Objective:To explore the cardioprotective effect of hesperidin against arsenic trioxide-induced cardiac toxicity in rats.Methods:Cardiac toxicity was induced by oral administration of 4 mg/kg arsenic trioxide for 30 d...Objective:To explore the cardioprotective effect of hesperidin against arsenic trioxide-induced cardiac toxicity in rats.Methods:Cardiac toxicity was induced by oral administration of 4 mg/kg arsenic trioxide for 30 days.Hematological,biochemical,electrocardiography,echocardiography,and histopathological examinations were performed.Results:Hesperidin decreased the neutrophil-to-lymphocyte ratio,calcium,creatine kinase-myoglobin binding,lactate dehydrogenase,IL-6,and lipid peroxidation,as well as increased sodium and potassium concentration and superoxide dismutase and catalase activity in arsenic trioxide-intoxicated rats.Moreover,it reduced peak systolic velocity and end-diastolic velocity while increasing heart rate.Arsenic trioxide-induced histopathological damage to cardiac tissue was prominently alleviated by hesperidin treatment.Conclusions:Hesperidin attenuates arsenic trioxide-induced cardiac toxicity in rats.Therefore,it can be further explored as a cardioprotective agent.展开更多
In this study, arsenic trioxide(ATO) was encapsulated in liposomes via copper acetate(Cu(OAc)2) gradients and high entrapment efficiency of over 80% was obtained. The average particle size and the zeta-potential of th...In this study, arsenic trioxide(ATO) was encapsulated in liposomes via copper acetate(Cu(OAc)2) gradients and high entrapment efficiency of over 80% was obtained. The average particle size and the zeta-potential of the liposomes were detected to be 115.1 ± 29.1 nm and-21.97 ± 0.6 m V, respectively. The TEM images showed rod-like precipitates in the inner aqueous phase, which was supposed be due to the formation of insoluble ATO–Cu complex.The in vitro drug release of ATO–Cu liposomes exhibited a sustained release over 72 h, and the release rates decreased with the increase of the p H of release media. Pharmacokinetic and tissue distribution studies of ATO liposomes showed significantly reduced plasma clearance rate, increased AUC0–12h and T1/2, and improved tumor distribution of As compared to iv administration of ATO solution. The anti-tumor effect of ATO loaded liposomes to S180 tumor-bearing mice was significantly improved with a tumor inhibition rate of 61.2%,meanwhile the toxicity of encapsulated ATO was greatly decreased. In conclusion, ATO can be effectively encapsulated into liposomes by remote loading method via Cu(OAc)2 gradients;the co-administration of ATO and Cu(Ⅱ) via liposomal formulation may find wide applications in the treatment of various tumors.展开更多
All-trans retinoic acid(ATRA)and pre-upfront arsenic trioxide(ATO)have revolutionized the therapy of acute promyelocytic leukemia(APL).However,internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)mutatio...All-trans retinoic acid(ATRA)and pre-upfront arsenic trioxide(ATO)have revolutionized the therapy of acute promyelocytic leukemia(APL).However,internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)mutations is associated with increased risk of relapse.The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA,idarubicin(IDA)and/or ATO,followed by ATRA plus ATO along with anthracycline,as consolidation therapy.A total of 72 patients newly diagnosed with APL were included in this study.83.3%of the patients achieved complete remission(CR)after induction therapy.FLT3-ITD mutations were detected in 16(22.2%)patients and closely related to bcr-3 PML-RARa transcript(P<0.001).The 5-year overall survival(OS)rate was 100%in both FLT3-ITDposltlve and FLT3-ITD^(negatlve)groups,and there was no significant difference in 5-year event-free survival(EFS)between the two groups(78.3%vs.83.3%,P=0.85).ATRA plus ATO and anthracycline-based chemotherapy achieved great outcome in newly diagnosed APL regardless of the FLT3-ITD mutation status.展开更多
BACKGROUND Arsenic trioxide(ATO)is recommended for patients who do not achieve molecular remission or who have molecular or morphologic relapse.However,there are no guidelines for adjusting ATO dosage in patients with...BACKGROUND Arsenic trioxide(ATO)is recommended for patients who do not achieve molecular remission or who have molecular or morphologic relapse.However,there are no guidelines for adjusting ATO dosage in patients with severe renal failure or on dialysis.Herein,we report the successful treatment of relapsed acute promyelocytic leukemia(APL)in a patient on hemodialysis with ATO single agent and review the cases in literature.CASE SUMMARY A 46-year-old woman who has been on hemodialysis to chronic glomerulonephritis for 15 years visited our hospital for pancytopenia.She had been seen for pancytopenia 3 years ago and had been diagnosed with APL.She also received chemotherapy for APL but unfortunately was lost to follow-up after her second consolidation chemotherapy.She was noted to have pancytopenia by her nephrologist during hemodialysis 1 mo ago.Bone marrow biopsy and reverse transcriptase-polymerase chain reaction(RT-PCR)tests revealed a diagnosis of relapsed APL.Treatment for relapsed APL with ATO single agent was started and she achieved molecular remission after administering 24 doses of ATO.Thus far,four consolidation therapies have been performed with the ATO single agent,and,to date,the molecular remission has been maintained as negative promyelocytic leukemia/retinoic acid receptor-αfusion gene as confirmed by RTPCR testing for two years.CONCLUSION This is a rare case of relapsed APL successfully treated with the single agent ATO in a patient on hemodialysis.展开更多
Objective: To understand whether arsenic trioxide (As2O3 )-induced biological effects are associated with degradation of PML proteins. Methods Acute promyelocytic leukemia (APL) cell line NB4, acute T-lymphocytic leuk...Objective: To understand whether arsenic trioxide (As2O3 )-induced biological effects are associated with degradation of PML proteins. Methods Acute promyelocytic leukemia (APL) cell line NB4, acute T-lymphocytic leukemia cell line Jurkat, acute myeloid leukemia cell line U937, and chronic myelocytic leukemia blast crisis cell line K562 were used as in vitro models In different cell lines, the As2O3-induced biological effects were determined by cell growth, cell viability, cell morphology, and flow cytometry assay on sub G1 cell content. The alteration of PML proteins was analyzed by immunofluorescence Results in terms of growth inhibition and apoptosis induction, 1. 0μmol/L As2O3 had different effects on different cell lines. However, degradation of PML proteins occurred in all the cell lines with As2O3 treatment. Conclusion As2O3-indued biological effects may be independent of PML protein-degradation.展开更多
