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AIM: To observe the effect of histone deacetylase inhibitor (HDACi) Belinostat on the viability of osteosarcoma cells and to study the underlying mechanism. METHODS: Osteosarcoma cell lines SAOS-2 and U2OS were incubated with Belinostat at different concentrations in vitro . The viability of the cells was measured by MTT assay. The activity of caspase-3/-7 and the DNA fragmentation were detected by fluorescence probe and ELISA, respectively. Western blot was used to detect the levels of histone acetylation, expression of PTEN, caspase-3, Bcl-xL and Akt, and phosphorylation of glycogen synthetase kinase 3β (GSK-3β) and Akt. Finally, the cells were incubated with Belinostat and doxorubicin at different concentrations, and then the combination index (CI) was calculated by MTT. RESULTS: Belinostat at 0.5, 1, 2.5 and 5 μmol/L inhibited the viability of U2OS cells and SAOS-2 cells in a dose-dependent manner, induced DNA fragmentation, enhanced caspase-3/-7 activity, and promoted the activation of caspase-3. At the same time, in the SAOS-2 cells, the expression of Bcl-xL was reduced, and the acetylation of histones H3 and H4 was increased. The results of Western blot showed that phosphorylation levels of Akt and GSK-3β in U2OS cells and SAOS-2 cells were decreased significantly after treatment with Belinostat (P <0.05). MTT results showed that combination of Belinostat and doxorubicin further reduced the viability of U2OS and SAOS-2 cells (CI<1). CONCLUSION: Belinostat inhibits the viability of osteosarcoma cells treated with doxorubicin, and the mechanism may be related to the inhibition of Akt signaling pathway. 相似文献
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AIM:To study the effect of nuclear factor E2-related factor 2 (NRF2) on oxidative stress injury and lysosomal dysfunction in doxorubicin (DOX)-induced rat myocardial H9C2 cells. METHODS:The H9C2 cells were treated with DOX. The expression of NRF2 at mRNA and protein levels was determined by real-time PCR and Western blot. The H9C2 cells stably over-expressing NRF2 were established by lentiviral infection. Real-time PCR and Western blot were used to identify the efficiency of over-expression. After DOX treatment, the cell viability was measured by CCK-8 assay, the activity of lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), and the content of malondialdehyde (MDA) in the cell supernatant were detected. FITC-dextran was used to analyze lysosomal pH, and the protein expression of lysosomal-associated membrane protein 1 (LAMP1) and cathepsin B was determined by Western blot.RESULTS:The expression of NRF2 at mRNA and protein levels in DOX-treated H9C2 cells was significantly decreased (P<0.05). Over-expression of NRF2 significantly up-regulated the mRNA and protein expression of NRF2 in DOX-treated H9C2 cells (P<0.05). After DOX treatment, the cell viability was decreased, and LDH activity was increased. The activity of SOD, GSH-Px and CAT was decreased, and the content of MDA was increased (P<0.05). The lysosomal pH was increased, and the protein expression of LAMP1 and cathepsin B decreased (P<0.05). Over-expression of NRF2 increased the cell viability, decreased LDH activity, increased the activity of SOD, GSH-Px and CAT, and decreased the content of MDA in cell supernatant (P<0.05). Over-expression of NRF2 also decreased the lysosomal pH, and increased the protein expression of LAMP1 and cathepsin B (P<0.05). CONCLUSION:DOX inhibits the expression of NRF2 in the myocardial H9C2 cells. Over-expression of NRF2 attenuates oxidative stress and lysosomal dysfunction in the H9C2 cells induced by DOX. 相似文献
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H. Petznek M. Kleiter A. Tichy A. Fuchs-Baumgartinger C. Hohenadl 《Research in veterinary science》2014
Therapy of cats suffering from feline injection site sarcomas (FISS) is still a challenging problem, as the recurrence rate after surgery is up to 70%. Four FISS-derived primary tumour cell lines and corresponding xenograft tumour mouse models were established to evaluate the efficacy of a concomitant chemo-/radiation therapy with doxorubicin. In vitro, strongly depending upon the timing of administration, pre-treatment with 0.25 µmol doxorubicin resulted in a significant enhancement of radiation-induced (3.5 Gy) tumour cell death. This result was confirmed in vivo, where only the combined chemo-/radiation therapy resulted in a significant reduction in tumour growth compared to the respective mono-therapies with either doxorubicin or radiation. These results support the use of the concomitant chemo-/radiation therapy for adjuvant treatment of FISS, particularly in advanced or recurrent disease where surgery alone is no longer feasible. 相似文献
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AIM: To investigate the changes of peroxisome proliferator-activated receptors (PPAR)α/peroxisome proliferator activated receptor coactivator 1 alpha (PGC-1α) in doxorubicin (DOX) induced dilated cardiomyopathy (DCM) and its effect on the energy metabolism and myocardial function in mice. METHODS: Forty mice were randomly divided into 4 groups: control group, DOX group, PPARα inhibitor group and PPARα agonist group. The DCM model was established by injection of DOX. The protein levels of PPARα/PGC-1α were detected. The PPARα inhibitor and PPARα agonist were used 2 weeks beforeinjection of DOX. The contents of adenine acid and phosphocreatine (Pcr) in the mitochondria were measured by high-performance liquid chromatography (HPLC). The ANT activity was analyzed by the atractyloside-inhibitor stop technique. The changes of the echocardiography and hemodynamics were also observed. RESULTS: DOX induced DCM model was successfully established. The protein levels