harmine and Ovarian-Neoplasms

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and

Topics: Adenosine Triphosphate; Animals; Binding Sites; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase 9; Drug Design; Drug Evaluation, Preclinical; Dyrk Kinases; Female; Humans; Mice; Mice, Nude; Molecular Docking Simulation; Ovarian Neoplasms; Phosphorylation; Protein Isoforms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyrimidines; Structure-Activity Relationship

Ovarian cancer is the most lethal gynaecological cancer and the sixth most common cause of cancer related death among Western women. Recent studies show that harmine, a small-molecular β-carboline alkaloid present in medicinal plants, displayed obvious anticancer effects in several cancer cells. However, the effect of harmine on ovarian cancer is not well understood. In the present study, the effect of harmine on the cell proliferation and migration of ovarian cancer SKOV-3 cells and the underlying mechanism were investigated. Our results indicated that harmine significantly suppressed the proliferation of SKOV-3 cells in a dose-dependent manner. Interestingly, it also inhibited the epidermal growth factor (EGF)-induced proliferation of SKOV-3 cells. Moreover, the migration of SKOV-3 cells was markedly inhibited by harmine treatment. Further study showed that harmine inhibited not only the basal phosphorylation level of extra-cellular signal-regulated kinase 1/2 (ERK1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) but also EGF-induced ERK1/2 and CREB phosphorylation. Finally, harmine significantly suppressed the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) family MMP-2, and MMP-9. In conclusion, our data revealed that harmine inhibited the proliferation and migration of SKOV-3 cells, which might be mediated by ERK/CREB pathway. These findings elucidate that harmine may act as a potential therapeutic drug for ovarian cancer treatment.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclic AMP Response Element-Binding Protein; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; Harmine; Humans; MAP Kinase Signaling System; Ovarian Neoplasms; Phosphorylation

Epithelial ovarian cancer (EOC) generates multicellular aggregates called spheroids that detach from the primary tumor and disseminate through ascites. Spheroids possess a number of characteristics of tumor dormancy including withdrawal from the cell cycle and resistance to chemotherapeutics. This report systematically analyzes the effects of RNAi depletion of 21 genes that are known to contribute to negative regulation of the cell cycle in 10 ovarian cancer cell lines. Interestingly, spheroid cell viability was compromised by loss of some cyclin-dependent kinase inhibitors such as p57

Topics: Carboplatin; Carcinoma, Ovarian Epithelial; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dyrk Kinases; Harmine; Humans; Kv Channel-Interacting Proteins; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Repressor Proteins; Spheroids, Cellular; Trans-Activators; Tumor Cells, Cultured