| Budget Amount *help |
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| 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.
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