AIM To study the effects of arsenic trioxide andHCPT on different degrees of differentiated gastriccancer cells（SGC-7901,MKN-45,MKN-28）withrespect to both cytotoxicity and induction ofapoptosis in vitro.METHODS The ...AIM To study the effects of arsenic trioxide andHCPT on different degrees of differentiated gastriccancer cells（SGC-7901,MKN-45,MKN-28）withrespect to both cytotoxicity and induction ofapoptosis in vitro.METHODS The cytotoxicity of As<sub>2</sub>O<sub>3</sub> and HCPTon gastric cancer cells was determined by MTTassay.Morphologic changes of apoptosis ofgastric cancer cells were observed by lightmicroscopy and transmission electron microscopy.Apoptosis and cell cycle changes of gastric cancercells induced by HCPT and As<sub>2</sub>O<sub>3</sub> were investigatedby TUNEL method and flow cytometry.RESULTS As<sub>2</sub>O<sub>3</sub> and HCPT had remarkablecytotoxic effects on different degrees ofdifferentiated gastric cancer cells.The IC<sub>50</sub>ofAs<sub>2</sub>O<sub>3</sub> on well differentiated gastric cancer cellMKN-28,moderately differentiated gastric cancercell SGC-7901,and poorly differentiated gastriccancer cell MKN-28 were 8.91 μmol/L,10.57μmol/L,and 11.65 μmol/L,respectively.The IC<sub>50</sub>of HCPT on MKN-28,SGC-7901,and MKN-45 were9.35 mg/L,10.21 mg/L,and 12.63 mg/Lrespectively after 48 h treatment.After 12 h ofexposure to both drugs,gastric cancer cellsexhibited morphologic features of apoptosis,including cell shrinkage,nuclear condensation, and formation of apoptotic bodies.A typicalsubdiploid peak before G<sub>0</sub>/G<sub>1</sub> phase was observedby flow cytometry.The apoptotic rates of SGC-7901,MKN-45,and MKN-28 were 13.84%,22.52%,and 9.68%,respectively after 48 hexposure to 10 μmol/L As<sub>2</sub>O<sub>3</sub>.The apoptotic ratesof SGC-7901,MKN-45,and MKN-28 were 21.88%,12.35%,and 30.26%,respectively after 48 hexposure to 10 mg/L HCPT.The apoptotic indicewere 7%-15% as assessed by TUNEL method.The effect of As<sub>2</sub>O<sub>3</sub> on SGC-7901 showedremarkable cell cycle specificity,which inducedcell death in G<sub>1</sub> phase,and blocked G<sub>2</sub>/M phase.HCPT also showed a remarkable cell cyclespecificity,by inducing cell death and apoptosis inG<sub>1</sub> phase and arrest of proliferation at S phase.CONCLUSION As<sub>2</sub>O<sub>3</sub> and HCPT exhibitsignificant cytotoxicity on gastric cancer cells byinduction of apoptosis.As<sub>2</sub>O<sub>3</sub> and HCPT mighthave a promising prospect in the treatment ofgastric cancer,which needs to be further studied.展开更多
INTRODUCTION Cell apoptosis,which involves the biologic regulation of the numbers and vital activity of cells,is an important metaboloc process in both normal cells and tumor cells.
AIM To study the effect of a varyingconcentrations of arsenic trioxide on humanhepatoma cell line BEL-?402 cultured in vitro andits mechanism of action.METHODS The BEL-7402 cells were treatedwith arsenic trioxide（at ...AIM To study the effect of a varyingconcentrations of arsenic trioxide on humanhepatoma cell line BEL-?402 cultured in vitro andits mechanism of action.METHODS The BEL-7402 cells were treatedwith arsenic trioxide（at the concentrations of0.5,1,2 μmol/L,respectively）for 4 successivedays.The cell growth and proliferation wereobserved by cell counting and cell-growth curve.Morphologic changes were studied withelectronmicroscopy.Flow cytometry was usedto assay celI-DNA distribution and the proteinexpression of Bcl-2 and Bax detected byimmunocytochemical method.RESULTS The cell growth was significantlyinhibited by varying concentrations of arsenictrioxide as revealed by cell counting and cell-growth curve,which was dose- and time-dependent.Arsenic trioxide treatment at 0.5,1and 2 μmol/L resulted in a sub-G1 cell peak,theapoptosis rate of the control group was 9.31%and that of 0.5 μmol/L arsenic trioxide 15.53%,no significant difference was seen between thetwo.The apoptosis rates of 1,2 μmol/L arsenictrioxide were 19.10% and 21.87% respectively,which were much higher（both P【0.05）.Decrease of G<sub>0</sub>/G<sub>1</sub> phase cells and increase of Sphase cells were observed by flow cytometry,suggesting the inhibition effect of 0.5,1,2 μmol/L arsenic trioxide on BEL-7402 cell lay in the G<sub>0</sub>/G<sub>1</sub> phase.Morphologic changes such asintact cell membrane,nucleic condensation,apoptotic body formation were seen undertransmission electronmicrescopy,whereas the0.5 mol/L arsenic trioxide-treated BEL-7402cells showed decrease of nucleocytoplasmicratio,round nucleus,well-differentiatedorganelles in the cytoplasm.The processes andmicrovilli on the cell surface of the experimentalgroups under scanning electron microscopy weresignificantly decreased.High expressions ofBcl-2 and Bax were detected in 1 and 2 μmol/Larsenic trioxide-treated cells,these were 46%,87.33% and 83.08%,95.83% respectively,among which that of Bax was more significant.Arsenic trioxide treatment at 0.5 μmol/Lresulted in a higher expression level of Bcl-2 andlower expression level of Bax,which were8.81% and 3.83% respectively,as comparedwith that of the control group（15.33%）（P<sub>1</sub>【0.01,P<sub>2</sub>【0.01）.CONCLUSION Arsenic trioxide not onlyinhibited proliferation but also induced apoptosisof human hepatoma cell line BEL-7402.Theinduced-apoptosis effect of 1,2 μmol/L arsenictrioxide was related to the expression level ofBcl-2 and Bax.展开更多
AIM:To investigate the changes in apoptosis in gastrointestinal cancer cells from patients with gastrointestinal cancers treated with arsenic trioxide(As2O3);and to study the possible molecular mechanisms of such chan...AIM:To investigate the changes in apoptosis in gastrointestinal cancer cells from patients with gastrointestinal cancers treated with arsenic trioxide(As2O3);and to study the possible molecular mechanisms of such changes by detecting the expression levels of p53and Bcl-2.METHODS:Twenty patients with gastrointestinal adenocarcinoma based on endoscopic and biopsy findings(ten patients with gastric cancer and ten patients with colorectal cancer)who received treatment in our hospital between August 2007 and December 2008were included in this study.None of the patients had received anti-tumour agents prior to As2O3 treatment.As2O3 was administered intravenously at a dose of 0.01g/d diluted with 5%glucose in normal saline for 2-3h for 3 consecutive days before surgery.Morphological changes associated with apoptosis of gastrointestinal cancer cells were observed by light microscopy.Changes in the apoptotic index induced by As2O3 were investigated using the terminal deoxynucleotidyl transferase dUTP nick end labelling method.Expression levels of p53 and Bcl-2 proteins in gastrointestinal cancer tissues were determined by immunohistochemistry.RESULTS:The apoptotic index of human gastrointestinal cancer cells was higher in cells from patients treated with As2O3 than in those not treated(P<0.05).p53 protein expression in gastrointestinal tissues was unchanged by As2O3(P>0.05).However,Bcl-2 protein expression in gastrointestinal tissues was downregulated by As2O3(P<0.01).CONCLUSION:These results demonstrate that As2O3treatment in patients with gastrointestinal cancers can induce apoptosis in gastrointestinal cancer cells and down-regulate Bcl-2 protein expression.展开更多
