OBJECTIVE: To explore the effect of Qinghuang Powder (QHP,()combined with Bupi Yishen Decoction (BPYS, ) on myelodysplastic syndromes (MDS) patients with refractory cytopenia with multilineage dysplasia (RCMD) and determine the change of DNA methylation in MDS-RCMD patients after the treatment of Chinese medicine formula. METHODS: All 308 MDS-RCMD patients were treated with QHP combined with BPYS for 2 months at least, absolute neutrophil count (ANC), hemoglobin (Hb), platelets (PLT), primitive bone marrow cells and chromosome karyotype were chosen as the main evaluation indexes to analyze the treatment effect according to criteria from the MDS International Working Group. Then 43 bone marrow samples from 15 MDS-RCMD patients and 28 healthy donors were obtained for the examination of DNA methylation. Gene Ontology (GO) and Pathway analysis were applied to analyze the methylation data. RESULTS: The overall MDS response rate to QHP was 61.68% (190/360) including hematologic improvement-neutrophil (HI-N) or hematologic improvement-erythroid (HI-E) or hematologic improvement-platelet (HI-P). Patients with anemia had a better response rate than patients with neutropenia or thrombocypenia (55.88% vs 31.54% or 55.88% vs. 36.9%). The DNA methylation microarray analysis disclosed that 4,257 hypermethylated genes were demethylated upon the treatment with QHP and BPYS. GO analysis and Pathway analysis showed that these demethylated genes were involved in a lot of tumor-related pathways and functions. CONCLUSIONS QHP combined with BPYS could effectively treat MDS-RCMD patients through hematologic improvement (HI-N, HI-P or HI-E) and PLT and RBC transfusion independence due to the demethylation, thereby providing another choice for the treatment of patients with MDS-RCMD.
Arsenicals ; administration & dosage ; pharmacology ; therapeutic use ; Cell Lineage ; drug effects ; DNA Methylation ; drug effects ; Demethylation ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; therapeutic use ; Female ; Gene Ontology ; Humans ; Leukocyte Disorders ; drug therapy ; genetics ; Male ; Middle Aged ; Powders ; Treatment Outcome

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 observe the clinical efficacy of a low dose Qinghuang Powder (QP) combined with Chinese drugs for Shen supplementing and Pi invigorating (CDSSPI) in treatment of hypocellular myelodysplastic syndromes (hypo-MDS).

METHODSTotally 33 hypo-MDS patients enrolled in this study came from outpatient clinics between November 2011 and December 2012. A self-control method was used in this study. Patients took QP (0.4 g per day) combined with CDSSPI (one dose per day), and Stanozolol Tablet (2 mg each time, three times per day), 3 months as one therapeutic course, a total of 2 courses. The clinical efficacy was evaluated timely at the end of each therapeutic course. The venous blood was withdrawn before treatment, at month 3 and 6 after treatment. Changes of neutrophils (ANC), hemoglobin (Hb), and platelet (PLT) were mainly observed.

RESULTSTotally 31 patients in this study finished the treatment. Three months after treatment ANC, Hb, and PLT increased more than before treatment (P < 0.05). Six months after treatment Hb and PLT increased (P < 0.01, P < 0.05), but with no statistical difference in ANC (P > 0.05). Hb increased higher at month 6 after treatment than at month 3 after treatment (P < 0.01), but with no statistical difference in ANC or PLT (P > 0.05). After 3-month treatment the number of hematologic progress, stability, disease progression were: 13 cases (41.9%), 15 cases (48.4%), and 3 cases (9.7%), respectively; after 6-month treatment the number of hematologic improvement, stability, and disease progression were: 18 cases (58.1%), 7 cases (22.6%), 6 cases (19.3%), respectively. There was no significant difference between 3-month efficacy and 6-month efficacy (P > 0.05). There was no correlation between the efficacy and ages of hypo-MDS patients or the efficacy and courses of hypo-MDS patients (P > 0.05).

CONCLUSIONSA low dose QP combined with CDSSPI showed confirmative efficacy in treatment of hypo-MDS. But the efficacy had little correlation with ages and courses of hypo-MDS patients.

Arsenicals ; administration & dosage ; pharmacology ; therapeutic use ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; therapeutic use ; Hemoglobins ; Humans ; Medicine, Chinese Traditional ; methods ; Myelodysplastic Syndromes ; drug therapy ; Neutrophils ; Phytotherapy ; methods

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

The early molecular kinetics during all-trans retinoic acid (ATRA) plus arsenic-based induction therapy and its prognostic value for acute promyelocytic leukemia (APL) remain unclear. This study was purposed to investigate the molecular and cytogenetic kinetics and its clinical significance in treatment of APL with ATRA plus arsenic-based induction. The molecular and cytogenetic kinetics was assessed by real-time quantitative RT-PCR and interphase fluorescence in situ hybridization (FISH) in 32 newly diagnosed APL patients. The results showed that the median PML-RARα transcript levels (PML-RARα/ABL) were very significantly up-regulated at 14 days of induction therapy compared with that of pre-treatment (40.10% vs 57.74%, P < 0.01), and then decreased at 28 days of induction therapy and at the end of consolidation therapy (6.97% and 0%), respectively. The total of 65.62% and 31.25% patients showed up-regulation of PML-RARα transcript at 14 and 28 days after induction, as compared with pretreatment. The PML-RARα copies per APL cell before treatment, and at 14 and 28 days after induction were calculated as 0.9, 2.2, 1.4 by the formula of PML-RARA/ABL(%)×2/APL cells (%). With the median follow-up time of 22 months, 32 patients were still in continuous clinical remission and no molecular relapse occurred. Up-regulation of PML-RARa expression during the induction had no effect on outcomes of APL patients. It is concluded that up-regulation of PML-RARa expression is a common event during induction therapy with ATRA plus arsenics. Up-regulation of PML-RARa expression during induction therapy hasn't influenced the long-term prognosis of APL.
Adolescent ; Adult ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Arsenicals ; administration & dosage ; Female ; Humans ; Leukemia, Promyelocytic, Acute ; diagnosis ; drug therapy ; metabolism ; Male ; Middle Aged ; Oncogene Proteins, Fusion ; metabolism ; Prognosis ; Tretinoin ; administration & dosage ; Up-Regulation ; drug effects ; Young Adult

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