米托蒽醌脂质体对卵巢癌细胞增殖、迁移及干性的影响OA

OBJECTIVE To investigate the effects of Mitoxantrone liposomes(Lipo-MIT)on the proliferation,migration and cancer stem cell(CSCs)stemness of ovarian cancer cells,as well as to explore its mechanism of action based on the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathway.METHODS The effects of Lipo-MIT on cell proliferation,migration and the stemness characteristics of CSCs were investigated through in vitro experiments.A human ovarian cancer A2780 cells xenograft tumor model of nude mouse was established to explore the effects of Lipo-MIT at doses of 2 and 5 mg/kg on the safety of tumor-bearing mice,as well as in vivo tumor growth and the pathological characteristics of tumor tissues.The influence of Lipo-MIT on the expression levels of PI3K/AKT pathway-related proteins,epithelial-mesenchymal transition related proteins,and stemness related proteins in both cells and tumor tissues was also investigated.RESULTS The half maximal inhibitory concentrations of Lipo-MIT against A2780,SK-OV3,and OV-CAR5 cells were 0.72,5.41,and 2.77 μmol/L,respectively.Compared with solvent control(0.1%dimethyl sulfoxide),0.5-2.5 μmol/L Lipo-MIT significantly reduced the cell colony formation rate,shortened the cell migration distance,decreased the number of migrated cells,down-regulated the protein expression of N-cadherin,up-regulated the protein expression of E-cadherin(P＜0.05),and also decreased the stem cell sphere formation frequency and down-regulated the protein expression of aldehyde dehydrogenase 1A1(ALDH1A1)(P＜0.05).Additionally,1.0 and 2.5 μmol/L Lipo-MIT significantly reduced the stem cell sphere formation probability and down-regulated the protein expression of sex determining region Y box protein 2 in cells(P＜0.05).In vivo experimental results demonstrated that 2,5 mg/kg Lipo-MIT had no significant effects on the body weight,food intake,water intake,and organ(heart,liver,spleen,lung,and kidney)indices of tumor-bearing nude mice(P＞0.05),but could significantly improve the pathological changes of tumor tissues and remarkably inhibit the protein expressions of N-cadherin,CD133 and ALDH1A1(only at 5 mg/kg Lipo-MIT),up-regulate the expression of E-cadherin(only at 5 mg/kg Lipo-MIT)in tumor tissues(P＜0.05).Lipo-MIT at different concentrations/doses significantly reduced the phosphorylation levels of PI3K and AKT proteins in cells/tumor tissues(P＜0.05).CONCLUSIONS Lipo-MIT can inhibit the proliferation and migration of ovarian cancer cells and the stemness by suppressing the activity of the PI3K/AKT pathway.