ABSTRACT
Neocarzinostatin (NCS) is a member of enediyne antibiotics with high anticancer potential. Our study was performed to explore the synergistic anti-glioma effects of NCS and paclitaxel (PTX) in vitro and in vivo. By 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the cytotoxicities of the drugs to human glioma cells U87MG and rat glioma cells C6 were evaluated. The results showed that the combinations of NCS and PTX can synergistically inhibit glioma cells survival. Cell apoptosis was detected by flow cytometry, and the results showed that the combinations of NCS and PTX synergistically enhanced apoptosis ratio of glioma cells. Western blot revealed that the cell signaling pathways of proliferation and apoptosis were synergistically regulated, in which Akt was synergistically inactivated, p53 was up-regulated with down-regulation of bcl-2. Meanwhile, with the subcutaneous model of U87MG cells and intracerebral implantation model of C6 cells, the combination strategy could synergistically delay the glioma growth and significantly prolong the survival of rats bearing orthotopic glioma. This study demonstrates that the combination of NCS and PTX can potentiate the effect on survival and apoptosis of glioma cells via suppression of Akt, bcl-2, and activations of p53; Meanwhile, the in vivo studies also confirmed that the combination of NCS and PTX synergistically inhibit the gliom growth. Our data about the combinational effects of NCS with PTX may provide an alternative strategy for glioma therapy.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Brain Neoplasms/drug therapy , Glioma/drug therapy , Paclitaxel/therapeutic use , Zinostatin/therapeutic use , Animals , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Synergism , Glioma/pathology , Humans , Male , Mice, Nude , Paclitaxel/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats, Wistar , Tumor Burden/drug effects , Tumor Suppressor Protein p53/metabolism , Zinostatin/pharmacologyABSTRACT
Objective To evaluate the effect of dexmedetomidine on myocardial injury induced by renal ischemia-reperfusion (I/R) injury in rats.Methods Twenty-four male Wistar rats,weighing 280-300 g,were randomly divided into 3 groups (n =8 each):sham operation group (group S),group I/R and dexmedetomidine group (group Dex).Renal ischemia was induced by occlusion of bilateral renal arteries for 45 min followed by reperfusion in I/R and Dex groups.At 20 min before ischemia,dexmedetomidine 50 μg/kg was injected intraperitoneally in group Dex,and the rest procedures were similar to those previously described in group I/R.The rats were sacrificed at 24 h of reperfusion and myocardial specimens were obtained for determination of malondialdehyde (MDA) content and superoxide dismutase (SOD) activity.The apoptosis in cardiomyocytes was examined by flow cytometry.Apoptosis index was calculated.The expression of Bcl-2 and Bax was detected by immunohistochemistry,and Bcl-2/Bax ratio was calculated.Results Compared with group S,apoptosis index and MDA content were significantly increased in I/R and Dex groups,Bcl-2/Bax ratio was decreased in group I/R,and Bcl-2/Bax ratio was increased in group Dex.Compared with group I/R,apoptosis index and MDA content were significantly decreased,and SOD activity and Bcl-2/Bax ratio were increased in group Dex.Conclusion Dexmedetomidine can attenuate myocardial injury induced by renal I/R in rats,and the mechanism may be related to inhibited apoptosis in cardiomyocytes and reduced lipid peroxidation.
