Exp Mol Med.  2013 Oct;45(10):e50.

Combination treatment with 2-methoxyestradiol overcomes bortezomib resistance of multiple myeloma cells

• Song IS
• Jeong YJ
• Jeong SH
• Heo HJ
• Kim HK
• Lee SR
• Ko TH
• Youm JB
• Kim N
• Ko KS
• Rhee BD
• Han J

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 Ca2+ 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.

Keyword

bortezomib; combination therapy; multiple myeloma; 2-methoxyestradiol; resistance; superoxide dismutase 2

MeSH Terms

Acetylcysteine/pharmacology
Apoptosis/*drug effects
Boronic Acids/*pharmacology
Calcium/metabolism
Cell Line, Tumor
*Drug Resistance, Neoplasm
Drug Synergism
Estradiol/*analogs & derivatives/pharmacology
Humans
Mitochondria/drug effects/metabolism
Mitogen-Activated Protein Kinase Kinases/metabolism
Pyrazines/*pharmacology
Reactive Oxygen Species/metabolism
Acetylcysteine
Boronic Acids
Calcium
Estradiol
Mitogen-Activated Protein Kinase Kinases
Pyrazines
Reactive Oxygen Species