harmine and Glioblastoma

Glioblastoma, the most common tumor in the brain, has witnessed very little clinical progress over the last decades. Exploring and discovering new therapeutic strategies for glioblastoma has become a critical problem. Harmine (HM), belonging to the beta-carboline alkaloid, is a natural product and isolated from the seeds of

Topics: Antineoplastic Agents; Glioblastoma; Harmine; Humans; Nanoparticles; Serum Albumin, Bovine

Glioblastoma is one of the most invasive tumors of the central nervous system, and has a high degree of malignancy and poor prognosis. Harmine, an active ingredient extracted from perennial herbs, has been reported to have obvious antitumor effects on various tumors. However, the effects of harmine on glioblastoma growth remain unknown. We here explored the effects of harmine on glioblastoma and its underlying molecular mechanisms related to tumorigenesis.. CCK-8 and immunofluorescent assay were performed to measure anti-proliferative effect of harmine on U251-MG and U373-MG cells. Wound healing assay was performed to measure the effects of harmine on cell migration. qRT-PCR and western blot were performed to detect the protein/gene expression. BALB/c nude mice bearing U251-MG xenografts was used to measure the effects of harmine on the growth of glioblastoma in vivo.. Harmine treatment significantly suppressed the proliferation of U251-MG and U373-MG cells in a dose and time-dependent way. Mechanistically, harmine reduced the basal and EGF-enhanced the phosphorylation level of FAK and AKT. Moreover, harmine inhibited the cell viability of U251-MG and U373-MG cells by downregulating the phosphorylation of the FAK/AKT pathway. Besides, harmine significantly suppressed the migration of U251-MG cells by suppressing the expression of MMP2, MMP9 and VEGF. Subsequently, orthotopic xenograft models revealed that harmine treatment dramatically inhibited the growth of glioblastoma in vivo.. In conclusion, these results suggest that harmine suppresses the proliferation and migration of U251-MG and U373-MG cells by inhibiting the FAK/AKT signaling pathway. Our findings elucidate harmine could be a promising drug for glioblastoma therapy.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; China; Focal Adhesion Kinase 1; Glioblastoma; Harmine; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays

The DYRK family contains kinases that are up-regulated in malignancy and control several cancer hallmarks. To assess the anticancer potential of inhibitors targeting DYRK kinases, we developed a series of novel DYRK inhibitors based on the 7-azaindole scaffold. All compounds were tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the structurally related CLK1. The library was screened for anticancer efficacy in established and stem cell-like glioblastoma cell lines. The most potent inhibitors (IC

Topics: Brain Neoplasms; Glioblastoma; Humans; Phosphorylation; Protein Kinases; Structure-Activity Relationship; Tyrosine

Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumor-initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dyrk Kinases; ErbB Receptors; Gene Expression; Gene Knockdown Techniques; Glioblastoma; Harmine; Humans; Mice; Mice, Nude; Neoplastic Stem Cells; Neural Stem Cells; Protein Serine-Threonine Kinases; Protein Stability; Protein-Tyrosine Kinases; Proteolysis; RNA, Small Interfering; Signal Transduction; Spheroids, Cellular; Tumor Burden; Xenograft Model Antitumor Assays

Harmine hydrochloride (Har-hc), a derivative from Harmine which is a natural extractive from plants, has been considered for treatment of kinds of cancers and cerebral diseases. In this study, we found that Har-hc clearly decreased cell viability, induced apoptosis and inhibited Akt phosphorylation in glioblastoma cell lines. Moreover, Har-hc had the ability to inhibit self-renewal and promote differentiation of glioblastoma stem like cells (GSLCs) accompanied by inhibition of Akt phosphorylation. Especially, we demonstrated that Har-hc inhibited neurosphere formation of human primary GSLCs. In vivo test also confirmed Har-hc decreased the tumorigenicity of GSLCs. Thus we conclude that Har-hc has potent anti-cancer effects in glioblastoma cells, which is at least partially via inhibition of Akt phosphorylation. Administration of Har-hc may act as a new approach to glioblastoma treatment.

Topics: Analysis of Variance; Animals; Apoptosis; bcl-2-Associated X Protein; Brain; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Chromones; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Glioblastoma; Harmine; Humans; Monoamine Oxidase Inhibitors; Morpholines; Neoplastic Stem Cells; Nerve Tissue Proteins; Oncogene Protein v-akt; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Time Factors