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
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
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
To study the mechanisms involved in the inhibition of chronic myeloid leukemic cells (K562) proliferation induced by arsenic trioxide (As 2O 3) and to explore the potential role of Survivin, an inhibitor of apoptosi...To study the mechanisms involved in the inhibition of chronic myeloid leukemic cells (K562) proliferation induced by arsenic trioxide (As 2O 3) and to explore the potential role of Survivin, an inhibitor of apoptosis protein, in the regulation of As 2O 3 induced cell apoptosis, K562 cells were cultured with As 2O 3 of different concentrations. Cells were collected for proliferation analysis by MTT assay. Cell cycle distribution and cell apoptosis were analyzed by flow cytometry. Expression of Survivin protein and mRNA were detected by flow cytometry and RT-PCR, respectively. Our results showed that As 2O 3 (2-10 μmol/L) inhibited K562 cells growth effectively, but it did not induce cells apoptosis significantly. The percentage of K562 cells at G 2/M phase increased in proportion to As 2O 3 concentrations, and the expression of Survivin mRNA and content of Survivin protein was up-regulated accordingly. It is concluded that As 2O 3 inhibited K562 cells growth by inducing cell cycle arrest mainly at G 2/M phase. Over-expression of Survivin gene and protein might be one of the possible mechanisms contributing to K562 cells' resistance to As 2O 3-induced apoptosis.展开更多
Objective: To investigate the distribution and recruitment of pulm onary dendritic cells (DCs) and the influence of low dosage arsenic trioxide (As 2O 3) on them in the airway of asthmatic mice. Methods: Thirty BAL...Objective: To investigate the distribution and recruitment of pulm onary dendritic cells (DCs) and the influence of low dosage arsenic trioxide (As 2O 3) on them in the airway of asthmatic mice. Methods: Thirty BALB/c mice were randomly divided into 3 groups: the control group, the asthmat ic group and the As 2O 3 treated group. The mice asthmatic model was induced v ia sensitizing with peritoneal injection of ovalbumin (OVA) for two times and th en provocated with aerosol inhalation of OVA for a week. The treated group was p eritoneally injected with 0.2 ml solution of As 2O 3 (4mg/kg) 0.5h after each provocation. The immunohistochemistry and computerised image analysis were appli ed to detect quantitatively the DCs in the lung and airway of mice. Resul ts: All intraepithelial nonlymphoid dendritic cells 145 (NLDC 145) throughout the respiratory tree in the mice of the control group formed a netwo rk with the density of DCs varying from (575±54) cells/mm 2 epithelial surface in the large airway, to (68±12) cells/mm 2 epithelial surface in the small ai rway. The distribution of airway NLDC 145 + in the asthmatic group was simil ar to that in the control group, but its density was significantly upregulated ( P <0.01). The distribution of airway NLDC 145 in the treated group was sim ilar to that in the asthmatic group, only its density was significantly downregu lated ( P <0.01). Conclusion: There is an integral network of N LDC 145 + throughout the respiratory tree. To downregulate the density but n ot change the distribution of pulmonary DCs could be an important therapeutic me chanism of low dosage As 2O 3 in treating asthma.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 μmol/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
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
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 ...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
The therapeutic action of arsenic trioxide( As203 ) on solid tumors has aroused widespread interest among scholars. To study the impact of As2O3 on human colorectal carcinoma cells( LS-174T cell) and the activity ...The therapeutic action of arsenic trioxide( As203 ) on solid tumors has aroused widespread interest among scholars. To study the impact of As2O3 on human colorectal carcinoma cells( LS-174T cell) and the activity of telomerase, the methods of PCR-ELISA, flow cytometry (FCM) and MTT assay in vitro were utilized. The results show that (1) with an increase in the concentration of As2O3, the ratio of living the cells to dead cells decreases significantly, and the IC50 value is 5.23 μg/mL; (2) the cells of the experimental groups can endure a series of morphological changes similar to the features of apoptosis ; (3) the apoptotic curves of FCM pictures appear after 24 h, and the cells show the apoptosis in a time-dependent manner; (4) As2O3 can inhibit the activity of telomerase of the cell extraction obviously in a concentration-dependent and time-dependent manner after 24 h. It can be concluded from the experiment results in vitro that As2O3 can induce the apoptosis of LS-174T cells and inhibit the telomerase activity. Therefore, it has been proposed, for the first time, that these two factors (the apoptosis of LS-174T cells and the inhibition to the telomerase activity) are important causes of the LS-174T cell death caused by As2O3.展开更多
