title: TM-233, a novel analog of 1'-acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK/STAT and proteasome activities.
abstract: 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 IC50 than ACA. Treatment with TM-233 inhibited constitutive activation of JAK2 and STAT3, 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.
authors.affiliation: Department of Hematology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan.
authors.forename: Morihiko
authors.initials: M
authors.lastname: Sagawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tabayashi
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kimura
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Tomikawa
authors.forename: Tomoe
authors.initials: T
authors.lastname: Nemoto-Anan
authors.forename: Reiko
authors.initials: R
authors.lastname: Watanabe
authors.forename: Michihide
authors.initials: M
authors.lastname: Tokuhira
authors.forename: Masaki
authors.initials: M
authors.lastname: Ri
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kizaki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001592:Benzyl Alcohols / Q000737:chemistry* / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D009101:Multiple Myeloma / Q000201:enzymology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011719:Pyrazines / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D001592:Benzyl Alcohols; D001897:Boronic Acids; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C000599971:TM-233; D051020:bcl-X Protein; D000069286:Bortezomib; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D046988:Proteasome Endopeptidase Complex; C047948:1'-acetoxychavicol acetate
keywords: 1′-acetoxychavicol acetate; NF-κB; apoptosis; bortezomib; multiple myeloma