Abstract
GATA-1, a zinc finger transcription factor, has been demonstrated to play a key role in the progression of leukemia. In this study, we investigate the effects of wogonoside, a naturally bioactive flavonoid derived from Scutellaria baicalensis Georgi, on cell growth and cell cycle in chronic myeloid leukemia (CML) cells, and uncover its underlying mechanisms. The experimental design comprised CML cell lines K562, imatinib-resistant K562 (K562r) cells, and primary CML cells, treated in vitro or in vivo, respectively, with wogonoside; growth and cell cycle were then evaluated. We found that wogonoside could induce growth inhibition and G0/G1 cell cycle arrest in both normal and K562r cells. Wogonoside promotes the expression of GATA-1 and facilitates the binding to methyl ethyl ketone (MEK) and p21 promoter, thus inhibiting MEK/extracellular signal-regulated kinase signaling and cell cycle checkpoint proteins, including CDK2, CDK4, cyclin A, and cyclin D1, and increasing p21 expression. Furthermore, in vivo studies showed that administration of wogonoside decreased CML cells and prolonged survival in NOD/SCID mice with CML cell xenografts. In conclusion, these results clearly revealed the inhibitory effect of wogonoside on the growth in CML cells and suggested that wogonoside may act as a promising drug for the treatment of imatinib-resistant CML.
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Abbreviations
- GATA-1:
-
GATA binding protein 1
- CML:
-
Chronic myeloid leukemia
- ERK:
-
Extracellular signal-regulated kinase
- MEK:
-
Methyl ethyl ketone
- CKI:
-
Cyclin-dependent kinase inhibitor
- DMSO:
-
Dimethyl sulfoxide
- NOD/SCID:
-
Non-obese diabetic/severe combined immunodeficiency
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Acknowledgments
This work was supported by the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. JKGZ201101, SKLNMZZ201210, SKLNMZZCX201303 SKLNMZZJQ201302 and No. G140042), Science Fund for Distinguished Young Scholars of Jiangsu province (BK20130024), the National Science & Technology Major Project (No. 2012ZX09304-001, 2012ZX09103101-050), the National Natural Science Foundation of China (Nos. 81300379, 81373449, 91029744, and 81173086), Natural Science Foundation of Jiangsu province (No. BK20140668), the Key Project supported by medical science and technology development Foundation of Nanjing Department of Health (No. ZKX14015), Six big talent peak in Jiangsu province project (2014-WSN-049), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT-IRT1193), and Huahai Graduate Innovation Fund (CX13B-006HH), and the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Fundamental Research Funds for the Central Universities (PY2014YX0001; ZL2014YX0034).
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Hui Li and Hui Hui have contributed equally to this work.
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Viable cells were counted using a hemocytometer after trypan blue staining to assess anti-proliferation activity. (TIFF 1483 kb)
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Li, H., Hui, H., Xu, J. et al. Wogonoside induces growth inhibition and cell cycle arrest via promoting the expression and binding activity of GATA-1 in chronic myelogenous leukemia cells. Arch Toxicol 90, 1507–1522 (2016). https://doi.org/10.1007/s00204-015-1552-3
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DOI: https://doi.org/10.1007/s00204-015-1552-3