Objective: To explore the effects of arsenic trioxide (ATO) on the apoptosis of glucocorticoid (GC)-resistant T-acute lymphoblastic leukemia (ALL) CEM-C1 cells and its possible mechanisms. Methods: Different ...Objective: To explore the effects of arsenic trioxide (ATO) on the apoptosis of glucocorticoid (GC)-resistant T-acute lymphoblastic leukemia (ALL) CEM-C1 cells and its possible mechanisms. Methods: Different concentrations of ATO (0.25 μmol/L-5 μmol/L) were used to induce the apoptosis of CEM-C1 cells. The inhibition rate of cell proliferation and apoptosis were detected by MTT test, Annexin V-FITC/PI flow cytometry and optical microscopy, respectively. RT-PCR was applied to semi-quantitatively analyze the mRNA expression of pro-apoptotic proteins (Bad and PDCD4) and anti-apoptotic proteins (XIAP and MCL-1) induced by different concentrations of ATO at different time points. Results: ATO could inhibit proliferation and induce apoptosis of CEM-C1 cells at a concentration and time dependent manner. Low-dose ATO mildly inhibited the proliferation of CEM-C1 cells while higher concentrations (1 μmol/L and 5 μmol/L) had strong anti-tumor effect with the inhibiting rates of 40.07±7.98% and 88.67±2.88%, respectively. Annexin V-FITC/PI flow cytometry showed that the apoptotic rates of CEM-C1 ceils were significantly increased after 48 hours treatment of different concentrations of ATO. RT-PCR demonstrated up-regulated mRNA expression of pro-apoptotic protein Bad and PDCD4 but down-regulated mRNA expression of anti-apoptotic protein XIAP when CEM-C1 cells were treated with different concentrations of ATO at different time points. The MCL-1 mRNA expression was down-regulated only after the treatment of 5 μmol/L ATO. Conclusion: ATO can inhibit cell proliferation and induce cell apoptosis in GC-resistant CEM-C1 cells. The molecular mechanisms might involve the increased mRNA expression of pro-apoptotic protein Bad and PDCD-4, and rapid down-regulation of XIAP mRNA expression.展开更多
In order to explore the molecular mechanism of arsenic trioxide treating multiple myeloma (MM) via inhibition of angiogenesis, the expression of brain derived neurotrophic factor (BDNF) and its specific receptor T...In order to explore the molecular mechanism of arsenic trioxide treating multiple myeloma (MM) via inhibition of angiogenesis, the expression of brain derived neurotrophic factor (BDNF) and its specific receptor TrkB in human MM cell line KM3 and endothelial cell line ECV304 was detected by Western blotting. The angiogenic activity was evaluated by wound migration assay and tubule formation assay in vitro. The results showed that BDNF was detected in the MM cells and TrkB in the endothelial cells. Furthermore, 100 ng/mL BDNF could significantly induced endothelial cell tubule formation and wound migration. As2O3 depressed the expression of BDNF and TrkB in the dose- and time-dependent manner. As2O3 inhibited BDNF-induced wound migration and capillary tube formation. It was concluded that BDNF is a novel angiogenic protein as well as VEGF and has a relation with the pathogenesis of MM. As2O3 interrupts a paracrine loop between MM cells and endothelial cells by down-regulating the TrkB expression in endothelial cells and inhibiting BDNF production in MM cells, finally resulting in inhibition of MM angiogenesis. This is probably one part of the mechanisms of the As2O3 treating MM via the inhibition of angiogenesis.展开更多
Arsenic trioxide albumin microspheres (As_2O_3-BSA-NS) were prepared by using methods of chemical cross-linking. The desirability function (DF), calculated according to the size (<1 μm) distribution, drug loading ...Arsenic trioxide albumin microspheres (As_2O_3-BSA-NS) were prepared by using methods of chemical cross-linking. The desirability function (DF), calculated according to the size (<1 μm) distribution, drug loading and drug trapping efficiency, was introduced as a total index for the microspheres formulation. Four factors, inculding W/O ratio, decentralization speed, BSA concentration and stirring stabilization time, were selected and arranged in an orthogonal experimental table. The release characteristic was studied by the drug release experiment in vitro. The four factors affected DF differently. Decentralization speed behaved as the maximum (P<0.01), followed by BSA concentration (P<0.05) and the W/O ratio dose (P<0.05). Stirring stabilization time did not influence DF (P>0.05). The release experiment in vitro showed that As_2O_3 in As_2O_3-BSA-NS was released more slower than pure As_2O_3. It was concluded that regular As_2O_3-BSA-NS may be prepared by the methods of chemical cross-linking, which was optimized by orthogonal experimental analysis of different factors, and the microspheres can release As_2O_3 slowly.