2013 Fiscal Year Final Research Report

Study of the agent targetting for ER stress-induced XBP1 activity in refractory lymphoid malignancies.

Research Project

Project/Area Number	23791085
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Hematology
Research Institution	Nagoya City University
Principal Investigator	RI MASAKI 名古屋市立大学, 医学(系)研究科(研究院), 助教 (00567539)
Project Period (FY)	2011 – 2013
Keywords	骨髄腫 / XBP1
Research Abstract	In this study, we identified toyocamycin, an adenosine analog, as an XBP1 inhibitor isolated from culture broth of an Actinomycete strain. Toyocamycin as well as other adenosine analogs suppressed XBP1 activation and induced apoptosis in ER-stressed tumor cells. In addition, toyocamycin inhibited the constitutive activation of XBP1 in MM cells, showed synergistic cytotoxic effects with bortezomib, and triggered dose-dependent apoptosis of MM cell lines as well as primary MM cells. Toyocamycin showed biological activities at the nanomolar level and mediated a growth inhibitory effect in an MM xenograft model similar to bortezomib. These results provide a rationale for initiating clinical trials using toyocamycin or other adenosine analogs, alone or in combination with bortezomib, for patients with MM refractory to immunomodulatory drugs and bortezomib. Also, toyocamycin could be a lead compound to further develop more specific inhibitors of the IRE1-XBP-1 pathway.