L-Ascorbic acid and α-Tocopherol synergistically triggers apoptosis inducing antileukemic effects of arsenic trioxide via oxidative stress in human acute promyelocytic leukemia cells.
ABSTRACT: Chemosensitization is an effective strategy to overcome the drawbacks of arsenic trioxide (As2O3) treatment which may be possible through the use of dietary supplements in combination. Proteomic analysis revealed that the combination of arsenic trioxide with vitamins can alter a number of proteins related to the translation, cell cycle, oxidative stress and apoptotic pathways that adds to their effectiveness in the treatment of acute promyelocytic leukemia. This study provides the fact that HL-60 cells became more vulnerable to As2O3 in the presence of L-Ascorbic acid and α-Tocopherol indicating that this combination may be a hopeful approach to increase the outcome of As2O3 in the treatment of acute promyelocytic leukemia.
Project description:Endocardial endothelium, which lines the chambers of the heart, is distinct in its origin, structure, and function. However, though functionally very important, no studies at protein level have been conducted so far characterizing endocardial endothelium. In this study, we used endothelial cells from pig heart to investigate if endocardial endothelial cells are distinct at the proteome level. Using a high throughput liquid chromatography-tandem mass spectrometry for proteome profiling and expression, we identified sets of proteins that belong to specific biological processes and metabolic pathways in endocardial endothelial cells supporting its specific structural and functional roles.
Project description:All-trans retinoic acid combined to anthracycline-based chemotherapy is the standard regimen of acute promyelocytic leukemia. The advent of arsenic trioxide has contributed to improve the anti-leukemic efficacy in acute promyelocytic leukemia. The objectives of the current study were to evaluate if dual induction by all-trans retinoic acid and arsenic trioxide could accelerate the recovery of abnormality of coagulation and fibrinolysis in patients with acute promyelocytic leukemia.Retrospective analysis was performed in 103 newly-diagnosed patients with acute promyelocytic leukemia. Hemostatic variables and the consumption of component blood were comparably analyzed among patients treated by different induction regimen with or without arsenic trioxide.Compared to patients with other subtypes of de novo acute myeloid leukemia, patients with acute promyelocytic leukemia had lower platelet counts and fibrinogen levels, significantly prolonged prothrombin time and elevated D-dimers (P<0.001). Acute promyelocytic leukemia patients with high or intermediate risk prognostic stratification presented lower initial fibrinogen level than that of low-risk group (P<0.05). After induction treatment, abnormal coagulation and fibrinolysis of patients with acute promyelocytic leukemia was significantly improved before day 10. The recovery of abnormal hemostatic variables (platelet, prothrombin time, fibrinogen and D-dimer) was not significantly accelerated after adding arsenic trioxide in induction regimens; and the consumption of transfused component blood (platelet and plasma) did not dramatically change either. Acute promyelocytic leukemia patients with high or intermediate risk prognostic stratification had higher platelet transfusion demands than that of low-risk group (P<0.05).Unexpectedly, adding arsenic trioxide could not accelerate the recovery of abnormality of coagulation and fibrinolysis in acute promyelocytic leukemia patients who received all-trans retinoic acid combining chemotherapy.
Project description:Enterococcus faecalis is a major nosocomial pathogen frequently isolated from non- healing wound infections. The major factor responsible for the virulence and establishment of infection is its ability to form robust biofilm. This renders the recalcitrant nature of Enterococci towards the current treatment strategies. In the present study, the quantitative proteomic approach is carried out to elucidate the protein expression levels in E. faecalis at planktonic and biofilm stages. This will help to identify biofilm associated pathways in E. faecalis which inturn can be considered as novel targets for biofilm inhibition.