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 study the effect of arsenic trioxide (As203) on the expression of drug transporting molecules in multidrug resistance malignant neoplasma acute promyelocytic leukemia (APL) MR2 cell line. Methods: ...Objective: To study the effect of arsenic trioxide (As203) on the expression of drug transporting molecules in multidrug resistance malignant neoplasma acute promyelocytic leukemia (APL) MR2 cell line. Methods: MR2 resistant to alltrans retinoic acid (ATRA) and non-ATRA resistant APL cell line NB4 were used. Expressions of P-glycoprotein (Pgp), multidrug resistance protein (MRP) and lung resistance-related protein (LRP) were detected by immunocytochemical assay. Results: The expression of Pgp was significantly higher in MR2(30%-40%) than that in NB4(10%-20%) (P 〈 0.001), and the expression of MRP was also higher in MR2 (56.9 ± 3.4 - 21.2 ± 1.1) than that in NB4 (20.6 ± 5.3 - 16.7 ± 1.2) (P 〈 0.001). As2O3 ranging from 0.5-2.0 μmol/L, could significantly decrease the expressions of Pgp and MRP. The expression of Pgp and MRP in MR.2 cell line were negatively correlated with the dose and duration of action of As2O3. Conclusion: Pgp and MRP may be the sensitive targets of As2O3 to overcome drug-resistance. ATRA might be the substrates of Pgp and MRP.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
cDNA microarray was used to compare the gene expression profiles of multiple myeloma cell line RPMI8226 24 h before and after treatment with arsenic trioxide. Two cDNA probes were prepared by mRNA reverse transcriptio...cDNA microarray was used to compare the gene expression profiles of multiple myeloma cell line RPMI8226 24 h before and after treatment with arsenic trioxide. Two cDNA probes were prepared by mRNA reverse transcription of both arsenic trioxide-treated and untreated RPMI8226 cells. The probes were labeled with Cy3 and Cy5 fluorescence dyes separately, hybridized with cDNA microarray representing 4096 different human genes, and scanned for fluorescence intensity. The differences in gene expression were calculated on the basis of the ratios of signal intensity of treated and untreated samples. The up- and down-regulated genes were screened through the analysis of gene expression ratios. The results showed that 273 genes were differentially altered at mRNA level, 121 genes were up-regulated and 152 were down-regulated. It is concluded that the treatment with arsenic trioxide can induce a variety of gene changes in RPMI8226 cell line. Many genes may be involved in the pathogenesis of multiple myeloma. ALK-1 and TXNIP genes may play an important role in the apoptosis and partial differentiation of RPMI8226 cells.展开更多
Objective: To observe the effects of arsenic trioxide (As2O3) on human renal cell carcinoma (RCC) lines in vitro and to explore its possible molecular mechanisms. Methods: The microculture tetrazoli-um (MTT) assay was...Objective: To observe the effects of arsenic trioxide (As2O3) on human renal cell carcinoma (RCC) lines in vitro and to explore its possible molecular mechanisms. Methods: The microculture tetrazoli-um (MTT) assay was used to determine the anti-proliferative effects of As2O3 on human RCC lines. Flow cy-tometry was performed to investigate the effects of As2O3 on cell cycle and cell apoptosis. The reverse tran-scription-polymerase chain reaction (RT-PCR) was conducted to detect mRNA expression of Bcl-2, Bax, p53 and c-myc. Results: As2O3 inhibited the growth of RCC lines in vitro in a concentration-dependent manner. At the concentrations of 0.5, 1.0, 2.0 and 4.0μmol/L, the inhibition rates of As2O3 on RCC-WCS cells were 27.60%, 30.09%, 41.03% and 50.77%, respectively. Compared with untreated RCC-WCS, there was significant difference at each concentration (P<0.01). As2O3 induced a G1 phase arrest in RCC-LSL cells, but a G2/M phase arrest in RCC-WCS and RCC-SHK. As2O3 induced cell apoptosis in these cell lines. The mRNA level of p53 and c-myc decreased, but no detectable changes of Bcl-2 and Bax were observed after As2O3 treatmen. Conclusion: As2O3 in therapeutic concentrations inhibited the in vitro growth of RCC lines via cell cycle arrest and apoptosis. One of its possible mechanisms was down-regulation of p53 and c-myc. Our results suggest that As2O3 is probably a new candidate agent for the treatment of human renal carcinoma.展开更多
