Open Access
ARTICLE
Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/b-Catenin Pathway
Yulong Jin*, Li Xu*, Xiaodong Wu†, Juan Feng*, Mimi Shu*, Hongtao Gu*, Guangxun Gao*,
Jinyi Zhang‡, Baoxia Dong*, Xiequn Chen*
* Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, P.R. China
† Department of Cell Biology, Fourth Military Medical University, Xi’an, Shaanxi, P.R. China
‡ Department of School of Life Sciences, Jinzhou Medical University, Jinzhou, Liaoning, P.R. China
Oncology Research 2019, 27(6), 729-737. https://doi.org/10.3727/096504018X15443011011637
Abstract
Multiple myeloma (MM) is a hematopoietic malignancy characterized by the clonal proliferation of antibodysecreting plasma cells. Bortezomib (BZM), the first FDA-approved proteasome inhibitor, has significant
antimyeloma activity and prolongs the median survival of MM patients. However, MM remains incurable
predominantly due to acquired drug resistance and disease relapse. -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 reexpression based
on its gene-specific DNA hypomethylation. DAC has been implicated in modulating Wnt/ -catenin signaling
by promoting the demethylation of the Wnt/ -catenin antagonists sFRP and DKK. In this study, we report the
effects of single reagent DAC therapy and DAC combined with BZM on -catenin accumulation, myeloma
cell survival, apoptosis, and treatment sensitivity. Our study proved that DAC demethylated and induced the
reexpression of the Wnt antagonists sFRP3 and DKK1. DAC also reduced GSK3 (Ser9) phosphorylation
and decreased -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 BZM-induced 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/ -catenin signaling. Our results can be used to optimize therapeutic regimens for MM.
Keywords
Cite This Article
Jin, Y., Xu, L., Wu, X., Feng, J., Shu, M. et al. (2019). Synergistic Efficacy of the Demethylation Agent Decitabine in Combination With the Protease Inhibitor Bortezomib for Treating Multiple Myeloma Through the Wnt/b-Catenin Pathway.
Oncology Research, 27(6), 729–737.