morusin and Glioblastoma

Malignant brain tumors remain a major cause of concern and mortality as successful treatment is hindered due to the poor transport and low penetration of chemotherapeutics across the blood-brain barrier (BBB). In this study, a nano formulation composed of chlorotoxin (CTX)-conjugated morusin loaded PLGA nanoparticles (PLGA-MOR-CTX) was devised against Glioblastoma Multiforme (GBM) and its anti-proliferative effects were evaluated in vitro. The synthesized nanoparticles were loaded with morusin, a naturally derived chemotherapeutic drug, and surface conjugated with CTX, a peptide derived from scorpion venom, highly specific for chloride channels (CIC-3) expressed in glioma tumor cells, as well as for matrix metalloproteinase (MMP-2), which is up regulated in the tumor microenvironment. Subsequently, the anti-cancer potential of the NPs was assessed in U87 and GI-1 (human glioblastoma) cells. Antiproliferative, cell apoptosis, and other cell-based assays demonstrated that the PLGA-MOR-CTX NPs resulted in enhanced inhibitory effects on U87 and GI-1 glioma cells. Prominent cytotoxicity parameters such as ROS generation, enhanced caspase activity, cytoskeletal destabilization, and inhibition of MMP-activity were observed in glioblastoma cells upon PLGA-MOR-CTX NP treatment. The cytocompatibility observed with normal human neuronal cells (HCN-1A) and the enhanced lethal effects in glioblastoma cells highlight the potential of PLGA-MOR-CTX nanoparticles as promising therapeutic nanocarriers towards GBM.

Topics: Autophagy; Biological Transport; Brain Neoplasms; Cell Line, Tumor; Cytoskeleton; Drug Carriers; Drug Liberation; Flavonoids; Glioblastoma; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Molecular Targeted Therapy; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Reactive Oxygen Species; Scorpion Venoms

Glioblastoma is one of the most malignant primary tumors, and the prognosis for glioblastoma patients remains poor. Tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer agent due to its remarkable ability to selectively kill tumor cells. However, since many cancers are resistant to TRAIL, strategies to overcome resistance are required for the successful use of TRAIL in the clinic. In the present study, the potential of morusin as a TRAIL sensitizer in human glioblastoma cells was evaluated. Treatment with TRAIL or morusin alone showed weak cytotoxicity in human glioblastoma cells. However, combination treatment of TRAIL with morusin synergistically decreased cell viability and increased apoptosis compared with single treatment. Morusin induced expression of death receptor 5 (DR5), but not DR4 or decoy receptors (DcR1 and DcR2). Furthermore, morusin significantly decreased anti-apoptotic molecules survivin and XIAP. In addition, morusin reduced expression of EGFR and PDFGR as well as phosphorylation of STAT3, possibly mediating down-regulation of survivin and XIAP. Together these results suggest that morusin enhances TRAIL sensitivity in human glioblastoma cells through regulating expression of DR5 and EGFR. Therefore, the combination treatment of TRAIL and morusin may be a new therapeutic strategy for malignant glioma patients.

Topics: Apoptosis; Down-Regulation; ErbB Receptors; Flavonoids; Glioblastoma; Humans; Male; Molecular Structure; Receptors, TNF-Related Apoptosis-Inducing Ligand; STAT3 Transcription Factor; TNF-Related Apoptosis-Inducing Ligand

Glioblastoma multiforme (GBM) cancer stem cells (GSCs) are responsible for the progression and recurrence of GBM after conventional therapy. Morusin possesses anti-cancer activity in vitro. The purpose of this study is to confirm the growth inhibition effect of morusin on human GSCs growth in vitro and in vivo and to explore the possible mechanism of its activity. Human GSCs were enriched under nonadhesive culture system, and characterized through neurosphere formation, toluidine blue staining, immunofluorescence staining, Western blotting analysis of stemness markers of CD133, nestin, Sox2 and Oct4, and tumorigenecity in vivo; the growth inhibition effect of morusin on human GSCs in vitro and in vivo were tested by cell cytotoxicity, neurosphere formation inhibition, adipogenic differentiation, apoptosis induction, and tumor growth inhibition in vivo assays. The potential molecular mechanisms underlying the growth inhibition effect of morusin on GSCs in vitro and in vivo were investigated with Western blotting evaluation of stemness, adipogenic, and apoptotic proteins in morusin treated GSCs and tumor tissues. GSCs enriched under nonadhesive culture system possess stemness characterstics; Morusin inhibited GSCs growth in vitro and in vivo, it reduced stemness of GSCs, induced them adipocyte-like transdifferention and apoptosis. Morusin has the potential to inhibit human GSCs growth in vitro and in vivo through stemness attenuation, adipocyte transdifferentiation, and apoptosis induction.

Topics: Animals; Apoptosis; Biomarkers; Cell Line, Tumor; Cell Self Renewal; Cell Transdifferentiation; Disease Models, Animal; DNA Fragmentation; Flavonoids; Gene Expression; Glioblastoma; Humans; Mice; Neoplastic Stem Cells; Spheroids, Cellular; Tumor Burden; Tumor Cells, Cultured