Objective: To investigate the effects of various concentrations As 2O 3 on malignant melanoma. Methods: The viability of Cloundman melanoma S91 cells treated with As 2O 3 was measured by MTT [3-(4, 5-dimethyl-2-thiazo...Objective: To investigate the effects of various concentrations As 2O 3 on malignant melanoma. Methods: The viability of Cloundman melanoma S91 cells treated with As 2O 3 was measured by MTT [3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide] assay. The apoptosis was determined by transferase-mediated dUTP nick end labeling (TUNEL) detection, and the morphology of apoptotic cells was observed through transmission electron microscopy (TEM). The cells growth phase were analyzed by flow cytometry (FCM). Results: A time-and dose-dependent decrease in cell viability was induced in S91 cells after treatment with As 2O 3 at the concentration of 1-5 μmol/L respectively. The TUNEL indices were 0.033±0.018, 0.062±0.012, 0.102±0.016, 0.132±0.031, and 0.162±0.027 respectively, which were much higher compared with the control group (0.017±0.004, P<0.01). The flow cytometry showed that hypodiploid peak after treatment with 3 μmol/L and 5 μmol/L of As 2O 3 for 48 h were 9.99% and 17.59% respectively, which increased significantly compared with the control cells (3.05% P<0.01,). The apoptotic morphology observed by transmission electron microscope showed the chromatin became condensed and attached to the inner surface of nuclear membrane. Conclusion: Arsenic trioxide can induce melanoma Cloundman S91 cell apoptosis at the concentration of 1-5 μmol/L, which will provide enhanced benefit in melanoma therapy.展开更多
Objective: The effects of arsenic trioxide(As2O3) on hepatocellular carcinoma have been documented widely. Autophagy plays dual roles in the survival and death of cancer cells. Therefore, we investigated the exact rol...Objective: The effects of arsenic trioxide(As2O3) on hepatocellular carcinoma have been documented widely. Autophagy plays dual roles in the survival and death of cancer cells. Therefore, we investigated the exact role of autophagy in As2O3-induced apoptosis in liver cancer cells.Methods: The viability of hepatoma cells was determined using the MTT assay with or without fetal bovine serum. The rate of apoptosis in liver cancer cells treated with As2O3was evaluated using flow cytometry, Hoechst 33258 staining, and TUNEL assays. The rate of autophagy among liver cancer cells treated with As2O3was detected using immunofluorescence, Western blot assay and transmission electron microscopy.Results: Upon treatment with As2O3, the viability of HepG2 and SMMC-7721 cells was decreased in a time-and dose-dependent manner. The apoptosis rates of both liver cancer cell lines increased with the concentration of As2O3, as shown by flow cytometry. Apoptosis in liver cancer cells treated with As2O3was also shown by the activation of the caspase cascade and the regulation of Bcl-2/Bax expression.Furthermore, As2O3treatment induced autophagy in liver cancer cells;this finding was supported by Western blot, immunofluorescence of LC3-II and beclin 1, and transmission electron microscopy. In liver cancer cells, As2O3inhibited the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR) signal pathway that plays a vital role in both apoptosis and autophagy. The PI3K activator SC-79 partially reversed As2O3-induced autophagy and apoptosis. Furthermore, inhibiting autophagy with 3-methyladenine partially reversed the negative effects of As2O3on cell viability.Serum starvation increased autophagy and amplified the effect of As2O3on cell death.Conclusion: As2O3induces apoptosis and autophagy in liver cancer cells. Autophagy induced by As2O3may have a proapoptotic effect that helps to reduce the viability of liver cancer cells. This study provides novel insights into the effects of As2O3against liver cancer.展开更多
Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer. Although major breakthroughs have been achieved in preventative tumor vaccines targeting on...Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer. Although major breakthroughs have been achieved in preventative tumor vaccines targeting oncogenic viruses, limited advances have been made in curative vaccines for virus-irrelevant malignancies. Accumulating evidence suggests that preconditioning tumor cells with certain cytotoxic drugs can generate whole-cell tumor vaccines with strong prophylactic activities. However, the immunogenicity of these vaccines is not sufficient to restrain the outgrowth of existing tumors. In this study, we identified arsenic trioxide (ATO) as a wide-spectrum cytotoxic and highly immunogenic drug through multiparameter screening. ATO preconditioning could generate whole-cell tumor vaccines with potent antineoplastic effects in both prophylactic and therapeutic settings. The tumor-preventive or tumor-suppressive benefits of these vaccines relied on CD8^(+) T cells and type I and II interferon signaling and could be linked to the release of immunostimulatory danger molecules. Unexpectedly, following ATO-induced oxidative stress, multiple cell death pathways were activated, including autophagy, apoptosis, necroptosis, and ferroptosis. CRISPR‒Cas9-mediated knockout of cell death executors revealed that the absence of Rip3, Mlkl, or Acsl4 largely abolished the efficacy of ATO-based prophylactic and therapeutic cancer vaccines. This therapeutic failure could be rescued by coadministration of danger molecule analogs. In addition, PD-1 blockade synergistically improved the therapeutic efficacy of ATO-based cancer vaccines by augmenting local IFN-γ production.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.