of PPARα and PGC-1α in control group were significantly higher than those in DOX group (P<0.05). Both of the high-energy phosphate contents and the transport activity of ANT were decreased in DOX group (P<0.05), and the hemodynamic parameters were disordered (P<0.01). Compared with DOX group, PPARα inhibitor pre-treatment significantly reduced the PPARα/PGC-1α expression. Meanwhile, high-energy phosphate contents in the mitochondria and the ANT transport activity of the mitochondria decreased, as well as the left ventricular function (P<0.05). On the other hand, PPARα agonist significantly increased the expression of PPARα and PGC-1α, and improved the transport activity of ANT. In addition, the hemodynamic parameters were ameliorated, but the high-energy phosphate contents of the mitochondria did not significantly change. CONCLUSION: PPARα/PGC-1α plays an important role in the regulation of ANT transport activity in dilated cardiomyopathy induced by DOX, and the activation of PPARα/PGC-1α has protective effects on the DCM induced by DOX. 相似文献
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AIM: To investigate the effect and mechanism of osthole on increasing the cytotoxicity of doxorubicin (DOX) to prostate cancer cells. METHODS: MTT assay was performed to evaluate the viability of LNCaP cells treated with osthole and DOX. The protein expression of silent information regulator 1 (SIRT1), p53, acetylated p53 and Puma, as well as release of cytochrome C and activation of caspase-9 and caspase-3 in the LNCaP cells treated with osthole and DOX were determined by Western blot. The apoptosis of the LNCaP cells treated with osthole and DOX was analyzed by flow cytometry. RESULTS: Osthole significantly increased the cytotoxicity of DOX against p53-wildtype prostate cancer cell line LNCaP. Osthole significantly inhibited the expression of SIRT1 in the LNCaP cells. Transfection with SIRT1 plasmid decreased the cytotoxicity of osthole and DOX co-treatment against LNCaP cells. Combination with osthole and DOX significantly induced the over-expression and acetylation of p53. Transfection with p53 siRNA significantly decreased the synergistic effect of osthole on cytotoxicity of DOX-treated LNCaP cells. Combination with osthole and DOX significantly induced the release of cytochrome C into the cytoplasm from mitochondria, followed by activation of caspase-9 and its downstream molecule caspase-3, thus leading to cell apoptosis in the LNCaP cells. CONCLUSION: Osthole promotes the p53-dependent apoptosis in DOX-treated prostate cancer LNCaP cells by down-regulating the expression of SIRT1. 相似文献
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AIM: To investigate the changes of cardiac function, oxidative stress and apoptosis in myocardium of rat model of heart failure induced by adriamycin (ADR). METHODS: At the end of the study, we observed content of malondialdehyde (MDA), activity of superoxide dismutase (SOD) and apoptosis. Expression of P53 protein and p53 mRNA were measured with immunohistochemical method and RT-PCR, respectively. RESULTS: Our data showed that content of MDA increased, activity of SOD decreased and apoptosis in myocardium happened while cardiac function decreased after ADR treatment. p53 gene expression and P53 protein obviously increased in heart failure group. CONCLUSION: There were oxidative stress and apoptosis occurred significantly in a model of heart failureinduced by ADR. p53 gene might play an important role in the apoptosis. Correlation analyses suggested that apoptosis in myocardium was related to oxidative stress in ADR-induced heart failure model. 相似文献
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Lana S U'ren L Plaza S Elmslie R Gustafson D Morley P Dow S 《Journal of veterinary internal medicine / American College of Veterinary Internal Medicine》2007,21(4):764-769
BACKGROUND: Hemangiosarcoma (HSA) is a highly metastatic and often rapidly fatal tumor in dogs. At present, conventional adjuvant chemotherapy provides only a modest survival benefit for treated dogs. Continuous oral administration of low-dose chemotherapy (LDC) has been suggested as an alternative to conventional chemotherapy protocols. Therefore, we evaluated the safety and effectiveness of LDC using a combination of cyclophosphamide, etoposide, and piroxicam as adjuvant therapy for dogs with stage II HSA. HYPOTHESIS: We hypothesized that oral adjuvant therapy with LDC could be safely administered to dogs with HSA and that survival times would be comparable to those attained with conventional doxorubicin (DOX) chemotherapy. ANIMALS: Nine dogs with stage II splenic HSA were enrolled in the LDC study. Treatment outcomes were also evaluated retrospectively for 24 dogs with stage II splenic HSA treated with DOX chemotherapy. METHODS: Nine dogs with stage II splenic HSA were treated with LDC over a 6-month period. Adverse effects and treatment outcomes were determined. The pharmacokinetics of orally administered etoposide were determined in 3 dogs. Overall survival times and disease-free intervals were compared between the 9 LDC-treated dogs and 24 DOX-treated dogs. RESULTS: Dogs treated with LDC did not develop severe adverse effects, and long-term treatment over 6 months was well-tolerated. Oral administration of etoposide resulted in detectable plasma concentrations that peaked between 30 and 60 minutes after dosing. Both the median overall survival time and the median disease-free interval in dogs treated with LDC were 178 days. By comparison, the overall survival time and disease-free interval in dogs treated with DOX were 133 and 126 days, respectively. CONCLUSIONS: Continuous orally administered LDC may be an effective alternative to conventional high-dose chemotherapy for adjuvant therapy of dogs with HSA. 相似文献