title: Combination treatment with 2-methoxyestradiol overcomes bortezomib resistance of multiple myeloma cells.
abstract: Bortezomib is a proteasome inhibitor used for the treatment of relapsed/refractory multiple myeloma (MM). However, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. In a previous report, we demonstrated that changes in the expression of mitochondrial genes lead to changes in mitochondrial activity and bortezomib susceptibility or resistance, and their combined effects contribute to the differential sensitivity or resistance of MM cells to bortezomib. Here we report that the combination treatment of bortezomib and 2-methoxyestradiol (2ME), a natural estrogen metabolite, induces mitochondria-mediated apoptotic cell death of bortezomib-resistant MM KMS20 cells via mitochondrial reactive oxygen species (ROS) overproduction. Bortezomib plus 2ME treatment induces a higher level of cell death compared with treatment with bortezomib alone and increases mitochondrial ROS and Ca(2+) levels in KMS20 cells. Pretreatment with the antioxidant N-acetyl-L-cysteine scavenges mitochondrial ROS and decreases cell death after treatment with bortezomib plus 2ME in KMS20 cells. Moreover, we observed that treatment with bortezomib plus 2ME maintains the activation of c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase kinase 4/7 (MKK4/7). Collectively, combination treatment with bortezomib and 2ME induces cell death via JNK-MKK4/7 activation by overproduction of mitochondrial ROS. Therefore, combination therapy with specific mitochondrial-targeting drugs may prove useful to the development of novel strategies for the treatment of bortezomib-resistant MM patients.
authors.affiliation: National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea.
authors.forename: In-Sung
authors.initials: IS
authors.lastname: Song
authors.forename: Yu Jeong
authors.initials: YJ
authors.lastname: Jeong
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Jeong
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Heo
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
authors.forename: Sung Ryul
authors.initials: SR
authors.lastname: Lee
authors.forename: Tae Hee
authors.initials: TH
authors.lastname: Ko
authors.forename: Jae Boum
authors.initials: JB
authors.lastname: Youm
authors.forename: Nari
authors.initials: N
authors.lastname: Kim
authors.forename: Kyung Soo
authors.initials: KS
authors.lastname: Ko
authors.forename: Byoung Doo
authors.initials: BD
authors.lastname: Rhee
authors.forename: Jin
authors.initials: J
authors.lastname: Han
mesh_terms: D000077584:2-Methoxyestradiol; D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D017382:Reactive Oxygen Species; D004958:Estradiol; D000069286:Bortezomib; D000077584:2-Methoxyestradiol; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium; D000111:Acetylcysteine