piplartine and Glioblastoma

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

Piperlongumine (PL) is recently found to kill cancer cells selectively and effectively via targeting reactive oxygen species (ROS) responses. To further explore the therapeutic effects of PL in cancers, we investigated the role and mechanisms of PL in cancer cell migration. PL effectively inhibited the migration of human glioma (LN229 or U87 MG) cells but not normal astrocytes in the scratch-wound culture model. PL did not alter EdU(+)-cells and cdc2, cdc25c, or cyclin D1 expression in our model. PL increased ROS (measured by DCFH-DA), reduced glutathione, activated p38 and JNK, increased IκBα, and suppressed NFκB in LN229 cells after scratching. All the biological effects of PL in scratched LN229 cells were completely abolished by the antioxidant N-acetyl-L-cysteine (NAC). Pharmacological administration of specific p38 (SB203580) or JNK (SP600125) inhibitors significantly reduced the inhibitory effects of PL on LN229 cell migration and NF κ B activity in scratch-wound and/or transwell models. PL prevented the deformation of migrated LN229 cells while NAC, SB203580, or SP600125 reversed PL-induced morphological changes of migrated cells. These results suggest potential therapeutic effects of PL in the treatment and prevention of highly malignant tumors such as glioblastoma multiforme (GBM) in the brain by suppressing tumor invasion and metastasis.

Topics: Astrocytes; Cell Line, Tumor; Cell Migration Assays; Cell Movement; Cell Nucleus; Cell Proliferation; Dioxolanes; Enzyme Activation; Glioblastoma; Humans; I-kappa B Proteins; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; NF-kappa B; NF-KappaB Inhibitor alpha; p38 Mitogen-Activated Protein Kinases; Protein Transport; Reactive Oxygen Species

Piperlongumine (PL), a natural alkaloid isolated from the long pepper, may have anti-cancer properties. It selectively targets and kills cancer cells but leaves normal cells intact. Here, we reported that PL selectively killed glioblastoma multiforme (GBM) cells via accumulating reactive oxygen species (ROS) to activate JNK and p38. PL at 20μM could induce severe cell death in three GBM cell lines (LN229, U87 and 8MG) but not astrocytes in cultures. PL elevated ROS prominently and reduced glutathione levels in LN229 and U87 cells. Antioxidant N-acetyl-L-cysteine (NAC) completely reversed PL-induced ROS accumulation and prevented cell death in LN229 and U87 cells. In LN229 and U87 cells, PL-treatment activated JNK and p38 but not Erk and Akt, in a dosage-dependent manner. These activations could be blocked by NAC pre-treatment. JNK and p38 specific inhibitors, SB203580 and SP600125 respectively, significantly blocked the cytotoxic effects of PL in LN229 and U87 cells. Our data first suggests that PL may have therapeutic potential for one of the most malignant and refractory tumors GBM.

Topics: Astrocytes; Cell Death; Cell Line, Tumor; Dioxolanes; Drug Screening Assays, Antitumor; Enzyme Activation; Glioblastoma; Humans; JNK Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Reactive Oxygen Species