| Background:Glioma is a primary tumor of the central nervous system.It is one of the most difficult cancers to cure in the world.It originates from the constituent cells of the brain itself.Glioblastoma(GBM)is the highest grade form of glioma,which is grade IV glioma.GBM is the most common glioma in adults and one of the most deadly cancers.Because of its high invasiveness and rapid proliferation,it has no obvious boundary with normal brain tissue,and it is difficult to completely remove the tumor.GBM cannot be cured,and the average survival period of patients is only 14 months.At present,the effective drug for the treatment of glioma is temozolomide(TMZ),but it is easy to produce drug resistance.The prognosis of patients with both surgical treatment and drug treatment is extremely poor,and the 5-year survival rate is still very low.Therefore,there is an urgent need to develop new safe and effective therapeutic drugs to prolong the survival of patients.In recent years,clinical evidence and pharmacological studies have shown that Chinese herbal medicines and their extracts have great potential as novel and effective cancer interventions.Sophocarpine is a naturally occurring tetracyclic quinazoline alkaloid.Many studies have shown that sophocarpine can play an effective anti-tumor role in malignant tumors such as liver cancer and head and neck cancer,gastric cancer and colorectal cancer.However,so far,there is no research report on the direction of sophocarpine in the treatment of glioma.Objective:So far,the effect and mechanism of sophocarpine on glioma are still unclear.Therefore,this study needs to further explore the inhibitory effect of sophocarpine on glioblastoma and clarify its mechanism of action.Methods:(1)Using cell lines U251 and C6 as experimental subjects,CCK-8 assay,cell clonin g,transwell assay and ratch assay were used to detect the effect of sophorine on the activi ty,proliferation and migration of glioblastoma cells;(2)The effect of sophorine on gliom a cell cycle and apoptosis was studied by flow cytometry and Western blot;(3)q-PCR an d Western blot were used to determine the relevant signaling pathways;(4)To reconfirm the role of sophorine in the pathway of action against glioblastoma cells by using PTEN i nhibitors;(5)The inhibitory effect and molecular mechanism of sophorine on in-vivo gli oma were analyzed by immunohistochemical staining,tissue immunofluorence,Western blot,in vivo glioma model and other experiments.Results:(1)A series of experimental results of CCK8 and cell biology showed that sophocarpine could significantly inhibit the proliferation and migration of glioblastoma cells;(2)Flow cytometry and Western blot showed that sophocarpine induced cell cycle arrest in G0/G1 phase and induced apoptosis in glioblastoma cells;(3)Through biological experiments,it can be determined that sophocarpine inhibits the proliferation and migration of glioblastoma cells by up-regulating the expression of PTEN and inhibiting the PI3K/AKT signaling pathway;(4)Flow cytometry and CCK8 results showed that the use of PTEN antagonist bp V could antagonize the anti-cancer effect of sophocarpine in glioblastoma cells,confirming that PTEN is a key regulatory site for sophocarpineinduced glioblastoma cell death;(5)Immunohistochemical staining,Western blot and tissue immunofluorescence experiments showed that sophocarpine also induced apoptosis and inhibited cell proliferation by up-regulating PTEN in glioblastoma(ectopic and in situ)in nude mice,and sophocarpine had less toxic and side effects on other organs in nude mice.Conclusion:Sophorine can inhibit the proliferation,migration and invasion of glioblastoma by up-regulating PTEN and inhibiting the activation of AKT,promote the cycle arrest and apoptosis of glioblastoma,and achieve effective antitumor effects on the glioblastoma model of subcutaneous xenotransplantation and the orthotopic glioblastoma model of xenotransplantation.It is a potential natural drug for glioblastoma treatment. |
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