harmine and Brain-Neoplasms

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

The β-carboline alkaloids are plant substances that exhibit a wide spectrum of neuropharmacological, psychopharma-cological and antitumor effects. In the present study, we found that harmol, a β-carboline alkaloid, induced autophagy and suppression of survivin expression, and subsequently induced apoptotic cell death in U251MG human glioma cells. Autophagy was induced within 12 h by treatment with harmol. When treated for over 36 h, however, apoptotic cell death was induced. Harmol treatment also reduced survivin protein expression. Small interfering RNA (siRNA)-mediated knockdown of survivin enhanced the harmol-induced apoptosis. Knockdown of survivin by siRNA also induced autophagy. Therefore, harmol-induced apoptosis is a result of the reduction in survivin protein expression. Treatment with 3-methyladenine (3-MA) in the presence of harmol did not affect the expression of survivin and diminished harmol-induced cell death. Treatment with chloroquine in the presence of harmol did not suppress the reduction of survivin expression and increased harmol-induced cell death. From these results, harmol-induced reduction of survivin expression was closely related to autophagy. It is assumed that when isolation membrane formation is inhibited by treatment with 3-MA, reduction of survivin protein expression and apoptotic cell death were not induced. However, when isolation membrane formation is started and an autophagosome is formed, survivin expression is suppressed and apoptosis is executed. Harmol treatment reduced phosphorylation of Akt, mammalian target of rapamycin (mTOR) and its downstream targets p70-ribosomal protein S6 kinase and 4E-binding protein 1, resulting in induction of autophagy. Conversely, activation of the Akt/mTOR pathway inhibited harmol-induced autophagy and cell death. These findings indicate that harmol-induced autophagy involves the Akt/mTOR pathway. Taken together, autophagy induced by harmol represented a pro-apoptotic mechanism, and harmol suppressed the expression of survivin and subsequently induced apoptosis.

Topics: Apoptosis; Autophagy; Brain Neoplasms; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Glioma; Harmine; Humans; Inhibitor of Apoptosis Proteins; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Signal Transduction; Survivin; TOR Serine-Threonine Kinases