BACKGROUNDDespite great reduction of in-stent restenosis, first-generation drug-eluting stents (DESs) have increased the risk of late stent thrombosis due to delayed endothelialization. Arsenic trioxide, a natural substance that could inhibit cell proliferation and induce cell apoptosis, seems to be a promising surrogate of sirolimus to improve DES performance. This randomized controlled trial was to evaluate the efficacy and safety of a novel arsenic trioxide-eluting stent (AES), compared with traditional sirolimus-eluting stent (SES).

METHODSPatients with symptoms of angina pectoris were enrolled and randomized to AES or SES group. The primary endpoint was target vessel failure (TVF), and the second endpoint includes rates of all-cause death, cardiac death or myocardial infarction, target lesion revascularization (TLR) by telephone visit and late luminal loss (LLL) at 9-month by angiographic follow-up.

RESULTSFrom July 2007 to 2009, 212 patients were enrolled and randomized 1:1 to receive either AES or SES. At 2 years of follow-up, TVF rate was similar between AES and SES group (6.67% vs. 5.83%, P = 0.980). Frequency of all-cause death was significantly lower in AES group (0 vs. 4.85%, P = 0.028). There was no significant difference between AES and SES in frequency of TLR and in-stent restenosis, but greater in-stent LLL was observed for AES group (0.29 ± 0.52 mm vs. 0.10 ± 0.25 mm, P = 0.008).

CONCLUSIONSAfter 2 years of follow-up, AES demonstrated comparable efficacy and safety to SES for the treatment of de novo coronary artery lesions.

Aged ; Arsenicals ; administration & dosage ; therapeutic use ; Coronary Angiography ; Coronary Artery Disease ; diagnostic imaging ; surgery ; Drug-Eluting Stents ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Oxides ; administration & dosage ; therapeutic use ; Percutaneous Coronary Intervention ; methods ; Polymers ; chemistry ; Sirolimus ; administration & dosage ; therapeutic use

Antineoplastic Combined Chemotherapy Protocols ; Arsenicals ; administration & dosage ; Carcinoma, Hepatocellular ; drug therapy ; secondary ; Chemoembolization, Therapeutic ; methods ; Humans ; Liver Neoplasms ; Lung Neoplasms ; drug therapy ; secondary ; Niacinamide ; administration & dosage ; analogs & derivatives ; Oxides ; administration & dosage ; Phenylurea Compounds ; administration & dosage

This study was purposed to explore the effects of a methylation inhibitor arsenic trioxide (As2O3, ATO) and 5-Aza-2'-deoxycytidine (5-aza-CdR) on the expression of JAK-STAT signal transduction pathway in family members JAK3, TYK2 and hematopoietic cell phosphatase SHP-1 in chronic myeloid leukemia cell line K562 and their roles in pathogenesis of leukemia. The K562 cells were divided into 3 groups:single drug-treated group, combined 2 drugs-treated group, group without drug treatment as control. The concentration of 5-aza-CdR were 0.5, 1, 2 µmol/L; the concentration of ATO was 1, 2.5, 5 µmol/L; the concentration of combined drugs was ATO 1 µmol/L + 5-aza-CdR 0.5 µmol/L, ATO 2.5 µmol/L + 5-aza-CdR 1 µmol/L, and ATO 5 µmol/L + 5-aza-CdR 2 µmol/L. The K562 cells were treated with above-mentioned concentration of drugs for 24, 48 and 72 hours, then the total RNA of cells was extracted, the JAK3, TYK2 and SHP-1 expressions were detected by real-time quantitative-PCR. The results showed that after the K562 cells were treated with ATO and 5-aza-CdR alone and their combination, the expression of SHP-1 mRNA increased, the expressions of JAK3 mRNA and TYK2 mRNA decreased along with increasing of concentration and prolonging of time, displaying the concentration and time-dependency. The SHP-1 negatively related with JAK3 and TYK2. The effect of SHP-1 on JAK3 was significantly higher than that on TYK2. It is concluded that when the K562 cells are treated with ATO and 5-aza-CdR alone and their combination, the expression of SHP-1 is up-regulated and the expressions of JAK3, TYK2 are down-regulated in concentration-and time-dependent manners, moreover the ATO and 5-aza-CdR show synergies demethylation effect. The SHP-1 gene exert effect possibly through inhibiting the JAK/STAT pathway, the JAK3 is affected more than TYK2, the JAK3 may exert more important role in TAK/STAT pathway.
Arsenicals ; pharmacology ; Azacitidine ; administration & dosage ; analogs & derivatives ; pharmacology ; DNA Methylation ; Gene Expression Regulation, Leukemic ; drug effects ; Humans ; Janus Kinase 3 ; metabolism ; K562 Cells ; Oxides ; pharmacology ; Protein Tyrosine Phosphatase, Non-Receptor Type 6 ; metabolism ; TYK2 Kinase ; metabolism

OBJECTIVETo clarify the effects and mechanisms of homoharringtonine (HHT) monomer therapy or combination therapy with arsenic trioxide (ATO) on human multiple myeloma (MM) cell line RPMI 8226 in in vitro researches.

