Journal
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume 36, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13046-017-0563-8
Keywords
Alantolactone; Glioblastoma multiforme; Blood-brain barrier; Cox-2; IKK beta/NF-kappa B
Categories
Funding
- National Natural Science Foundation of China [81,372,714, 81672480, 81,622,047, 81,473,334]
- Dalian Outstanding Youth Science and Technology Talent [2015J12JH201]
- Liaoning Provincial Natural Science Foundation of China [201602244]
- Distinguished Professor Project of Liaoning Province
- Special Grant for Translational Medicine, Dalian Medical University [2015002]
- Distinguished professor of Liaoning Province - Liaoning BaiQianWan Talents Program and Innovation Team of Dalian Medical University
Ask authors/readers for more resources
Background: Glioblastoma multiforme (GBM) is one of the most refractory and palindromic central nervous system (CNS) neoplasms, and current treatments have poor effects in GBM patients. Hence, the identification of novel therapeutic targets and the development of effective treatment strategies are essential. Alantolactone (ATL) has a wide range of pharmacological activities, and its anti-tumor effect is receiving increasing attention. However, the molecular mechanism underlying the anti-GBM activity of ATL remains poorly understood. Methods: The biological functions of ATL in GBM cells were investigated using migration/invasion, colony formation and cell cycle/apoptosis assays. The localization of nuclear factor kappa B (NF-kappa B) p50/p65 and its binding to the cyclooxygenase 2 (COX-2) promoter were determined using confocal immunofluorescence, a streptavidin-agarose pulldown assay and a chromatin immunoprecipitation (ChIP) assay. IKK beta kinase activity was determined using a cell IKK beta kinase activity spectrophotometry quantitative detection kit and a molecular docking study. LC-MS/MS analysis was performed to determine the ability of ATL to traverse the blood-brain barrier (BBB). The in vivo anti-tumor efficacy of ATL was also analyzed in xenografted nude mice. Western blot analysis was performed to detect the protein expression levels. Results: ATL significantly suppressed the growth of GBM in vivo and in vitro. ATL significantly reduced the expression of COX-2 by inhibiting the kinase activity of IKK beta by targeting the ATP-binding site and then attenuating the binding of NF-kappa B to the COX-2 promoter region. Furthermore, ATL induced apoptosis by activating the cytochrome c (cyt c)/caspase cascade signaling pathway. Moreover, ATL could penetrate the BBB. Conclusions: ATL exerts its anti-tumor effects in human GBM cells at least in part via NF-kappa B/COX-2-mediated signaling cascades by inhibiting IKK beta kinase activity. ATL, which is a natural small molecule inhibitor, is a promising candidate for clinical applications in the treatment of CNS tumors.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available