Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma

Journal of Hematology & Oncology
Zhihong ZhengYubin Kang

Abstract

Although current chemotherapy using bortezomib (Velcade) against multiple myeloma in adults has achieved significant responses and even remission, a majority of patients will develop acquired resistance to bortezomib. Increased thioredoxin level has been reported to be associated with carcinogenesis; however, the role of thioredoxin in bortezomib drug resistance of myeloma remains unclear. We generated several bortezomib-resistant myeloma cell lines by serially passaging with increased concentrations of bortezomib over a period of 1.5 years. Thioredoxin expression was measured by real-time PCR and western blot. The role of thioredoxin in the survival of bortezomib-resistant myeloma cells was determined by specific shRNA knockdown in vitro and in vivo. Thioredoxin inhibitor (PX12) was used to determine the effectiveness of thioredoxin inhibition in the treatment of bortezomib-resistant myeloma cells. The effect of thioredoxin inhibition on mitophagy induction was examined. The correlation of thioredoxin expression with patient overall survival was interrogated. Thioredoxin expression was significantly upregulated in bortezomib-resistant myeloma cells and the change correlated with the increase of bortezomib concentration. Thiore...Continue Reading

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Mar 22, 2019·The Kaohsiung Journal of Medical Sciences·Ying-Ying XuMing Chen
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Methods Mentioned

BETA
PCR
electrophoresis
transmission electron microscopy
xenograft
gene knockdown
transfection

Software Mentioned

Pro Plus
Image
String

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