piplartine and Brain-Neoplasms

Glioblastoma multiforme (GBM) is the most aggressive and mortal primary glioma in adults. Temozolomide (TMZ) is a first-line clinical chemotherapeutic drug. However, TMZ resistance causes treatment failure in patients. Thus, exploring effective adjuvant drugs for GBM is crucial. Piperlongumine (PL), a bioactive alkaloid isolated from long pepper, possesses promising anticancer abilities. However, PL-mediated cytotoxic mechanisms in GBM are still unclear. We attempted to identify PL-regulated networks in suppressing GBM malignancy.. PL treatment significantly induced more apoptotic death in several GBM cell lines than in normal astrocytes. Decreased cell invasion, colony generation, and sphere formation, and enhanced TMZ cytotoxicity were found in PL-treated cells. Through RNA sequencing, PL-mediated transcriptomic profiles were established. By intersecting PL-downregulated genes, higher expressing genes in The Cancer Genome Atlas (TCGA) tumor tissues, and risk genes in three different GBM databases, tripartite motif-containing 14 (TRIM14) was selected. Higher TRIM14 expression was correlated with poor patient survival, and it existed in tumor samples, in mesenchymal type of GBM patients, and in GBM cells. PL significantly reduced TRIM14 expression through activating the p38/MAPK pathway. Overexpression or knockdown of TRIM14 influenced cell growth, PL-inhibited cell viability, invasion, colony generation, and sphere formation. Finally, using a gene set enrichment analysis, genes positively correlated with TRIM14 levels were enriched in epithelial-to-mesenchymal transition signaling. TRIM14 overexpression attenuated PL-regulated mesenchymal transition signaling.. PL inhibited TRIM14 signaling through activating the p38/MAPK pathway to inhibit GBM malignancy. Our findings may provide better insights and directions for future GBM therapies.

Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; Dioxolanes; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Intracellular Signaling Peptides and Proteins; Temozolomide; Tripartite Motif Proteins

Piplartine (PPL), also known as piperlongumine, is a biologically active alkaloid extracted from the

Topics: Acrylamides; Brain Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dioxolanes; Drug Screening Assays, Antitumor; Glioblastoma; Humans; Molecular Docking Simulation; Piperidones

Piplartine (

Topics: Apoptosis; Biological Availability; Brain Neoplasms; Cell Line, Tumor; Drug Screening Assays, Antitumor; Glioblastoma; Humans; Piperidones; Plant Extracts

Advances in the molecular biology of medulloblastoma revealed four genetically and clinically distinct subgroups. Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC, a high incidence of metastasis, and poor prognosis despite aggressive therapy. We investigated several potential small molecule inhibitors to target Group 3 medulloblastomas based on gene expression data using an in silico drug screen. The Connectivity Map (C-MAP) analysis identified piperlongumine as the top candidate drug for non-WNT medulloblastomas and the cyclin-dependent kinase (CDK) inhibitor alsterpaullone as the compound predicted to have specific antitumor activity against Group 3 medulloblastomas. To validate our findings we used these inhibitors against established Group 3 medulloblastoma cell lines. The C-MAP predicted drugs reduced cell proliferation in vitro and increased survival in Group 3 medulloblastoma xenografts. Alsterpaullone had the highest efficacy in Group 3 medulloblastoma cells. Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down-regulation of MYC. Our results demonstrate the preclinical efficacy of using a targeted therapy approach for Group 3 medulloblastomas. Specifically, we provide rationale for advancing alsterpaullone as a targeted therapy in Group 3 medulloblastoma.

Topics: Acetophenones; Animals; Antineoplastic Agents; Benzazepines; Benzopyrans; Brain Neoplasms; Cell Line; Cell Proliferation; Cyclin-Dependent Kinases; Dioxolanes; Drug Screening Assays, Antitumor; Flunarizine; Gene Expression Profiling; Genomics; Humans; Indoles; Medulloblastoma; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Prognosis; Proto-Oncogene Proteins c-myc; RNA

Piperlongumine, a natural plant product, kills multiple cancer types with little effect on normal cells. Piperlongumine raises intracellular levels of reactive oxygen species (ROS), a phenomenon that may underlie the cancer-cell killing. Although these findings suggest that piperlongumine could be useful for treating cancers, the mechanism by which the drug selectively kills cancer cells remains unknown.. We treated multiple high-grade glioma (HGG) sphere cultures with piperlongumine and assessed its effects on ROS and cell-growth levels as well as changes in downstream signaling. We also examined the levels of putative piperlongumine targets and their roles in HGG cell growth.. Piperlongumine treatment increased ROS levels and preferentially killed HGG cells with little effect in normal brain cells. Piperlongumine reportedly increases ROS levels after interactions with several redox regulators. We found that HGG cells expressed higher levels of the putative piperlongumine targets than did normal neural stem cells (NSCs). Furthermore, piperlongumine treatment in HGG cells, but not in normal NSCs, increased oxidative inactivation of peroxiredoxin 4 (PRDX4), an ROS-reducing enzyme that is overexpressed in HGGs and facilitates proper protein folding in the endoplasmic reticulum (ER). Moreover, piperlongumine exacerbated intracellular ER stress, an effect that was mimicked by suppressing PRDX4 expression.. Our results reveal that the mechanism by which piperlongumine preferentially kills HGG cells involves PRDX4 inactivation, thereby inducing ER stress. Therefore, piperlongumine treatment could be considered as a novel therapeutic option for HGG treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Databases, Factual; Dioxolanes; Endoplasmic Reticulum Stress; Glioma; Humans; Mice; Peroxiredoxins; Reactive Oxygen Species; Survival Analysis; Tumor Cells, Cultured