To study the effects of arsenic trioxide (As2O3) on the in vitro growth of human bladder cancer cells and the mechanisms. The growth inhibition rates of human bladder cancer cell line BIU87 by various concentrations o...To study the effects of arsenic trioxide (As2O3) on the in vitro growth of human bladder cancer cells and the mechanisms. The growth inhibition rates of human bladder cancer cell line BIU87 by various concentrations of As2O3 were detected by using MTT method. Cell apoptosis was detected by in situ terminally labeled transferase technique and bcl-2 gene expression of BIU-87 cells was observed by SABC immunohistochemical method. The results showed that As2O3 could inhibit the growth of BIU-87 effectively in a dose-dependent manner. After drug’s action, the apoptotic bladder cancer cells were obviously increased, which depended on the prolongation of the action time and Bcl-2 expression of BIU-87 cells was decreased significantly. It was suggested that As2O3 could significantly inhibit the growth of bladder human cancer cells. Inducing cell apoptosis by down- regulating the expression of hcl-2 gene might be one of its action mechanisms.展开更多
Objective: To evaluate whether arsenic trioxide (AS2O3) could downregulate human telomerase reverse transcriptase (hTERT) gene expression and telomerase activity during induction of apoptosis of HL-60 cells. Methods: ...Objective: To evaluate whether arsenic trioxide (AS2O3) could downregulate human telomerase reverse transcriptase (hTERT) gene expression and telomerase activity during induction of apoptosis of HL-60 cells. Methods: Apoptosis was detected by morphological observation and flow cytomertric cell cycle analysis. The expression of hTERT at mRNA and protein levels was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence using fluoresce isothiocyanate (FITC) label, respectively. Telomerase activity was determined by polymerase chain reaction enzyme-linked immunoassay (PCR-ELISA). Results: Treatment of 2 祄ol/L at As2O3 could induce apoptosis of HL-60 cells. hTERT was decreased at both mRNA and protein levels during apoptosis of HL-60 cells. Telomerase activity of HL-60 cells was significantly inhibited. Conclusion:It is suggested that telomerase activity of HL-60 cells might be specifically inhibited by AS2O3 through the downregulation of hTERT gene expression.展开更多
AIM: To investigate the effect of arsenic trioxide on human gastric cancer cell line MKN45 with respect to both cytotoxicity and induction of apoptosis in vitro. METHODS: MKN45 cells were treated with arsenic trioxide...AIM: To investigate the effect of arsenic trioxide on human gastric cancer cell line MKN45 with respect to both cytotoxicity and induction of apoptosis in vitro. METHODS: MKN45 cells were treated with arsenic trioxide(As2O3) at the concentration of 1, 5, and 10 μmol/L,respectively, for three successive days. Cell growth and proliferation were observed by cell counting and trypanblue exclusion. Cytotoxicity of As2O3 was determined by MTT assay. Morphologic changes were studied with light microscopy. Flow cytometry was used to assay cell DNA distribution and apoptotic cells were confirmed with terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling (TUNEL) and DNA electrophoresis.RESULTS: The growth of MKN45 cells was significantlyinhibited by As2O3 which was confirmed by colony-forming assay. After 7 d of culture with various concentrations of As2O3, colony-forming capacity of MKN45 cells decreased with As2O3 increment in comparison with that of control group. The inhibitory rate of colony-formation was 38.5%, 99.1%, and 99.5% when the concentration of As2O3 was1, 5, and 10 iμmol/L in culture medium, respectively. The cell number of a single colony in drug treatment groups was less than that of control group. The cell-killing rate of As2O3 to MKN45 cells was both dose- and timedependent with an IC50 of (11.05±0.25) μmol/L. After incubation in 10 μmol/L As2O3 for 24 h, the cell-killing rate was 27.1%, and it was close to 50% after 48 h. The results showed that As2O3 induced time- and dosedependent apoptosis in MKN45 cells, blocked at G2/M phase. The apoptotic peak (sub-G1 phase) appeared and cell apoptotic rate in MKN45 cells was 18.3-32.5% aftertreatment by 10 μmol/L As2O3 for 48 h. The percentage of G2/M cell of the experimental groups was 2.0-5.0 times than that of the control group. Gel electrophoresis of DNA from cells treated with each concentration of As2O3 for 48 h revealed a 'ladder' pattern, indicating preferential DNA degradation at the internucleosomal, linker DNA sections. TUNEL also demonstrated strand breaks in DNA of MKN45 cells treated with As2O3, while control cellsshowed negative labeling.CONCLUSION: As2O3 can induce apoptosis of human gastric carcinoma cells MKN45, which is the basis of its effectiveness. It shows great potential in the treatment of gastric carcinoma.展开更多
INTRODUCTIONThe main component of a traditional Chinese drug 'Pishuang'. arsenic trioxide (As2O3), has obviously selective anti-tumor effect on human hepatocellular carcinoma (HCC)in both in vitro and in vivo ...INTRODUCTIONThe main component of a traditional Chinese drug 'Pishuang'. arsenic trioxide (As2O3), has obviously selective anti-tumor effect on human hepatocellular carcinoma (HCC)in both in vitro and in vivo studies[1-5]. Due to limited effectiveness when any anti-carcinogen is used alone and obviously increased toxicity when the dose is raised, there is no exception for As2O3. Furthermore, combined chemotherapy contributes to improve therapeutic effectiveness, disperse toxicity and surmount drug-resistance,in which the combination of traditional Chinese and modern medicine has more advantages and characteristics. As a result,we made an experimental study on anti-tumor effect of As2O3in combination with cisplantin (PDD) or doxorubicin (ADM)on HCC. to investigate the possibility of AS2O3 in combination with PDD or ADM and nature of interaction between them,and to provide experimental basis for clinical application.展开更多