METHODSEffects of HHT, ATO, and HHT combined ATO on the growth of MM cell line RPMI 8226 were detected using MTT assay. The morphological changes of cell apoptosis were detected by Hoechst staining. The early apoptosis rate was detected using flow cytometry. Expressions of Caspase-3, Caspase-9, poly-ADP-ribose polymerase (PARP), Bcl-2, Mcl-1, Bcl-xl, and AKT protein were detected by Western blot.

RESULTSHHT and ATO inhibited the proliferation of RPM1 8226 cell line in a time- and dose-dependent manner (P < 0.05). Synergistic effects was shown in the combination group (Cl < 1). HHT and ATO induced the apoptosis of RPMI 8226 in a dose-dependent manner with typical morphological changes of apoptosis and higher early stage apoptosis rate. The enhancement in apoptotic induction was seen when two agents were combined. HHT activated expressions of Caspase-3 and PARP in a dose dependent manner at 24 h. HHT at 40 ng/mL and ATO at 8.5 micromol/L could significantly activate expressions of Caspase-3 and Caspase-9, and down-regulate expressions of anti-apoptotic proteins Bcl-xl and Mcl-1. In addition, the combination therapy of HHT at 40 ng/mL and ATO at 8.5 micromol/L inhibited phosphorylation of AKT in a time-dependent manner.

CONCLUSIONHTT, ATO, and combination therapy of HHT and ATO induced the apoptosis of RPMI 8226 cell line possibly through activating Caspase pathways, regulating expressions of Bcl-2 families, and inhibiting phosphorylation of AKT.

Apoptosis ; drug effects ; Arsenicals ; administration & dosage ; pharmacology ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Cell Line, Tumor ; Harringtonines ; administration & dosage ; pharmacology ; Humans ; Multiple Myeloma ; metabolism ; pathology ; Myeloid Cell Leukemia Sequence 1 Protein ; metabolism ; Oxides ; administration & dosage ; pharmacology ; Phosphorylation ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; bcl-X Protein ; metabolism

OBJECTIVE: To study the inhibitory effect of Arsenic Trioxide (As2O3) combined with diamminedichloroplatinum (DDP) on the growth of human nasopharyngeal carcinoma cell strain CNE-2Z xenograft in nude mice, and to explore the possible effect mechanisms of the antitumor. METHOD: The models of human poorly differentiated nasopharyngeal carcinoma in nude mice were established and randomly divided into four groups, control group, As2O3 group, DDP group and As2O3 + DDP group. The effect of antitumor on each group was studied. The specimen obtained from the mice were detected by optical microscope and tdt-mediated dutp rock end labeling (tunel) method. Expression of DAPK was detected by real time-PCR and immunohistochemistry. RESULT: As2O3 group and AS2O3 + DDP group could obviously inhibit the growth of tumor, induce the apoptosis of human naso pharyngeal carcinoma cell and up-regulate the expression of RASSF1A. CONCLUSION As2O3 can greatly inhibit the growth of human nasopharyngeal carcinoma cell strain CNE-2Z xenograft in nude mice, which were related to the induced apoptosis of human nasopharyngeal carcinoma cell and up-regulated expression of DAPK Combination of As2O3 with DDP seem to be more effective.
Animals ; Apoptosis ; drug effects ; Arsenic Trioxide ; Arsenicals ; administration & dosage ; pharmacology ; Carcinoma ; Cell Line, Tumor ; Cisplatin ; administration & dosage ; pharmacology ; Death-Associated Protein Kinases ; metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Mice, Nude ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms ; metabolism ; pathology ; Oxides ; administration & dosage ; pharmacology ; Xenograft Model Antitumor Assays

