| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
|
|---|
| Outline of Final Research Achievements |
We focused on the effect of histone deacetylase (HDAC) inhibitors in MM resistant to lenalidomide. We found that the HDAC inhibitors could activate NK cell activity by enhancing the expression of natural killer group 2D ligands (NKG2DLs) initiating an immune response against the target cells. Thus, HDAC inhibitors strengthen antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies (mAbs) irrespective of cereblon (CRBN), a primary target for lenalidomide. Resistance to lenalidomide is also caused by enhanced phosphorylation of glycogen synthase kinase-3 (p-GSK-3). GSK-3 is known to degrade c-Myc and inactivated through phosphorylation by PI3K/Akt. Thus, enhanced p-GSK-3 by Akt leads to stabilization of c-Myc and elongated survival of MM cells. Akt inhibitor, blocked p-GSK-3 and this inhibition was enhanced by addition of HDAC inhibitors. Combination of HDAC and Akt inhibitors had a synergistic effect in terms of cell cytotoxicity and c-Myc suppression.
|