AIM: To investigate the inhibitory effect of As2O3 on angiogenesis of tumor and expression of vascular endothelial growth factor (VEGF) in tumor cells in vivo and in vitro. METHODS: The solid tumor model was formed in...AIM: To investigate the inhibitory effect of As2O3 on angiogenesis of tumor and expression of vascular endothelial growth factor (VEGF) in tumor cells in vivo and in vitro. METHODS: The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were randomly divided into three groups. As2O3 was injected into the arsenic-treated groups (2.5 mg/kg and 5 mg/kg) and the same volume of saline solution was injected into the control group. Microvessel density (MVD) and expression of VEGF were detected with immunofluorescence laser confocal technology. Further expression of VEGF protein and VEGF mRNA was measured with Western bloting and fluorescence quantitative RT- PCR in SGC-7901 cells treated with As2O3. RESULTS: In nude mice, after treatment with 5 mg/kg and 2.5 mg/kg As2O3 respectively, about 50% and 30% tumor growth inhibition were observed correspondingly (P < 0.05, P < 0.05). Decrease in MVD appeared in As2O3-treated tumors compared with control group (P < 0.001, P < 0.001). MVD in tumors was significantly lower in 5 mg/kg group than in 2.5 mg/kg group (P < 0.01). The fluorescence intensity levels of VEGF in tumor cells were significantly lowered in the arsenic-treated groups (P < 0.01, P < 0.01). The fluorescence intensity level of VEGF in 5 mg/kg group was lower than that in 2.5 mg/ kg group (P < 0.01). In vitro, the expression of VEGF protein decreased in dose- and time-dependent manner after the treatment with As2O3, but in VEGF mRNA no significant difference was found between the control group and the treated groups. CONCLUSION: As2O3 can inhibit solid tumor growth by inhibiting the formation of new blood vessels. One of the mechanisms is that As2O3 can inhibit VEGF protein expression.展开更多
Objective To observe the apoptosis of osteosarcoma MG-63 cells induced by As2O3 and to explore its possible mechanisms. Methods The flowcytometric analysis and transmission electronmicroscope were performed to investi...Objective To observe the apoptosis of osteosarcoma MG-63 cells induced by As2O3 and to explore its possible mechanisms. Methods The flowcytometric analysis and transmission electronmicroscope were performed to investigate the inducing apoptosis and inhibitative of As2O3 on osteosarcoma MG-63 cells. In order to study mechanism of apoptosis in MG-63 cells treated with As2 O3, microarray was performed. The down-regulated gene was confirmed by RT-PCR, Northern-blotting. Results After treated with As2O3, hypodiploid peak before G0/G1 phase was observed in MG-63 cells through FCM analysis. Loss of microvilli, condensation and fragmentation of nuclear chromatin, condensation of cytoplasmic organelles, dilatation of the endoplasmic reticulum shrinkage of cells and alterations in cell membranes and apoptosis bodies which were observed in MG-63 cells treated with As2O3 by transmission electronmicroscope. The results of microarray show that As2 O3 induced MG-63 cell apoptosis involves down-regulation of IEX-1 and the down-regulated gene is confirmed by RT-PCR and Northern-blotting.Conclusion The results show that As2 O3 selectively inhibits growth of the solid tumor MG-63 cells by triggering apoptosis and indicates MG-63 induced by As2O3 cell apoptosis may through the IEX-1 pathway.展开更多
AIM: To investigate the effect of arsenic trioxide (As2O3) on expression of vascular endothelial growth factor receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR) in human gastric tumor cells and proliferation of vascular e...AIM: To investigate the effect of arsenic trioxide (As2O3) on expression of vascular endothelial growth factor receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR) in human gastric tumor cells and proliferation of vascular endothelial cells. METHODS: The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were treated with As2O3. Microvessel density (MVD) and expression of Flt-1 and KDR were detected by immunofluorescence laser confocal microscopy. SGC-7901 cells were treated respectively by exogenous recombinant human VEGF165 or VEGF165 + As2O3. Cell viability was measured by MTT assay. Cell viability of ECV304 cells was measured by MTT assay, and cell cycle and apoptosis were analyzed using ? ow cytometry. RESULTS: The tumor growth inhibition was 30.33% and 50.85%, respectively, in mice treated with As2O3 2.5 and 5 mg/kg. MVD was signifi cantly lower in arsenic-treated mice than in the control group. The ? uorescence intensity levels of Flt-1 and KDR were significantly less in the arsenic-treated mice than in the control group. VEGF165 may accelerate growth of SGC7901 cells, but As2O3 may disturb the stimulating effect of VEGF165. ECV304 cell growth was suppressed by 76.51%, 71.09% and 61.49% after 48 h treatment with As2O3 at 0.5, 2.5 and 5 μmol/L, respectively. Early apoptosis in the As2O3- treated mice was 2.88-5.1 times higher than that in the controls, and late apoptosis was 1.17-1.67 times higherthan that in the controls. CONCLUSION: Our results showed that As2O3 delays tumor growth, inhibits MVD, down-regulates Flt-1 and KDR expression, and disturbs the stimulating effect of VEGF165 on the growth of SGC7901 cells. These results suggest that As2O3 might delay growth of gastric tumors through inhibiting the paracrine and autocrine pathways of VEGF/VEGFRs.展开更多
Double staining flow cytometry was performed using 7-amino actinomycin D and 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate,to detect the level fluctuation of reactive oxygen species (ROS) during the cel...Double staining flow cytometry was performed using 7-amino actinomycin D and 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate,to detect the level fluctuation of reactive oxygen species (ROS) during the cell cycle of normal NB4 cells. Our results showed that NB4 cells possessed higher level of ROS in G2/M phase than in G1 and S phases. Double staining flow cytometry,with TdT mediated dUTP nick end labeling (Tunel) and propidium iodide (PI),indicated that As2O3 (2 μM) could induce apoptosis in NB4 cells prevailingly from G2/M phase,and this efficacy was enhanced upon co-administration of 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) (2.5 μM) which could produce the endogenous ROS. These results suggested that different ROS level in different cell cycle phases of NB4 cells might determin the selective induction of G2/M apoptosis and the cells' susceptibility to apoptosis by As2O3.展开更多