This study was purposed to investigate the effect of bortezomib (Bor) and arsenic trioxide (As(2)O(3)) combination on multiple myeloma cell line KM3 and its mechanisms. KM3 cells were cultured with different concentration of Bor or As(2)O(3) as well as both for a certain time. The cell proliferation was analysed by MTT assay and the concentration of 50% proliferation inhibition (IC(50)) was calculated. Early apoptosis and late apoptosis of KM3 cells were detected by Annexin-V-FITC Kit, and the change of transmembrane potential was measured by flow cytometry. mRNA of Caspase-3, Bim and Bcl-xL were detected by RT-PCR. The results showed that the proliferation inhibitory rate of KM3 cells treated by Bor plus As(2)O(3) was much higher than that of KM3 cells treated by Bor only for 72 h [ (27.64 ± 0.81)% vs (21.67 ± 2.20)%, P < 0.05]. There were more KM3 cells treated by Bor plus As(2)O(3) in early apoptosis at 48 h and late apoptosis at 72 h than that of KM3 cells treated only by Bor [ (53.20 ± 3.70)% vs (35.40 ± 2.58)%, P < 0.01; (63.96 ± 2.97)% vs (54.08 ± 3.76)%, P < 0.01]. Transmembrane potential (Δψm) of KM3 cells treated by Bor plus As(2)O(3) decreased more at 48 h, as compared with Bor alone. The expression levels of caspase-3 mRNA and Bim mRNA in KM3 cells treated with Bor plus As(2)O(3) were higher than that in KM3 cells treated with Bor alone. But the expression level of Bcl-xL mRNA was lower than that in KM3 cells treated with Bor alone. It is concluded that As(2)O(3) can enhance the apoptosis-inducing effect of Bor on multiple myeloma cell line KM3, which is associated with decreasing the expression of Bcl-xl mRNA and increasing the expression of Caspase-3 and Bim mRNA.
Apoptosis ; drug effects ; Apoptosis Regulatory Proteins ; metabolism ; Arsenicals ; administration & dosage ; pharmacology ; Bcl-2-Like Protein 11 ; Boronic Acids ; administration & dosage ; pharmacology ; Bortezomib ; Caspase 3 ; metabolism ; Cell Line, Tumor ; Humans ; Membrane Proteins ; metabolism ; Multiple Myeloma ; metabolism ; pathology ; Oxides ; administration & dosage ; pharmacology ; Proto-Oncogene Proteins ; metabolism ; Pyrazines ; administration & dosage ; pharmacology ; bcl-X Protein ; metabolism

OBJECTIVETo study the demethylation effect of arsenic trioxide (As2O3) on ERα-negative human breast cancer MDA-MB-435s cells and its possible mechanisms, and to observe its treatment efficacy in combination with tamoxifen (TAM) after ERα re-expression.

METHODSMTT assay was used to examine the inhibitory effect of As2O3 treatment alone or in combination with TAM on cell proliferation. A nude mouse xenograft model was used to further examine the treatment efficacy in vivo. MSP was used to detect the methylation status of ERα gene after treated with As2O3 in MDA-MB-435s cells and the transplanted tumor tissues. RT-PCR was used to detect the mRNA expression of DNMT1 and Erα. Western bolt was used to detect the DNMT1 and ERα protein expression. The diameter of xenograft tumors was measured weekly, and the tumor growth curve was drawn.

RESULTSThe level of proliferation of the MDA-MB-435s cells was significantly suppressed after treatment with different concentration of As2O3 alone or As2O3 combined with TAM, and the 4 µmol/L As2O3 + TAM treatment for 72 h showed the highest inhibition rate (62.6%). 1, 2, 4 µmol/L As2O3 had demethylation effect on MDA-MB-435s cells, and the DNMT1 mRNA and protein expression was inhibited and accompanied by ERα mRNA and protein re-expression. The unmethylation specific bands of ERα gene were enhanced after treated by As2O3 alone or As2O3 combined with TAM in the xenograft tumors. The expression of DNMT1 mRNA and protein was inhibited, and accompanied by ERα mRNA and protein re-expression. An significant decrease of volume and weight of the xenograft tumors in the As2O3 treated alone or combined with TAM groups was observed compared with those of the normal saline group or TAM alone group (P < 0.05), and the 4 mg/kg As2O3 + TAM group had the highest inhibition rate of tumor weight (79.5%) and volume (76.4%).

CONCLUSIONSERα can be re-expressed in ERα-negative breast cancer MDA-MB-435s cells after treated with As2O3 by inhibiting the DNMT1 activity. MDA-MB-435s cells are re-sensitized to endocrine therapy after ERα re-expression. As2O3 combined with TAM may provide a new therapeutic approach for patients with ERα-negative breast cancer in the clinic.

Animals ; Antineoplastic Agents ; administration & dosage ; pharmacology ; Antineoplastic Agents, Hormonal ; administration & dosage ; Antineoplastic Combined Chemotherapy Protocols ; pharmacology ; Arsenicals ; administration & dosage ; pharmacology ; Breast Neoplasms ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases ; DNA Methylation ; Dose-Response Relationship, Drug ; Estrogen Receptor alpha ; genetics ; metabolism ; Female ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Oxides ; administration & dosage ; pharmacology ; RNA, Messenger ; metabolism ; Tamoxifen ; administration & dosage ; Tumor Burden ; drug effects ; Xenograft Model Antitumor Assays