Project description:Acute promyelocytic leukemia, a subtype of acute myeloid leukemia, is highly curable. In subgroup of patients with non-high-risk acute promyelocytic leukemia, intravenous arsenic trioxide plus all-trans-retinoic acid is considered the preferred regimen for acute promyelocytic leukemia. Recently, there are interests in the use of the oral form of arsenic, named the Realgar-Indigo naturalis formula, but the data on its efficacy and safety are still relatively limited. The current study was conducted with the aims to identify and summarize the results of all available randomized-controlled studies. A systematic review was conducted in the 2 major databases, utilizing the terms for arsenic and acute promyelocytic leukemia. Eligible studies had to be randomized-controlled studies that compared efficacy and/or adverse effects of oral arsenic versus intravenous arsenic for treatment of patients with acute promyelocytic leukemia. The Mantel-Haenszel method was used to pool the effect estimates and 95% confidence intervals of the included studies together. A total of 4 randomized controlled studies with 482 patients with acute promyelocytic leukemia (258 in Realgar-Indigo naturalis formula group and 224 in intravenous arsenic trioxide group) were included in the meta-analysis. The chances of achieving complete remission were numerically higher in the Realgar-Indigo naturalis formula group but the difference was not statistically significant (pooled odds ratio: 4.59, 95% CI: 0.74-28.57, I 2 = 0%). Similarly, other efficacy outcomes, including 30-day mortality rate, overall survival, and event-free survival, also tended to favor the Realgar-Indigo naturalis formula group but the difference was not statistically significant. There was no significant difference in the chance of developing differentiation syndrome, cardiac complications, grades 3 to 4 liver toxicity, grades 3 to 4 renal toxicity, and infection between the 2 groups. The results may suggest that all-trans-retinoic acid plus oral Realgar-Indigo naturalis formula regimen is, at minimum, not a worse alternative to the standard all-trans-retinoic acid plus intravenous intravenous arsenic trioxide regimen for treatment of acute promyelocytic leukemia, especially for patients with low-to-intermediate risk.
Project description:Previously, arsenic trioxide showed impressive regression rates of acute promyelocytic leukemia. Here, we investigated molecular determinants of sensitivity and resistance of cell lines of different tumor types towards arsenic trioxide. Arsenic trioxide was the most cytotoxic compound among 8 arsenicals investigated in the NCI cell line panel. We correlated transcriptome-wide microarray-based mRNA expression to the IC(50) values for arsenic trioxide by bioinformatic approaches (COMPARE and hierarchical cluster analyses, Ingenuity signaling pathway analysis). Among the identified pathways were signaling routes for p53, integrin-linked kinase, and actin cytoskeleton. Genes from these pathways significantly predicted cellular response to arsenic trioxide. Then, we analyzed whether classical drug resistance factors may also play a role for arsenic trioxide. Cell lines transfected with cDNAs for catalase, thioredoxin, or the anti-apoptotic bcl-2 gene were more resistant to arsenic trioxide than mock vector transfected cells. Multidrug-resistant cells overexpressing the MDR1, MRP1 or BCRP genes were not cross-resistant to arsenic trioxide. Our approach revealed that response of tumor cells towards arsenic trioxide is multi-factorial.
Project description:A 78-year-old-male with chronic myeloid leukemia (CML) treated for seven years with dasatinib developed an acute promyelocytic leukemia complicated by disseminated intravascular coagulopathy. A promyelocytic blast crisis was diagnosed by demonstrating co-expression of chimeric BCL/ABL and PML/RAR? translocations by karyotyping, fluorescence in situ hybridization, and quantitative real-time polymerase chain reaction. Promyelocytic blast crisis of CML is a rare event with historically poor outcomes. Treatment of our patient with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) resulted in complete morphologic remission. We review here the relevant literature of promyelocytic blast crisis and highlight the potential of ATRA/ATO as first line management.
Project description:Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometastatic function in TNBC that can be targeted by arsenic trioxide. We found that, in TNBC patients, constitutive HIF1A activity induces high expression of PML, along with a number of HIF1A target genes that promote metastasis at multiple levels. Intriguingly, PML controls the expression of these genes by binding to their regulatory regions along with HIF1A. This mechanism is specific to TNBC cells and does not occur in other subtypes of breast cancer where PML and prometastatic HIF1A target genes are underexpressed. As a consequence, PML promotes cell migration, invasion, and metastasis in TNBC cell and mouse models. Notably, pharmacological inhibition of PML with arsenic trioxide, a PML-degrading agent used to treat promyelocytic leukemia patients, delays tumor growth, impairs TNBC metastasis, and cooperates with chemotherapy by preventing metastatic dissemination. In conclusion, we report identification of a prometastatic pathway in TNBC and suggest clinical development toward the use of arsenic trioxide for TNBC patients.