Since arsenic trioxide was first approved as the front line therapy for acute promyelocytic leukemia 25 years ago,its anti-cancer properties for various malignancies have been under intense investigation.However,the c...Since arsenic trioxide was first approved as the front line therapy for acute promyelocytic leukemia 25 years ago,its anti-cancer properties for various malignancies have been under intense investigation.However,the clinical successes of arsenic trioxide in treating hematological cancers have not been translated to solid cancers.This is due to arsenic's rapid clearance by the body's immune system before reaching the tumor site.Several attempts have henceforth been made to increase its bioavailability toward solid cancers without increasing its dosage albeit without much success.This review summarizes the past and current utilization of arsenic trioxide in the medical field with primary focus on the implementation of nanotechnology for arsenic trioxide delivery to solid cancer cells.Different approaches that have been employed to increase arsenic's efficacy,specificity and bioavailability to solid cancer cells were evaluated and compared.The potential of combining different approaches or tailoring delivery vehicles to target specific types of solid cancers according to individual cancer characteristics and arsenic chemistry is proposed and discussed.展开更多
文摘Objective:To explore the cardioprotective effect of hesperidin against arsenic trioxide-induced cardiac toxicity in rats.Methods:Cardiac toxicity was induced by oral administration of 4 mg/kg arsenic trioxide for 30 days.Hematological,biochemical,electrocardiography,echocardiography,and histopathological examinations were performed.Results:Hesperidin decreased the neutrophil-to-lymphocyte ratio,calcium,creatine kinase-myoglobin binding,lactate dehydrogenase,IL-6,and lipid peroxidation,as well as increased sodium and potassium concentration and superoxide dismutase and catalase activity in arsenic trioxide-intoxicated rats.Moreover,it reduced peak systolic velocity and end-diastolic velocity while increasing heart rate.Arsenic trioxide-induced histopathological damage to cardiac tissue was prominently alleviated by hesperidin treatment.Conclusions:Hesperidin attenuates arsenic trioxide-induced cardiac toxicity in rats.Therefore,it can be further explored as a cardioprotective agent.
基金Research Grant from Liaoning Province Office of EducationChina(No.L2014395)+1 种基金the Natural Science Foundation of Liaoning Province(No.201602711)Supporting Program for Young Researchers from Sheyang Pharmaceutical University。
文摘In this study, arsenic trioxide(ATO) was encapsulated in liposomes via copper acetate(Cu(OAc)2) gradients and high entrapment efficiency of over 80% was obtained. The average particle size and the zeta-potential of the liposomes were detected to be 115.1 ± 29.1 nm and-21.97 ± 0.6 m V, respectively. The TEM images showed rod-like precipitates in the inner aqueous phase, which was supposed be due to the formation of insoluble ATO–Cu complex.The in vitro drug release of ATO–Cu liposomes exhibited a sustained release over 72 h, and the release rates decreased with the increase of the p H of release media. Pharmacokinetic and tissue distribution studies of ATO liposomes showed significantly reduced plasma clearance rate, increased AUC0–12h and T1/2, and improved tumor distribution of As compared to iv administration of ATO solution. The anti-tumor effect of ATO loaded liposomes to S180 tumor-bearing mice was significantly improved with a tumor inhibition rate of 61.2%,meanwhile the toxicity of encapsulated ATO was greatly decreased. In conclusion, ATO can be effectively encapsulated into liposomes by remote loading method via Cu(OAc)2 gradients;the co-administration of ATO and Cu(Ⅱ) via liposomal formulation may find wide applications in the treatment of various tumors.
文摘All-trans retinoic acid(ATRA)and pre-upfront arsenic trioxide(ATO)have revolutionized the therapy of acute promyelocytic leukemia(APL).However,internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)mutations is associated with increased risk of relapse.The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA,idarubicin(IDA)and/or ATO,followed by ATRA plus ATO along with anthracycline,as consolidation therapy.A total of 72 patients newly diagnosed with APL were included in this study.83.3%of the patients achieved complete remission(CR)after induction therapy.FLT3-ITD mutations were detected in 16(22.2%)patients and closely related to bcr-3 PML-RARa transcript(P<0.001).The 5-year overall survival(OS)rate was 100%in both FLT3-ITDposltlve and FLT3-ITD^(negatlve)groups,and there was no significant difference in 5-year event-free survival(EFS)between the two groups(78.3%vs.83.3%,P=0.85).ATRA plus ATO and anthracycline-based chemotherapy achieved great outcome in newly diagnosed APL regardless of the FLT3-ITD mutation status.
基金Supported by Research fund from Chosun University,2020.
文摘BACKGROUND Arsenic trioxide(ATO)is recommended for patients who do not achieve molecular remission or who have molecular or morphologic relapse.However,there are no guidelines for adjusting ATO dosage in patients with severe renal failure or on dialysis.Herein,we report the successful treatment of relapsed acute promyelocytic leukemia(APL)in a patient on hemodialysis with ATO single agent and review the cases in literature.CASE SUMMARY A 46-year-old woman who has been on hemodialysis to chronic glomerulonephritis for 15 years visited our hospital for pancytopenia.She had been seen for pancytopenia 3 years ago and had been diagnosed with APL.She also received chemotherapy for APL but unfortunately was lost to follow-up after her second consolidation chemotherapy.She was noted to have pancytopenia by her nephrologist during hemodialysis 1 mo ago.Bone marrow biopsy and reverse transcriptase-polymerase chain reaction(RT-PCR)tests revealed a diagnosis of relapsed APL.Treatment for relapsed APL with ATO single agent was started and she achieved molecular remission after administering 24 doses of ATO.Thus far,four consolidation therapies have been performed with the ATO single agent,and,to date,the molecular remission has been maintained as negative promyelocytic leukemia/retinoic acid receptor-αfusion gene as confirmed by RTPCR testing for two years.CONCLUSION This is a rare case of relapsed APL successfully treated with the single agent ATO in a patient on hemodialysis.
基金Supported by the National Science Foundation of China(NNSFC)(39970270, 39730270), a NNSFC award for Outstanding Yong Scientist
文摘Objective: To understand whether arsenic trioxide (As2O3 )-induced biological effects are associated with degradation of PML proteins. Methods Acute promyelocytic leukemia (APL) cell line NB4, acute T-lymphocytic leukemia cell line Jurkat, acute myeloid leukemia cell line U937, and chronic myelocytic leukemia blast crisis cell line K562 were used as in vitro models In different cell lines, the As2O3-induced biological effects were determined by cell growth, cell viability, cell morphology, and flow cytometry assay on sub G1 cell content. The alteration of PML proteins was analyzed by immunofluorescence Results in terms of growth inhibition and apoptosis induction, 1. 0μmol/L As2O3 had different effects on different cell lines. However, degradation of PML proteins occurred in all the cell lines with As2O3 treatment. Conclusion As2O3-indued biological effects may be independent of PML protein-degradation.
