Abstract
BackgroundMatrine, a traditional Chinese medicine, has recently been shown to have antitumor properties in diverse cancer cells. Here, we explored the effect of matrine on human glioblastoma multiforme (GBM) cells.MethodsGlioblastoma multiforme cell lines were treated with matrine to assess proliferation and viability using EdU and CCK8 assays. SA‐β‐gal assays were used to evaluate cellular senescence, and a cytokine array and ELISA assay were used to screen for secreted cytokines altered in GBM cells after matrine treatment. Immunohistochemistry and Western blot analysis were performed to evaluate protein levels in matrine‐treated cell lines and in samples obtained from orthotopic xenografts. Specific activators of AKT and IGF1 were used to identify the pathways mediating the effect.ResultsMatrine potently inhibited growth of GBM cell lines in vitro. Based on in situ assays, growth arrest induced by matrine was primarily achieved through induction of cellular senescence. Matrine treatment led to decreased expression of proteins involved in promoting cell growth, IGF1, PI3K, and pAKT. Exposure of cells to a small molecule activating AKT (SC79) and recombinant IGF1 led to a reduced number of senescent SA‐β‐gal‐positive cells in the presence of matrine. Finally, matrine inhibited growth of orthotopic xenografts established from luciferase‐stable‐U251 or luciferase‐stable‐P3 cells and prolonged overall survival in mice.ConclusionsThese results indicated that matrine arrested cell growth through inhibition of IGF1/PI3K/AKT signaling. Matrine warrants further investigation as a potential therapy in the treatment of patients with GBM.
Highlights
Glioblastoma multiforme (GBM; WHO grade IV) is the most common malignant brain tumor, with characteristics of rapid progression, poor curative effect, and unfavorable prognosis.[1,2] Despite advances in combination treatments consisting of radiotherapy and chemotherapy, such as temozolomide which is considered the first-line adjuvant treatment for all patients,[3,4,5] the 5-y ear survival rate of glioblastoma multiforme (GBM) patients remains dismally at less than 5%.6 more effective therapies for the treatment of GBM are desperately needed.Studies in the past decade have greatly advanced our understanding of the genetic alterations that underlie the pathogenesis of glioblastoma
Our results demonstrated that the traditional Chinese medicine matrine possesses a potent antitumor effect against GBM cells in vitro and in vivo
We found that matrine elicits growth arrest in GBM cells, largely by inducing cellular senescence, and it does so importantly through the inhibition of PI3K/AKT signaling
Summary
This work was supported by the Natural Science Foundation of China Grant (81572487, 81702474, and 81701329), the Special Foundation for Taishan Scholars (ts20110814, tshw201502056, and tsqn20161067), the Department of Science & Technology of Shandong Province (2015ZDXX0801A01, 2017CXGC1502 and 2015GSF118061), the Natural Science Foundation of Shandong Province (ZR2017MH116 and ZR2017MH015), the Science Foundation of Qilu Hospital of Shandong University (2017QLQN02 and 2017QLQN03), and the University of Bergen and the K.G. Jebsen Brain Tumor Research Centre.
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