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.
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To study the mechanisms involved in the inhibition of chronic myeloid leukemic cells (K562) proliferation induced by arsenic trioxide (As 2O 3) and to explore the potential role of Survivin, an inhibitor of apoptosis protein, in the regulation of As 2O 3 induced cell apoptosis, K562 cells were cultured with As 2O 3 of different concentrations. Cells were collected for proliferation analysis by MTT assay. Cell cycle distribution and cell apoptosis were analyzed by flow cytometry. Expression of Survivin protein and mRNA were detected by flow cytometry and RT-PCR, respectively. Our results showed that As 2O 3 (2-10 μmol/L) inhibited K562 cells growth effectively, but it did not induce cells apoptosis significantly. The percentage of K562 cells at G 2/M phase increased in proportion to As 2O 3 concentrations, and the expression of Survivin mRNA and content of Survivin protein was up-regulated accordingly. It is concluded that As 2O 3 inhibited K562 cells growth by inducing cell cycle arrest mainly at G 2/M phase. Over-expression of Survivin gene and protein might be one of the possible mechanisms contributing to K562 cells' resistance to As 2O 3-induced apoptosis.
基金This study was supported by a research foundation from Jian gsu Provincial Administration Bureau of TCM (No.9974)
文摘Objective: To investigate the distribution and recruitment of pulm onary dendritic cells (DCs) and the influence of low dosage arsenic trioxide (As 2O 3) on them in the airway of asthmatic mice. Methods: Thirty BALB/c mice were randomly divided into 3 groups: the control group, the asthmat ic group and the As 2O 3 treated group. The mice asthmatic model was induced v ia sensitizing with peritoneal injection of ovalbumin (OVA) for two times and th en provocated with aerosol inhalation of OVA for a week. The treated group was p eritoneally injected with 0.2 ml solution of As 2O 3 (4mg/kg) 0.5h after each provocation. The immunohistochemistry and computerised image analysis were appli ed to detect quantitatively the DCs in the lung and airway of mice. Resul ts: All intraepithelial nonlymphoid dendritic cells 145 (NLDC 145) throughout the respiratory tree in the mice of the control group formed a netwo rk with the density of DCs varying from (575±54) cells/mm 2 epithelial surface in the large airway, to (68±12) cells/mm 2 epithelial surface in the small ai rway. The distribution of airway NLDC 145 + in the asthmatic group was simil ar to that in the control group, but its density was significantly upregulated ( P <0.01). The distribution of airway NLDC 145 in the treated group was sim ilar to that in the asthmatic group, only its density was significantly downregu lated ( P <0.01). Conclusion: There is an integral network of N LDC 145 + throughout the respiratory tree. To downregulate the density but n ot change the distribution of pulmonary DCs could be an important therapeutic me chanism of low dosage As 2O 3 in treating asthma.
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 μmol/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.
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.
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.
文摘The therapeutic action of arsenic trioxide( As203 ) on solid tumors has aroused widespread interest among scholars. To study the impact of As2O3 on human colorectal carcinoma cells( LS-174T cell) and the activity of telomerase, the methods of PCR-ELISA, flow cytometry (FCM) and MTT assay in vitro were utilized. The results show that (1) with an increase in the concentration of As2O3, the ratio of living the cells to dead cells decreases significantly, and the IC50 value is 5.23 μg/mL; (2) the cells of the experimental groups can endure a series of morphological changes similar to the features of apoptosis ; (3) the apoptotic curves of FCM pictures appear after 24 h, and the cells show the apoptosis in a time-dependent manner; (4) As2O3 can inhibit the activity of telomerase of the cell extraction obviously in a concentration-dependent and time-dependent manner after 24 h. It can be concluded from the experiment results in vitro that As2O3 can induce the apoptosis of LS-174T cells and inhibit the telomerase activity. Therefore, it has been proposed, for the first time, that these two factors (the apoptosis of LS-174T cells and the inhibition to the telomerase activity) are important causes of the LS-174T cell death caused by As2O3.
