Effect of traditional Chinese herbal medicine on brain tumor

Abstract

Gliomas are among the most fatal and morbid cancers in existence. Conventional therapies such as surgical debulking, radiation and cytotoxic chemotherapy, have had little effect on median survival time, and no clear-cut cure exists. However, traditional Chinese medical herbs which have been used to treat cancers for thousands of years may have potential as an interesting new treatment. In our study, we have screened 75 aqueous extracts from 50 plant families used in traditional Chinese medicine. Our results showed that the crude extracts from Chinese gall, Spica prunellae, and Paris polyphylla could inhibit glioma cell growth in vitro. We further studied the anti-glioma activity and possible underlying mechanisms of selected active components, gallic acid, ursolic acid, polyphyllin D, and paris saponin Pb from Chinese gall, Spica prunella, and Paris polyphylla, respectively. We employed various assays, including MTT, SRB, BrdU, flow cytometry, tube formation assay, invasion assay, real time RT-PCR and Western blotting to assess the effects of these four active compounds on human glioma U87 and U251n cells. All of these major active compounds exhibited cytotoxic effects on different glioma cell lines, but have selective cytotoxic effects on normal astrocytes and mouse brain endothelial cells. They could also inhibit cell proliferation and arrest cells at different phases of the cell cycle. A possible underlying mechanism could be the inhibition of Akt and Erk expression by these four compounds. Additionally, these effects could be due to an increase in p21 and p27 and decrease in cyclin B1 and cyclin E1 expression, because all these proteins are related to cell cycle regulation. Using flow cytometry and Hoechst 33342 staining, we determined that only ursolic acid could significantly induce apoptosis in a dose-dependent manner. The in vitro tube formation assay data showed that these four compounds could significantly reduce tube formation in mouse brain endothelial cells. Furthermore, these four compounds could significantly decrease U87 cell invasion in vitro. Interestingly, matrix metalloproteinase-2 activity, which plays a role in matrix degradation, was increased after treatment with any of these four compounds. This indicates that other pathways might be involved in the anti-invasive properties of these compounds. They may include the inhibition of phosphorylation of both Akt and Erk as well as the reduction of both expression and activity of ADAM17. In addition, our data showed that Transforming Growth Factor (TGF)-β1 can promote glioma cell migration and invasion, which may happen through stimulation of ADAM17. Taken together, these compounds may act through the suppression of TGF-β1 and ADAM17 and down-regulation of PI3K/Akt and Ras/MAPK signaling pathways to reduce glioma cell proliferation, migration and invasion. Thus, gallic acid, ursolic acid, polyphyllin D, and paris saponin Pb may be valuable candidate drugs for the treatment of gliomas.