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Mitochondrial modulation decreases the bortezomib‐resistance in multiple myeloma cells
Author(s) -
Song I.S.,
Kim H.K.,
Lee S.R.,
Jeong S.H.,
Kim N.,
Ko K.S.,
Rhee B.D.,
Han J.
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28149
Subject(s) - bortezomib , multiple myeloma , apoptosis , mitochondrion , cancer research , programmed cell death , proteasome inhibitor , drug resistance , biology , pharmacology , medicine , immunology , microbiology and biotechnology , biochemistry , genetics
Multiple myeloma (MM) is an incurable hematological malignancy that causes most patients to eventually relapse and die from their disease. The 20 S proteasome inhibitor bortezomib has emerged as an effective drug for MM treatment; however, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. We evaluated the involvement of mitochondria in resistance to bortezomib‐induced cell death in two different MM cell lines (bortezomib‐resistant KMS20 cells and bortezomib‐sensitive KMS28BM cells). Indices of mitochondrial function, including membrane potential, oxygen consumption rate and adenosine‐5′‐triphosphate and mitochondrial Ca 2+ concentrations, were positively correlated with drug resistance of KMS cell lines. Mitochondrial genes including CYPD , SOD2 and MCU were differentially expressed in KMS cells. Thus, changes in the expression of these genes lead to changes in mitochondrial activity and in bortezomib susceptibility or resistance, and their combined effect contributes to differential sensitivity or resistance of MM cells to bortezomib. In support of this finding, coadministration of bortezomib and 2‐methoxyestradiol, a SOD inhibitor, rendered KMS20 cells sensitive to apoptosis. Our results provide new insight into therapeutic modalities for MM patients. Studying mitochondrial activity and specific mitochondrial gene expression in fresh MM specimens might help predict resistance to proapoptotic chemotherapies and inform clinical decision‐making.