Project description:In standard-risk acute promyelocytic leukemia, recent results have shown that all-trans retinoic acid plus arsenic trioxide combinations are at least as effective as classical all-trans retinoic acid plus anthracycline-based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher-risk acute promyelocytic leukemia, and access to arsenic remains limited for front-line treatment of standard-risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared arsenic, all-trans retinoic acid and the "classical" cytarabine for consolidation treatment (after all-trans retinoic acid and chemotherapy induction treatment) in standard-risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher-risk disease. Patients with newly diagnosed acute promyelocytic leukemia with a white blood cell count <10x109/L, after an induction treatment consisting of all-trans retinoic acid plus idarubicin and cytarabine, received consolidation chemotherapy with idarubicin and cytarabine, arsenic or all-trans retinoic acid. Patients with a white blood cell count >10x109/L received consolidation chemotherapy with or without arsenic. Overall, 795 patients with acute promyelocytic leukemia were enrolled in this trial. Among those with standard-risk acute promyelocytic leukemia (n=581), the 5-year event-free survival rates from randomization were 88.7%, 95.7% and 85.4% in the cytarabine, arsenic and all-trans retinoic acid consolidation groups, respectively (P=0.0067), and the 5-year cumulative incidences of relapse were was 5.5%, 0% and 8.2%. (P=0.001). Among those with higher-risk acute promyelocytic leukemia (n=214), the 5-year event-free survival rates were 85.5% and 92.1% (P=0.38) in the chemotherapy and chemotherapy plus arsenic groups, respectively, and the corresponding 5-year cumulative incidences of relapse were 4.6% and 3.5% (P=0.99). Given the prolonged myelosuppression that occurred in the chemotherapy plus arsenic arm, a protocol amendment excluded cytarabine during consolidation cycles in the chemotherapy plus arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first-line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation in which we found myelosuppression to be significant. (ClinicalTrials.gov Identifier: NCT00378365).
Project description:The aim of this study was to gain insight into the potential mechanism of resistance to arsenic trioxide (ATO). The gene expression profile of naive (NB4) (Acute promyelocytic leukemia (APL) cell line and one of its in house generated ATO resistant sub clone (NB4-VM-AsR1) was done using whole genome microarray and compared to generate the differential expression profile which will give insight into the mechanisms of ATO resistance in APL. Agilent one-color experiment,Organism: Human ,Agilent Whole Genome Human 4x44k (AMADID: 014850) , Labeling kit: Agilent Quick-Amp labeling Kit (p/n5190-0442) naive versus arsenic trioxide resistant acute promyelocytic leukemia cell line NB4
Project description:p53 is frequently mutated in tumor cells, and mutant p53 is often highly expressed due to its increased half-life. Thus, targeting mutant p53 for degradation might be explored as a therapeutic strategy to manage tumors that are addicted to mutant p53 for survival. Arsenic trioxide, a drug for patients with acute promyelocytic leukemia, is found to target and degrade a class of proteins with high levels of cysteine residues and vicinal thiol groups, such as promyelocytic leukemia protein (PML) and PML-retinoic acid receptor ? fusion protein. Interestingly, wild type p53 is accumulated in cells treated with arsenic compounds, presumably due to arsenic-induced oxidative stresses. In this study, we found that wild type p53 is induced by arsenic trioxide in tumor cells, consistent with published studies. In contrast, we found that arsenic compounds degrade both endogenous and ectopically expressed mutant p53 in time- and dose-dependent manners. We also found that arsenic trioxide decreases the stability of mutant p53 protein through a proteasomal pathway, and blockage of mutant p53 nuclear export can alleviate the arsenic-induced mutant p53 degradation. Furthermore, we found that knockdown of endogenous mutant p53 sensitizes, whereas ectopic expression of mutant p53 desensitizes, tumor cells to arsenic treatment. Taken together, we found that mutant p53 is a target of arsenic compounds, which provides an insight into exploring arsenic compound-based therapy for tumors harboring a mutant p53.