基金the Natural Science Foundation of Committee of Science and Technology of Shanghai Municipality(№964119035)
文摘AIM To study the effects of arsenic trioxide andHCPT on different degrees of differentiated gastriccancer cells（SGC-7901,MKN-45,MKN-28）withrespect to both cytotoxicity and induction ofapoptosis in vitro.METHODS The cytotoxicity of As<sub>2</sub>O<sub>3</sub> and HCPTon gastric cancer cells was determined by MTTassay.Morphologic changes of apoptosis ofgastric cancer cells were observed by lightmicroscopy and transmission electron microscopy.Apoptosis and cell cycle changes of gastric cancercells induced by HCPT and As<sub>2</sub>O<sub>3</sub> were investigatedby TUNEL method and flow cytometry.RESULTS As<sub>2</sub>O<sub>3</sub> and HCPT had remarkablecytotoxic effects on different degrees ofdifferentiated gastric cancer cells.The IC<sub>50</sub>ofAs<sub>2</sub>O<sub>3</sub> on well differentiated gastric cancer cellMKN-28,moderately differentiated gastric cancercell SGC-7901,and poorly differentiated gastriccancer cell MKN-28 were 8.91 μmol/L,10.57μmol/L,and 11.65 μmol/L,respectively.The IC<sub>50</sub>of HCPT on MKN-28,SGC-7901,and MKN-45 were9.35 mg/L,10.21 mg/L,and 12.63 mg/Lrespectively after 48 h treatment.After 12 h ofexposure to both drugs,gastric cancer cellsexhibited morphologic features of apoptosis,including cell shrinkage,nuclear condensation, and formation of apoptotic bodies.A typicalsubdiploid peak before G<sub>0</sub>/G<sub>1</sub> phase was observedby flow cytometry.The apoptotic rates of SGC-7901,MKN-45,and MKN-28 were 13.84%,22.52%,and 9.68%,respectively after 48 hexposure to 10 μmol/L As<sub>2</sub>O<sub>3</sub>.The apoptotic ratesof SGC-7901,MKN-45,and MKN-28 were 21.88%,12.35%,and 30.26%,respectively after 48 hexposure to 10 mg/L HCPT.The apoptotic indicewere 7%-15% as assessed by TUNEL method.The effect of As<sub>2</sub>O<sub>3</sub> on SGC-7901 showedremarkable cell cycle specificity,which inducedcell death in G<sub>1</sub> phase,and blocked G<sub>2</sub>/M phase.HCPT also showed a remarkable cell cyclespecificity,by inducing cell death and apoptosis inG<sub>1</sub> phase and arrest of proliferation at S phase.CONCLUSION As<sub>2</sub>O<sub>3</sub> and HCPT exhibitsignificant cytotoxicity on gastric cancer cells byinduction of apoptosis.As<sub>2</sub>O<sub>3</sub> and HCPT mighthave a promising prospect in the treatment ofgastric cancer,which needs to be further studied.
文摘INTRODUCTION Cell apoptosis,which involves the biologic regulation of the numbers and vital activity of cells,is an important metaboloc process in both normal cells and tumor cells.
基金Heilongjiang Natural Science Foundation (G98L19-1)guided by Ministry of Health,China.98-2-269
文摘AIM To study the effect of a varyingconcentrations of arsenic trioxide on humanhepatoma cell line BEL-?402 cultured in vitro andits mechanism of action.METHODS The BEL-7402 cells were treatedwith arsenic trioxide（at the concentrations of0.5,1,2 μmol/L,respectively）for 4 successivedays.The cell growth and proliferation wereobserved by cell counting and cell-growth curve.Morphologic changes were studied withelectronmicroscopy.Flow cytometry was usedto assay celI-DNA distribution and the proteinexpression of Bcl-2 and Bax detected byimmunocytochemical method.RESULTS The cell growth was significantlyinhibited by varying concentrations of arsenictrioxide as revealed by cell counting and cell-growth curve,which was dose- and time-dependent.Arsenic trioxide treatment at 0.5,1and 2 μmol/L resulted in a sub-G1 cell peak,theapoptosis rate of the control group was 9.31%and that of 0.5 μmol/L arsenic trioxide 15.53%,no significant difference was seen between thetwo.The apoptosis rates of 1,2 μmol/L arsenictrioxide were 19.10% and 21.87% respectively,which were much higher（both P【0.05）.Decrease of G<sub>0</sub>/G<sub>1</sub> phase cells and increase of Sphase cells were observed by flow cytometry,suggesting the inhibition effect of 0.5,1,2 μmol/L arsenic trioxide on BEL-7402 cell lay in the G<sub>0</sub>/G<sub>1</sub> phase.Morphologic changes such asintact cell membrane,nucleic condensation,apoptotic body formation were seen undertransmission electronmicrescopy,whereas the0.5 mol/L arsenic trioxide-treated BEL-7402cells showed decrease of nucleocytoplasmicratio,round nucleus,well-differentiatedorganelles in the cytoplasm.The processes andmicrovilli on the cell surface of the experimentalgroups under scanning electron microscopy weresignificantly decreased.High expressions ofBcl-2 and Bax were detected in 1 and 2 μmol/Larsenic trioxide-treated cells,these were 46%,87.33% and 83.08%,95.83% respectively,among which that of Bax was more significant.Arsenic trioxide treatment at 0.5 μmol/Lresulted in a higher expression level of Bcl-2 andlower expression level of Bax,which were8.81% and 3.83% respectively,as comparedwith that of the control group（15.33%）（P<sub>1</sub>【0.01,P<sub>2</sub>【0.01）.CONCLUSION Arsenic trioxide not onlyinhibited proliferation but also induced apoptosisof human hepatoma cell line BEL-7402.Theinduced-apoptosis effect of 1,2 μmol/L arsenictrioxide was related to the expression level ofBcl-2 and Bax.
