Gene expression from total and polysomal RNA fractions after ATO treatment in LN229 cells.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE100523 | GEO | 2018/01/01
SECONDARY ACCESSION(S): PRJNA392415
REPOSITORIES: GEO
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Project description:The goal of this exploratory phase I/II single-center clinical trial is to evaluate effectiveness, tolerability, and safety of Intravenous D-isoascorbic Acid (D-VC) With Arsenic Trioxide in Patients With Advanced/Metastatic Colorectal Cancer Who Have Exhausted Standard Therapy The main questions are to learn about effectiveness, tolerability, and safety of Intravenous D-isoascorbic Acid (D-VC) With Arsenic Trioxide.
The study aims to:
1. Assess the tolerability and pharmacokinetics of D-isoascorbic acid (D-VC) with a single intravenous injection in the monotherapy regimen and in the sequential administration regimen with arsenic trioxide (ATO) in patients on standard therapy for advanced/metastatic malignancies (Phase I)
2. Evaluate the efficacy and safety of D-isoascorbic acid (D-VC) with repeated intravenous administration in the mode of sequential administration with arsenic trioxide (ATO) in patients who have exhausted standard therapy for advanced/metastatic colorectal cancer (Phase II)
In phase I participants will receive single intravenous administration as monotherapy of D-isoascorbic acid (D-VC) with dose escalation (0.05, 0.1, 0.2 g/kg/day) and with arsenic trioxide (ATO).
Patients who have satisfactorily tolerated the study drug in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.
To study the safety and efficacy of the study drug in phase II, D-VC after the administration of ATO will be implemented in 2 groups:
Study group 1: ATO (at a dose of 0.15 mg / kg / day) after intravenous administration after 2 hours D-VC intravenously once a day at the maximum tolerated dose, determined at the end of phase I for at least 15 patients.
Group 2 standard therapy: 15 patients.
For the phase I researchers will compare laboratory tests (including clinical biochemistry and hematology), vital signs, clinical adverse events (diseases, symptoms and complaints) and other specific safety tests (for example, an electrocardiogram, ophthalmic examination) between groups. They will also measure the degree to which overt adverse reactions can be subjectively tolerated by the subject of the study.
For the phase II researchers will compare degrees of tumor volume reduction on CT; objective response rate (ORR) based on BICR according to RECIST v1.1 between test and standard therapy groups. They will also continue evaluation of safety and tolerability of ATO + D-VC combination therapy.
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Project description:Glioblastoma is one of the deadliest malignancies worldwide and is virtually incurable due to its highly infiltrative growth and limited sensitivity to conventional treatment by radiochemotherapy. It is hypothesized that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. These cells are characterized by an enhanced DNA repair capacity and expression of stemness marker genes, and elimination of this population might delay or even stop tumor recurrence following radiochemotherapy. The aim of this study was to analyze whether interference with the Hedgehog signaling (Hh) pathway or combined Hh/Notch blockade can efficiently target these cancer stem cells and sensitize them to chemotherapeutic drugs. Using tumor sphere lines and primary glioma cells we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the Hh/Notch inhibitor arsenic trioxide (ATO) are capable to synergistically decrease proliferation and induce cell death in combination with the natural cotton derived anticancer agent (-)-Gossypol (Gos). In contrast to GANT in combination with Gos, the ATO/Gos combination also strongly prevented sphere formation and recovery. These synergistic effects were associated with major proteomic changes indicating decreased cell movement, distortion of cell cycle and DNA repair, as well as markedly reduced stemness. Collectively, our data show that ATO and Gos, two drugs that are safe for use in humans, represent a promising targeted therapy approach for the synergistic and specific elimination of glioma stem-like cells.
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Project description:BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a high mortality rate due to the lack of effective treatments and drugs. Arsenic trioxide (As2O3, ATO, arsenious acid), which has been proved to successfully treat acute promyelocytic leukemia (APL), was recently reported to show therapeutic potential in solid tumors including liver cancer. Although the mechanistic effects of ATO in APL are established, its anticancer mechanism of action in HCC is still unclear. METHODS: We established an HCC subcutaneous xenograft and intrahepatic metastasis mouse model. In CSC models, tumorspheres and the flow cytometry analysis of CSC markers together with limiting dilution and serial transplantation were used. We compared mRNA expression profiles of the ATO-treated and control cells with mRNA microarray. The expression of target molecule or a clinical correlation was analyzed by immunohistochemistry staining in tissues from ATO-treated mouse and 76 HCC patients. We generated five stable minichromosome maintenance protein 7 (MCM7)-knockdown and two stable MCM7-overexpression HCC cell lines. The chromatin immunoprecipitation (ChIP) assays, immunoprecipitation (IP) assays, the dual luciferase reporter assays, a green biarsenical labeling reagent (FlAsH-EDT2) and a “competing endogenous RNA” (ceRNA) analysis were used. RESULTS: ATO could inhibit the liver tumor-initiating capacity and distant metastasis and prolongs survival in mice. We then screened and found that ATO downregulates the overexpression of MCM7 which is correlated with the progression and prognosis in HCC patients. Knockdown of MCM7 expression recapitulates the inhibition function of ATO on self-renewal of cancer stem cells (CSCs), while overexpression of MCM7 abolishes the inhibition function of ATO on tumorsphere formation. Most importantly, we revealed that ATO directly binds to the MCM7 protein and disturbs the interaction between serum response factor (SRF) and MCM7, resulting in downregulation of MCM7 transcription. A ceRNA analysis also indicated the alterations of endogenous MCM7-associated gene networks involved in stemness-related signaling pathways and cell differentiation. CONCLUSIONS: Here, for the first time, we report that ATO inhibits liver CSCs through blocking the interaction between SRF/MCM7 and suppressing MCM7 autoregulation activity.
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Project description:Gene expression from total and polysomal RNA fractions after ATO treatment in LN229 cells.
| PRJNA392415 | ENA