (30634935)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 多発性骨髄腫 / プロテアソーム / オートファジー / マクロライド / 小胞体ストレス / クラリスロマイシン / アグリソーム / ボルテゾミブ

Outline of Final Research Achievements

The specific 26S proteasome inhibitor bortezomib (BZ) induces autophagy in myeloma (MM) cells. The macrolide antibiotics clarithromycin (CAM) blocked autophagy flux, and BZ+CAM enhanced cytotoxicity in MM cell lines. Its combination, for the simultaneous blocking of the proteasome and autophagy leads to enhanced MM cell apoptosis. As misfolded protein is recruited by histone HDAC6 to dynein motors for aggresome transport, serving to sequester misfolded proteins, we further investigated the cellular effects of targeting proteolytic pathways and aggresome formation concomitantly in MM cells. Pronounced apoptosis was induced by the combination of HDAC6 inhibitor SAHA with BZ+CAM compared with each reagent or a 2-reagent combination. BZ+CAM treatment induced aggresome formation in the perinuclear region, whereas they were inhibited in the presence of SAHA. Targeting the integrated networks of aggresome, proteasome, and autophagy is suggested to induce efficient apoptosis in MM cells.

Free Research Field

応用薬理学，細胞死，オートファジー