基金Supported by The Heilongjiang Provincial Natural Science Foundation of China,No.D2006-51
文摘AIM:To investigate the changes in apoptosis in gastrointestinal cancer cells from patients with gastrointestinal cancers treated with arsenic trioxide(As2O3);and to study the possible molecular mechanisms of such changes by detecting the expression levels of p53and Bcl-2.METHODS:Twenty patients with gastrointestinal adenocarcinoma based on endoscopic and biopsy findings(ten patients with gastric cancer and ten patients with colorectal cancer)who received treatment in our hospital between August 2007 and December 2008were included in this study.None of the patients had received anti-tumour agents prior to As2O3 treatment.As2O3 was administered intravenously at a dose of 0.01g/d diluted with 5%glucose in normal saline for 2-3h for 3 consecutive days before surgery.Morphological changes associated with apoptosis of gastrointestinal cancer cells were observed by light microscopy.Changes in the apoptotic index induced by As2O3 were investigated using the terminal deoxynucleotidyl transferase dUTP nick end labelling method.Expression levels of p53 and Bcl-2 proteins in gastrointestinal cancer tissues were determined by immunohistochemistry.RESULTS:The apoptotic index of human gastrointestinal cancer cells was higher in cells from patients treated with As2O3 than in those not treated(P<0.05).p53 protein expression in gastrointestinal tissues was unchanged by As2O3(P>0.05).However,Bcl-2 protein expression in gastrointestinal tissues was downregulated by As2O3(P<0.01).CONCLUSION:These results demonstrate that As2O3treatment in patients with gastrointestinal cancers can induce apoptosis in gastrointestinal cancer cells and down-regulate Bcl-2 protein expression.
文摘To study the effects of arsenic trioxide (As2O3) on the in vitro growth of human bladder cancer cells and the mechanisms. The growth inhibition rates of human bladder cancer cell line BIU87 by various concentrations of As2O3 were detected by using MTT method. Cell apoptosis was detected by in situ terminally labeled transferase technique and bcl-2 gene expression of BIU-87 cells was observed by SABC immunohistochemical method. The results showed that As2O3 could inhibit the growth of BIU-87 effectively in a dose-dependent manner. After drug’s action, the apoptotic bladder cancer cells were obviously increased, which depended on the prolongation of the action time and Bcl-2 expression of BIU-87 cells was decreased significantly. It was suggested that As2O3 could significantly inhibit the growth of bladder human cancer cells. Inducing cell apoptosis by down- regulating the expression of hcl-2 gene might be one of its action mechanisms.
基金This work was supported by the Guangdong Provincial Key Foundation of Science and Technology Program (99M01204G) and the Guangzhou City Key Foundation of Science and Technology Program (2001-Z-037-01).
文摘Objective: To evaluate whether arsenic trioxide (AS2O3) could downregulate human telomerase reverse transcriptase (hTERT) gene expression and telomerase activity during induction of apoptosis of HL-60 cells. Methods: Apoptosis was detected by morphological observation and flow cytomertric cell cycle analysis. The expression of hTERT at mRNA and protein levels was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence using fluoresce isothiocyanate (FITC) label, respectively. Telomerase activity was determined by polymerase chain reaction enzyme-linked immunoassay (PCR-ELISA). Results: Treatment of 2 祄ol/L at As2O3 could induce apoptosis of HL-60 cells. hTERT was decreased at both mRNA and protein levels during apoptosis of HL-60 cells. Telomerase activity of HL-60 cells was significantly inhibited. Conclusion:It is suggested that telomerase activity of HL-60 cells might be specifically inhibited by AS2O3 through the downregulation of hTERT gene expression.
基金Supported by the Zhejiang Province Science and Technology Fund for excellent returnee 2001-275
文摘AIM: To investigate the effect of arsenic trioxide on human gastric cancer cell line MKN45 with respect to both cytotoxicity and induction of apoptosis in vitro. METHODS: MKN45 cells were treated with arsenic trioxide(As2O3) at the concentration of 1, 5, and 10 μmol/L,respectively, for three successive days. Cell growth and proliferation were observed by cell counting and trypanblue exclusion. Cytotoxicity of As2O3 was determined by MTT assay. Morphologic changes were studied with light microscopy. Flow cytometry was used to assay cell DNA distribution and apoptotic cells were confirmed with terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling (TUNEL) and DNA electrophoresis.RESULTS: The growth of MKN45 cells was significantlyinhibited by As2O3 which was confirmed by colony-forming assay. After 7 d of culture with various concentrations of As2O3, colony-forming capacity of MKN45 cells decreased with As2O3 increment in comparison with that of control group. The inhibitory rate of colony-formation was 38.5%, 99.1%, and 99.5% when the concentration of As2O3 was1, 5, and 10 iμmol/L in culture medium, respectively. The cell number of a single colony in drug treatment groups was less than that of control group. The cell-killing rate of As2O3 to MKN45 cells was both dose- and timedependent with an IC50 of (11.05±0.25) μmol/L. After incubation in 10 μmol/L As2O3 for 24 h, the cell-killing rate was 27.1%, and it was close to 50% after 48 h. The results showed that As2O3 induced time- and dosedependent apoptosis in MKN45 cells, blocked at G2/M phase. The apoptotic peak (sub-G1 phase) appeared and cell apoptotic rate in MKN45 cells was 18.3-32.5% aftertreatment by 10 μmol/L As2O3 for 48 h. The percentage of G2/M cell of the experimental groups was 2.0-5.0 times than that of the control group. Gel electrophoresis of DNA from cells treated with each concentration of As2O3 for 48 h revealed a 'ladder' pattern, indicating preferential DNA degradation at the internucleosomal, linker DNA sections. TUNEL also demonstrated strand breaks in DNA of MKN45 cells treated with As2O3, while control cellsshowed negative labeling.CONCLUSION: As2O3 can induce apoptosis of human gastric carcinoma cells MKN45, which is the basis of its effectiveness. It shows great potential in the treatment of gastric carcinoma.
基金Supported by the Youth Science Grant of Jiangshu Province,No.BQ98048.
文摘INTRODUCTIONThe main component of a traditional Chinese drug 'Pishuang'. arsenic trioxide (As2O3), has obviously selective anti-tumor effect on human hepatocellular carcinoma (HCC)in both in vitro and in vivo studies[1-5]. Due to limited effectiveness when any anti-carcinogen is used alone and obviously increased toxicity when the dose is raised, there is no exception for As2O3. Furthermore, combined chemotherapy contributes to improve therapeutic effectiveness, disperse toxicity and surmount drug-resistance,in which the combination of traditional Chinese and modern medicine has more advantages and characteristics. As a result,we made an experimental study on anti-tumor effect of As2O3in combination with cisplantin (PDD) or doxorubicin (ADM)on HCC. to investigate the possibility of AS2O3 in combination with PDD or ADM and nature of interaction between them,and to provide experimental basis for clinical application.
