ABSTRACT
Objective To explore whether PI3K inhibitor combined with oncolytic virus can play an effective oncolytic effect on osteosarcoma. Methods The cytotoxicity to tumor cells was detected by MTT method, and the mechanism of enhancing the anti-tumor activity was explored by observation of the swelling of endoplasmic reticulum using electron microscope and the expression of apoptosis-related proteins using Western blotting. The tumor clearance ability of the combination of the PI3k inhibitor ZSTK474 and vesicular stomatitis virus A51 (VSVA51) was verified by anti-tumor experiment in vivo. The apoptosis of tumor cells was verified by immunohistochemistry. Results PI3K inhibitor could be used as sensitizers of oncolytic VSVA51, and confirmed that the)' promoted the strong apoptosis of osteosarcoma cells by aggravating the stress of endoplasmic reticulum in tumor cells (P < 0 . 01). In vivo experiments also showed that PI3K inhibitors combined with VSVA51 could significantly promote the oncolytic effect of osteosarcoma (P<0.001), and this combination therapy enhanced the infiltration of immune cells in the tumor (P<0.001). Conclusion PI3K inhibitors combined with oncolytic virus is a potential therapy for osteosarcoma.
ABSTRACT
OBJECTIVE:To study the inhibitory effects of phosphatidylinositol 3-kinase (PI3K) inhibitor LY29400 (“LY”) combined with indole-3-carbinol (I3C) on the proliferation of human anaplastic thyroid carcinoma FRO cells. METHODS:RFO cells in logarithmic growth phase were divided into blank control group,I3C (250 μmol/L) group,LY (10 μmol/L) group and combination (I3C of 250 μmol/L + LY of 10 μmol/L) group,which were subject to 24,48 and 72 h drug action. MTT method was used to determine and calculate the inhibitory rates of the cells in all groups,flow cytometry assay to determine the apoptosis rates after 48 h action,Western blot method to determine the expressions of Capspase-3 proteins thereafter and immunohistochemi-cal method to determine the expressions of Bcl-2 and Bax thereafter. RESULTS:The inhibitory rate obviously increased with the ex-tension of drug action time,with statistical significance at each time point in combination group (P<0.05). Compared to I3C group and LY group,combination group had higher inhibitory rate,apoptosis rate and the expressions of Capspase-3 protein and Bax,and lower Bcl-2 expression and ratio of Bcl-2 to Bax,with statistical significance (P<0.01). CONCLUSIONS:LY com-bined with I3C has synergistic inhibitory effects on the proliferation of FRO cells by a mechanism which may be related to apopto-sis induced by down-regulating Bcl-2 expression,up-regulating Bax expression and activating Caspase cascade reaction.
ABSTRACT
Objective Increasing evidence suggest that aberrant activation of PI3K/Akt is involved in many human cancers, and that inhibition of the PI3K/Akt pathway might be a promising strategy for cancer therapy. The study is to evaluate the effects of combined therapy of PI3K inhibitor (LY294002) and Ad-PTEN in athymic mice xenogeneic transplant model of human glioma and to reveal the possible mechanisms involved.Methods Twenty-four athymic mice were randomly divided into 4 groups (DMSO、Ad-vector plus DMSO、LY294002 alone and Ad-PTEN plus LY294002), and were treated, respectively. Athymic mice xenogeneic transplant model was established by inoculation (sc) with LN229 glioma cells. Body mass (BM) and diameter of tumor mass were measured. Furthermore, The protein expressions of PTEN、p-Akt、CyclinD1、Caspase-3、MMP-2、p-FAK in tumor tissues were analyzed with immunohistochemistry.Results The tumor-inhibiting rate of was significantly higher in Ad-PTEN plus LY294002 than in the LY294002 alone (92.46 vs 65.59%)( P <0.05).The protein expressions of PTEN and Caspase-3 were significantly higher, while PCNA、CyclinD1、bcl-2 and MMP-2、p-FAK was significantly lower in Ad-PTEN plus LY294002 group than in the other three groups ( P <0.05).Conclusions LY294002 plus Ad-PTEN achieve better outcome than either alone in treating glioma possibly through enhancement of the inhibitory action of PI3K/Akt pathway and Ad-PTEN pathway.