This study was aimed to investigate the effect of bortezomib alone or combined with arsenic trioxide on the apoptosis of Jurkat cells and expression of livin mRNA. The Jurkat cells were cultured and treated with different concentrations of bortezomib, arsenic trioxide or their combination for 24 hours. Then, the expression of livin mRNA was detected by RT-PCR, the cell proliferation was analyzed with MTT assay and flow cytometry. The results showed that 5 - 25 nmol/L bortezomib could effectively inhibit Jurkat cells in a dose-dependent manner, the group of bortezomib combined with arsenic trioxide showed more inhibitory effect on Jurkat cells than the effect of bortezomib alone or arsenic trioxide alone on Jurkat cells. The expression of livin mRNA in Jurkat cells decreased in a dose-dependent manner after treated with bortezomib, which was downregulated significantly after combined treatment. It is concluded that bortezomib and arsenic trioxide can induce apoptosis by inhibiting the expression of livin mRNA in Jurkat cells. The combination of bortezomib with arsenic trioxide displays a synergistic effect.
Adaptor Proteins, Signal Transducing ; genetics ; metabolism ; Apoptosis ; drug effects ; Arsenicals ; pharmacology ; Boronic Acids ; administration & dosage ; pharmacology ; Bortezomib ; Humans ; Inhibitor of Apoptosis Proteins ; genetics ; metabolism ; Jurkat Cells ; Neoplasm Proteins ; genetics ; metabolism ; Oxides ; pharmacology ; Pyrazines ; administration & dosage ; pharmacology ; RNA, Messenger ; genetics

OBJECTIVETo study the effect of arsenic trioxide (As2O3) and all-trans retinoic acid (ATRA) on human cervical carcinoma HeLa cell line.

METHODSHeLa cells were treated with As2O3 and ATRA. The cell proliferation was evaluated by MTT assay. The expressions of NDRG-1 protein and mRNA were determined by Western blot and RT-PCR analysis.

RESULTSMTT assay showed that As2O3 and ATRA inhibited the growth of human cervical carcinoma HeLa cells in vitro in a dose- and time-dependent manner. Western blot and RT-PCR techniques showed that As2O3 and ATRA down-regulated the expressions of NDRG-1 protein and mRNA (P < 0.05).

CONCLUSIONAs2O3 and ATRA can significantly inhibit the growth and proliferation of HeLa cells. The reason of these changes may be related with the down-regulation of expression of NDRG-1.

Antineoplastic Agents ; administration & dosage ; pharmacology ; Arsenicals ; administration & dosage ; pharmacology ; Blotting, Western ; Cell Cycle Proteins ; genetics ; metabolism ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; genetics ; metabolism ; Oxides ; administration & dosage ; pharmacology ; RNA, Messenger ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tretinoin ; administration & dosage ; pharmacology

OBJECTIVETo evaluate the effect and adverse effects of arsenic trioxide (As2O3) in the treatment of primary hepatocarcinoma patients, and conduct the pharmacokinetics study.

METHODSA total of one hundred and eleven advanced primary hepatocarcinoma patients in five centers were treated with As2O3 injection 7 - 8 mg/m(2) i.v. qd for 14 days and was repeated after 7 - 14 days. Evaluation of the clinical response and adverse effects was conducted after two cycles of treatment. The patient who had reached partial PR and SD was treated continuously until disease progression or intolerance.

RESULTSAmong the 102 patients evaluable for clinical efficacy analysis, there were 7 PR, 71 SD and 24 PD, the response rate was 6.9% and the clinical benefit rate was 76.5%. The quality of life was improved in 22.5% of patients. The pain relief rate was 71.7%, time to progress (TTP) was 97 days, and the median survival time (MST) was 195 days. The major adverse effects were reversible WHO I-II grade gastrointestinal reactions and bone marrow suppression. The results of pharmacokinetic study showed that the distribution and elimination characteristics in vivo was found to be a two-compartment model. The plasma elimination half-life was (23.94 ± 18.39) h.

CONCLUSIONSAs2O3 is effective in the management of primary hepatocarcinoma, with a significant analgesic effect. To some extent, it can extend TTP and MST in advanced liver cancer patients, while the treatment is well tolerated in the majority of patients.

Adult ; Aged ; Antineoplastic Agents ; administration & dosage ; adverse effects ; pharmacokinetics ; therapeutic use ; Arsenicals ; administration & dosage ; adverse effects ; pharmacokinetics ; therapeutic use ; Carcinoma, Hepatocellular ; blood ; drug therapy ; pathology ; Disease Progression ; Female ; Follow-Up Studies ; Half-Life ; Humans ; Injections ; Leukopenia ; chemically induced ; Liver Neoplasms ; blood ; drug therapy ; pathology ; Lung Neoplasms ; drug therapy ; secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Nausea ; chemically induced ; Neoplasm Staging ; Oxides ; administration & dosage ; adverse effects ; pharmacokinetics ; therapeutic use ; Quality of Life ; Remission Induction ; Survival Rate ; Vomiting ; chemically induced