基金Supported by the Science Fund of the Second Affiliated Hospital of Medical College, No. 2003-YL-35
文摘AIM: To investigate the inhibitory effect of As2O3 on angiogenesis of tumor and expression of vascular endothelial growth factor (VEGF) in tumor cells in vivo and in vitro. METHODS: The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were randomly divided into three groups. As2O3 was injected into the arsenic-treated groups (2.5 mg/kg and 5 mg/kg) and the same volume of saline solution was injected into the control group. Microvessel density (MVD) and expression of VEGF were detected with immunofluorescence laser confocal technology. Further expression of VEGF protein and VEGF mRNA was measured with Western bloting and fluorescence quantitative RT- PCR in SGC-7901 cells treated with As2O3. RESULTS: In nude mice, after treatment with 5 mg/kg and 2.5 mg/kg As2O3 respectively, about 50% and 30% tumor growth inhibition were observed correspondingly (P < 0.05, P < 0.05). Decrease in MVD appeared in As2O3-treated tumors compared with control group (P < 0.001, P < 0.001). MVD in tumors was significantly lower in 5 mg/kg group than in 2.5 mg/kg group (P < 0.01). The fluorescence intensity levels of VEGF in tumor cells were significantly lowered in the arsenic-treated groups (P < 0.01, P < 0.01). The fluorescence intensity level of VEGF in 5 mg/kg group was lower than that in 2.5 mg/ kg group (P < 0.01). In vitro, the expression of VEGF protein decreased in dose- and time-dependent manner after the treatment with As2O3, but in VEGF mRNA no significant difference was found between the control group and the treated groups. CONCLUSION: As2O3 can inhibit solid tumor growth by inhibiting the formation of new blood vessels. One of the mechanisms is that As2O3 can inhibit VEGF protein expression.
文摘Objective To observe the apoptosis of osteosarcoma MG-63 cells induced by As2O3 and to explore its possible mechanisms. Methods The flowcytometric analysis and transmission electronmicroscope were performed to investigate the inducing apoptosis and inhibitative of As2O3 on osteosarcoma MG-63 cells. In order to study mechanism of apoptosis in MG-63 cells treated with As2 O3, microarray was performed. The down-regulated gene was confirmed by RT-PCR, Northern-blotting. Results After treated with As2O3, hypodiploid peak before G0/G1 phase was observed in MG-63 cells through FCM analysis. Loss of microvilli, condensation and fragmentation of nuclear chromatin, condensation of cytoplasmic organelles, dilatation of the endoplasmic reticulum shrinkage of cells and alterations in cell membranes and apoptosis bodies which were observed in MG-63 cells treated with As2O3 by transmission electronmicroscope. The results of microarray show that As2 O3 induced MG-63 cell apoptosis involves down-regulation of IEX-1 and the down-regulated gene is confirmed by RT-PCR and Northern-blotting.Conclusion The results show that As2 O3 selectively inhibits growth of the solid tumor MG-63 cells by triggering apoptosis and indicates MG-63 induced by As2O3 cell apoptosis may through the IEX-1 pathway.
基金Supported by The Science Fund of the Second Affiliated Hospital of the Medical College,No.2003-YL-35
文摘AIM: To investigate the effect of arsenic trioxide (As2O3) on expression of vascular endothelial growth factor receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR) in human gastric tumor cells and proliferation of vascular endothelial cells. METHODS: The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were treated with As2O3. Microvessel density (MVD) and expression of Flt-1 and KDR were detected by immunofluorescence laser confocal microscopy. SGC-7901 cells were treated respectively by exogenous recombinant human VEGF165 or VEGF165 + As2O3. Cell viability was measured by MTT assay. Cell viability of ECV304 cells was measured by MTT assay, and cell cycle and apoptosis were analyzed using ? ow cytometry. RESULTS: The tumor growth inhibition was 30.33% and 50.85%, respectively, in mice treated with As2O3 2.5 and 5 mg/kg. MVD was signifi cantly lower in arsenic-treated mice than in the control group. The ? uorescence intensity levels of Flt-1 and KDR were significantly less in the arsenic-treated mice than in the control group. VEGF165 may accelerate growth of SGC7901 cells, but As2O3 may disturb the stimulating effect of VEGF165. ECV304 cell growth was suppressed by 76.51%, 71.09% and 61.49% after 48 h treatment with As2O3 at 0.5, 2.5 and 5 μmol/L, respectively. Early apoptosis in the As2O3- treated mice was 2.88-5.1 times higher than that in the controls, and late apoptosis was 1.17-1.67 times higherthan that in the controls. CONCLUSION: Our results showed that As2O3 delays tumor growth, inhibits MVD, down-regulates Flt-1 and KDR expression, and disturbs the stimulating effect of VEGF165 on the growth of SGC7901 cells. These results suggest that As2O3 might delay growth of gastric tumors through inhibiting the paracrine and autocrine pathways of VEGF/VEGFRs.
基金supported by research grants from National Natural Science Foundation of China(No.30170475)
文摘Double staining flow cytometry was performed using 7-amino actinomycin D and 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate,to detect the level fluctuation of reactive oxygen species (ROS) during the cell cycle of normal NB4 cells. Our results showed that NB4 cells possessed higher level of ROS in G2/M phase than in G1 and S phases. Double staining flow cytometry,with TdT mediated dUTP nick end labeling (Tunel) and propidium iodide (PI),indicated that As2O3 (2 μM) could induce apoptosis in NB4 cells prevailingly from G2/M phase,and this efficacy was enhanced upon co-administration of 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) (2.5 μM) which could produce the endogenous ROS. These results suggested that different ROS level in different cell cycle phases of NB4 cells might determin the selective induction of G2/M apoptosis and the cells' susceptibility to apoptosis by As2O3.
文摘Since arsenic trioxide was first approved as the front line therapy for acute promyelocytic leukemia 25 years ago,its anti-cancer properties for various malignancies have been under intense investigation.However,the clinical successes of arsenic trioxide in treating hematological cancers have not been translated to solid cancers.This is due to arsenic's rapid clearance by the body's immune system before reaching the tumor site.Several attempts have henceforth been made to increase its bioavailability toward solid cancers without increasing its dosage albeit without much success.This review summarizes the past and current utilization of arsenic trioxide in the medical field with primary focus on the implementation of nanotechnology for arsenic trioxide delivery to solid cancer cells.Different approaches that have been employed to increase arsenic's efficacy,specificity and bioavailability to solid cancer cells were evaluated and compared.The potential of combining different approaches or tailoring delivery vehicles to target specific types of solid cancers according to individual cancer characteristics and arsenic chemistry is proposed and discussed.