基金supported by a grant from the Science and Technology Committee of Sichuan Province (No2008JY0029-1)
文摘Objective: To explore the effects of arsenic trioxide (ATO) on the apoptosis of glucocorticoid (GC)-resistant T-acute lymphoblastic leukemia (ALL) CEM-C1 cells and its possible mechanisms. Methods: Different concentrations of ATO (0.25 μmol/L-5 μmol/L) were used to induce the apoptosis of CEM-C1 cells. The inhibition rate of cell proliferation and apoptosis were detected by MTT test, Annexin V-FITC/PI flow cytometry and optical microscopy, respectively. RT-PCR was applied to semi-quantitatively analyze the mRNA expression of pro-apoptotic proteins (Bad and PDCD4) and anti-apoptotic proteins (XIAP and MCL-1) induced by different concentrations of ATO at different time points. Results: ATO could inhibit proliferation and induce apoptosis of CEM-C1 cells at a concentration and time dependent manner. Low-dose ATO mildly inhibited the proliferation of CEM-C1 cells while higher concentrations (1 μmol/L and 5 μmol/L) had strong anti-tumor effect with the inhibiting rates of 40.07±7.98% and 88.67±2.88%, respectively. Annexin V-FITC/PI flow cytometry showed that the apoptotic rates of CEM-C1 ceils were significantly increased after 48 hours treatment of different concentrations of ATO. RT-PCR demonstrated up-regulated mRNA expression of pro-apoptotic protein Bad and PDCD4 but down-regulated mRNA expression of anti-apoptotic protein XIAP when CEM-C1 cells were treated with different concentrations of ATO at different time points. The MCL-1 mRNA expression was down-regulated only after the treatment of 5 μmol/L ATO. Conclusion: ATO can inhibit cell proliferation and induce cell apoptosis in GC-resistant CEM-C1 cells. The molecular mechanisms might involve the increased mRNA expression of pro-apoptotic protein Bad and PDCD-4, and rapid down-regulation of XIAP mRNA expression.
文摘In order to explore the molecular mechanism of arsenic trioxide treating multiple myeloma (MM) via inhibition of angiogenesis, the expression of brain derived neurotrophic factor (BDNF) and its specific receptor TrkB in human MM cell line KM3 and endothelial cell line ECV304 was detected by Western blotting. The angiogenic activity was evaluated by wound migration assay and tubule formation assay in vitro. The results showed that BDNF was detected in the MM cells and TrkB in the endothelial cells. Furthermore, 100 ng/mL BDNF could significantly induced endothelial cell tubule formation and wound migration. As2O3 depressed the expression of BDNF and TrkB in the dose- and time-dependent manner. As2O3 inhibited BDNF-induced wound migration and capillary tube formation. It was concluded that BDNF is a novel angiogenic protein as well as VEGF and has a relation with the pathogenesis of MM. As2O3 interrupts a paracrine loop between MM cells and endothelial cells by down-regulating the TrkB expression in endothelial cells and inhibiting BDNF production in MM cells, finally resulting in inhibition of MM angiogenesis. This is probably one part of the mechanisms of the As2O3 treating MM via the inhibition of angiogenesis.
基金This project was supported by State Youth Natural Sci-ences Foundation (No .30200284) .
文摘Arsenic trioxide albumin microspheres (As_2O_3-BSA-NS) were prepared by using methods of chemical cross-linking. The desirability function (DF), calculated according to the size (<1 μm) distribution, drug loading and drug trapping efficiency, was introduced as a total index for the microspheres formulation. Four factors, inculding W/O ratio, decentralization speed, BSA concentration and stirring stabilization time, were selected and arranged in an orthogonal experimental table. The release characteristic was studied by the drug release experiment in vitro. The four factors affected DF differently. Decentralization speed behaved as the maximum (P<0.01), followed by BSA concentration (P<0.05) and the W/O ratio dose (P<0.05). Stirring stabilization time did not influence DF (P>0.05). The release experiment in vitro showed that As_2O_3 in As_2O_3-BSA-NS was released more slower than pure As_2O_3. It was concluded that regular As_2O_3-BSA-NS may be prepared by the methods of chemical cross-linking, which was optimized by orthogonal experimental analysis of different factors, and the microspheres can release As_2O_3 slowly.
