| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
|
|---|
| 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.
|
