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Oncol Res. 2019 Mar 5. doi: 10.3727/096504018X15443011011637. [Epub ahead of print]

Synergistic efficacy of the demethylation agent decitabine in combination with the protease inhibitor bortezomib for treating multiple myeloma through the Wnt/βcatenin pathway.

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Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, Shaanxi,China.


Multiple myeloma (MM) is a hematopoietic malignancy characterized by the clonal proliferation of antibody-secreting plasma cells. Bortezomib (BZM), the first FDAapproved proteasome inhibitor, has significant anti-myeloma activity and prolongs the median survival of MM patients. However, MM remains incurable predominantly due to acquired drug resistance and disease relapse. β-catenin, a key effector protein in the canonical Wnt signaling pathway, has been implicated in regulating myeloma cell sensitivity to BZM. Decitabine (DAC) is an epigenetic modulating agent that induces tumor suppressor gene re-expression based on its gene-specific DNA hypomethylation. DAC has been implicated in modulating Wnt-β-catenin signaling by promoting the demethylation of the Wnt/β-catenin antagonists sFRP and DKK. In this study, we report the effects of single reagent DAC therapy and DAC combined with BZM on β-catenin accumulation, myeloma cell survival, apoptosis and treatment sensitivity. Our study proved that DAC demethylated and induced the re-expression of the Wnt antagonists sFRP3 and DKK1. DAC also reduced GSK3β (Ser9) phosphorylation and decreased β-catenin accumulation in the nucleus, which were induced by BZM. Thus, the transcription of cyclin D1, c-Myc and LEF/TCF was reduced, which synergistically inhibited cell proliferation, enhanced BZM-induced apoptosis, and promoted BZMinduced cell cycle arrest in myeloma cells. In summary, these results indicated that DAC could synergistically enhance myeloma cell sensitivity to BZM at least partly by regulating Wnt/β-catenin signaling. Our results can be used to optimize therapeutic regimens for MM.

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