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.
文摘Objective: To study the effect of arsenic trioxide (As203) on the expression of drug transporting molecules in multidrug resistance malignant neoplasma acute promyelocytic leukemia (APL) MR2 cell line. Methods: MR2 resistant to alltrans retinoic acid (ATRA) and non-ATRA resistant APL cell line NB4 were used. Expressions of P-glycoprotein (Pgp), multidrug resistance protein (MRP) and lung resistance-related protein (LRP) were detected by immunocytochemical assay. Results: The expression of Pgp was significantly higher in MR2(30%-40%) than that in NB4(10%-20%) (P 〈 0.001), and the expression of MRP was also higher in MR2 (56.9 ± 3.4 - 21.2 ± 1.1) than that in NB4 (20.6 ± 5.3 - 16.7 ± 1.2) (P 〈 0.001). As2O3 ranging from 0.5-2.0 μmol/L, could significantly decrease the expressions of Pgp and MRP. The expression of Pgp and MRP in MR.2 cell line were negatively correlated with the dose and duration of action of As2O3. Conclusion: Pgp and MRP may be the sensitive targets of As2O3 to overcome drug-resistance. ATRA might be the substrates of Pgp and MRP.
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 Science Foundation of Shaanxi Province (No. 2001-KG9).
文摘cDNA microarray was used to compare the gene expression profiles of multiple myeloma cell line RPMI8226 24 h before and after treatment with arsenic trioxide. Two cDNA probes were prepared by mRNA reverse transcription of both arsenic trioxide-treated and untreated RPMI8226 cells. The probes were labeled with Cy3 and Cy5 fluorescence dyes separately, hybridized with cDNA microarray representing 4096 different human genes, and scanned for fluorescence intensity. The differences in gene expression were calculated on the basis of the ratios of signal intensity of treated and untreated samples. The up- and down-regulated genes were screened through the analysis of gene expression ratios. The results showed that 273 genes were differentially altered at mRNA level, 121 genes were up-regulated and 152 were down-regulated. It is concluded that the treatment with arsenic trioxide can induce a variety of gene changes in RPMI8226 cell line. Many genes may be involved in the pathogenesis of multiple myeloma. ALK-1 and TXNIP genes may play an important role in the apoptosis and partial differentiation of RPMI8226 cells.
文摘Objective: To observe the effects of arsenic trioxide (As2O3) on human renal cell carcinoma (RCC) lines in vitro and to explore its possible molecular mechanisms. Methods: The microculture tetrazoli-um (MTT) assay was used to determine the anti-proliferative effects of As2O3 on human RCC lines. Flow cy-tometry was performed to investigate the effects of As2O3 on cell cycle and cell apoptosis. The reverse tran-scription-polymerase chain reaction (RT-PCR) was conducted to detect mRNA expression of Bcl-2, Bax, p53 and c-myc. Results: As2O3 inhibited the growth of RCC lines in vitro in a concentration-dependent manner. At the concentrations of 0.5, 1.0, 2.0 and 4.0μmol/L, the inhibition rates of As2O3 on RCC-WCS cells were 27.60%, 30.09%, 41.03% and 50.77%, respectively. Compared with untreated RCC-WCS, there was significant difference at each concentration (P<0.01). As2O3 induced a G1 phase arrest in RCC-LSL cells, but a G2/M phase arrest in RCC-WCS and RCC-SHK. As2O3 induced cell apoptosis in these cell lines. The mRNA level of p53 and c-myc decreased, but no detectable changes of Bcl-2 and Bax were observed after As2O3 treatmen. Conclusion: As2O3 in therapeutic concentrations inhibited the in vitro growth of RCC lines via cell cycle arrest and apoptosis. One of its possible mechanisms was down-regulation of p53 and c-myc. Our results suggest that As2O3 is probably a new candidate agent for the treatment of human renal carcinoma.
