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Although the introduction of bortezomib and immunomodulatory drugs has led to improved outcomes in patients with multiple myeloma, the disease remains incurable. In an effort to identify more potent and well‐tolerated agents for myeloma, we have previously reported that 1′‐acetoxychavicol acetate ( ACA ), a natural condiment from South‐East Asia, induces apoptotic cell death of myeloma cells  in vitro  and  in vivo  through inhibition of  NF ‐κB‐related functions. Searching for more potent  NF ‐κB inhibitors, we developed several  ACA  analogs based on quantitative structure–activity relationship analysis.  TM ‐233, one of these  ACA  analogs, inhibited cellular proliferation and induced cell death in various myeloma cell lines with a lower  IC  50  than  ACA . Treatment with  TM ‐233 inhibited constitutive activation of  JAK 2 and  STAT 3, and then downregulated the expression of anti‐apoptotic Mcl‐1 protein, but not Bcl‐2 and Bcl‐ xL  proteins. In addition,  TM ‐233 rapidly decreased the nuclear expression of  NF ‐κB and also decreased the accumulation of cytosolic  NF ‐κB. We also examined the effects of  TM ‐233 on bortezomib‐resistant myeloma cells that we recently established,  KMS ‐11/ BTZ  and  OPM ‐2/ BTZ .  TM ‐233, but not bortezomib, inhibited cellular proliferation and induced cell death in  KMS ‐11/ BTZ  and  OPM ‐2/ BTZ  cells. Interestingly, the combination of  TM ‐233 and bortezomib significantly induced cell death in these bortezomib‐resistant myeloma cells through inhibition of  NF ‐κB activity. These results indicate that  TM ‐233 could overcome bortezomib resistance in myeloma cells mediated through different mechanisms, possibly inhibiting the  JAK / STAT  pathway. In conclusion,  TM ‐233 might be a more potent  NF ‐κB inhibitor than  ACA , and could overcome bortezomib resistance in myeloma cells.

TM ‐233, a novel analog of 1′‐acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK / STAT and proteasome activities