文摘Objective: To investigate the effects of various concentrations As 2O 3 on malignant melanoma. Methods: The viability of Cloundman melanoma S91 cells treated with As 2O 3 was measured by MTT [3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide] assay. The apoptosis was determined by transferase-mediated dUTP nick end labeling (TUNEL) detection, and the morphology of apoptotic cells was observed through transmission electron microscopy (TEM). The cells growth phase were analyzed by flow cytometry (FCM). Results: A time-and dose-dependent decrease in cell viability was induced in S91 cells after treatment with As 2O 3 at the concentration of 1-5 μmol/L respectively. The TUNEL indices were 0.033±0.018, 0.062±0.012, 0.102±0.016, 0.132±0.031, and 0.162±0.027 respectively, which were much higher compared with the control group (0.017±0.004, P<0.01). The flow cytometry showed that hypodiploid peak after treatment with 3 μmol/L and 5 μmol/L of As 2O 3 for 48 h were 9.99% and 17.59% respectively, which increased significantly compared with the control cells (3.05% P<0.01,). The apoptotic morphology observed by transmission electron microscope showed the chromatin became condensed and attached to the inner surface of nuclear membrane. Conclusion: Arsenic trioxide can induce melanoma Cloundman S91 cell apoptosis at the concentration of 1-5 μmol/L, which will provide enhanced benefit in melanoma therapy.
基金supported by the grants from National Natural Science Foundation of China(No. 82074203, 82274328 and 81673655)。
文摘Objective: The effects of arsenic trioxide(As2O3) on hepatocellular carcinoma have been documented widely. Autophagy plays dual roles in the survival and death of cancer cells. Therefore, we investigated the exact role of autophagy in As2O3-induced apoptosis in liver cancer cells.Methods: The viability of hepatoma cells was determined using the MTT assay with or without fetal bovine serum. The rate of apoptosis in liver cancer cells treated with As2O3was evaluated using flow cytometry, Hoechst 33258 staining, and TUNEL assays. The rate of autophagy among liver cancer cells treated with As2O3was detected using immunofluorescence, Western blot assay and transmission electron microscopy.Results: Upon treatment with As2O3, the viability of HepG2 and SMMC-7721 cells was decreased in a time-and dose-dependent manner. The apoptosis rates of both liver cancer cell lines increased with the concentration of As2O3, as shown by flow cytometry. Apoptosis in liver cancer cells treated with As2O3was also shown by the activation of the caspase cascade and the regulation of Bcl-2/Bax expression.Furthermore, As2O3treatment induced autophagy in liver cancer cells;this finding was supported by Western blot, immunofluorescence of LC3-II and beclin 1, and transmission electron microscopy. In liver cancer cells, As2O3inhibited the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR) signal pathway that plays a vital role in both apoptosis and autophagy. The PI3K activator SC-79 partially reversed As2O3-induced autophagy and apoptosis. Furthermore, inhibiting autophagy with 3-methyladenine partially reversed the negative effects of As2O3on cell viability.Serum starvation increased autophagy and amplified the effect of As2O3on cell death.Conclusion: As2O3induces apoptosis and autophagy in liver cancer cells. Autophagy induced by As2O3may have a proapoptotic effect that helps to reduce the viability of liver cancer cells. This study provides novel insights into the effects of As2O3against liver cancer.
基金supported by the National Science and Technology Innovation 2030 Major Project of China(2022ZD0205700)Natural Science Foundation of China(NSFC,81972701)+2 种基金CAMS Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1-074,2022-I2M-2-004)National Special Support Program for High-level Talents,China Ministry of Science and Technology(National Key Research and Development Program,Grant 2017YFA0506200)Innovative and Entrepreneurial Team Program(Jiangsu Province).
文摘Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer. Although major breakthroughs have been achieved in preventative tumor vaccines targeting oncogenic viruses, limited advances have been made in curative vaccines for virus-irrelevant malignancies. Accumulating evidence suggests that preconditioning tumor cells with certain cytotoxic drugs can generate whole-cell tumor vaccines with strong prophylactic activities. However, the immunogenicity of these vaccines is not sufficient to restrain the outgrowth of existing tumors. In this study, we identified arsenic trioxide (ATO) as a wide-spectrum cytotoxic and highly immunogenic drug through multiparameter screening. ATO preconditioning could generate whole-cell tumor vaccines with potent antineoplastic effects in both prophylactic and therapeutic settings. The tumor-preventive or tumor-suppressive benefits of these vaccines relied on CD8^(+) T cells and type I and II interferon signaling and could be linked to the release of immunostimulatory danger molecules. Unexpectedly, following ATO-induced oxidative stress, multiple cell death pathways were activated, including autophagy, apoptosis, necroptosis, and ferroptosis. CRISPR‒Cas9-mediated knockout of cell death executors revealed that the absence of Rip3, Mlkl, or Acsl4 largely abolished the efficacy of ATO-based prophylactic and therapeutic cancer vaccines. This therapeutic failure could be rescued by coadministration of danger molecule analogs. In addition, PD-1 blockade synergistically improved the therapeutic efficacy of ATO-based cancer vaccines by augmenting local IFN-γ production.