harmine and Lung-Neoplasms

Reversion-inducing cysteine-rich protein with kazal motifs (RECK) is a novel tumor suppressor gene that is critical for regulating tumor cell invasion and metastasis. The expression of RECK is dramatically down-regulated in human cancers. Harmine, a tricyclic compound from Peganum harmala, has been shown to have potential anti-cancer activity.. Cell proliferation assay (CCK-8 cell viability assay), cell cycle analysis (detection by flow cytometry), apoptosis staining assay (TUNEL staining), cell migration assay and invasion assay (transwell assay) were carried out to investigate the Harmine's efficacy on non-small cell lung cancer (NSCLC) cells in vitro. A549-luciferase cell orthotropic transplantation xenograft mouse model was used to determine the effect of Harmine treatment on NSCLC in vivo. Western blotting analysis of cell growth and metastasis related signal pathways was conducted to investigate the molecular mechanism of Harmine's inhibitory effect on NSCLC.. Harmine treatment effectively inhibited cell proliferation and induced the G1/S cell cycle arrest of NSCLC cells. Further study proved that Harmine treatment led to apoptosis induction. Furthermore, treatment with NSCLC cells with Hamine resulted in decreased cell migration and cell invasion in vitro. More importantly, Harmine treatment significantly suppressed the NSCLC tumor growth and metastasis in mouse xenograft model in vivo. Mechanistically, in Harmine-treated NSCLC cells, RECK expression and its downstream signaling cascade were dramatically activated. As a consequence, the expression level of MMP-9 and E-cadherin were significantly decreased.. These findings identify Harmine as a promising activator of RECK signaling for metastatic NSCLC treatment.

Topics: A549 Cells; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cadherins; Carcinoma, Non-Small-Cell Lung; Cell Line; Cell Movement; Cell Proliferation; G1 Phase Cell Cycle Checkpoints; GPI-Linked Proteins; Harmine; Humans; Lung Neoplasms; Matrix Metalloproteinase 9; Mice; Mice, Nude; Peganum; S Phase Cell Cycle Checkpoints; Signal Transduction; Transplantation, Heterologous

Four different-anion Ag(I) compounds with the ligand norharmane (9H-Pyrido[3,4-b]indole; Hnor) and having the general formula [Ag(Hnor)2](anion) (anion=ClO4(-), NO3(-) and BF4(-)) [Ag(Hnor)2(MeCN)](PF6) are reported, and studied in detail regarding their coordination mode and in vitro antiproliferative effects. X-ray structural analysis revealed that the complex with the PF6(-) anion has a MeCN solvent molecule weakly coordinated to Ag(I), making the metal coordination T-shaped, while the other compounds present the classical linear Ag(I) coordination. The compounds showed certain cell growth inhibitory effects in two different cancer cell lines, with the perchlorate containing complex being the most toxic and in fact comparable to cisplatin. Notably, the compounds are stable in visible light; and the luminescence in the solid state was found to be extremely weak, whereas in MeOH solution all compounds show a moderate to weak emission band at 375 nm, when excited at 290 nm.

Topics: Carbolines; Cell Line, Tumor; Cell Proliferation; Harmine; Humans; Light; Lung Neoplasms; Proton Magnetic Resonance Spectroscopy; Silver; X-Ray Diffraction

Activation of p53 effectively inhibits tumor angiogenesis that is necessary for tumor growth and metastasis. Reactivation of the p53 by small molecules has emerged as a promising new strategy for cancer therapy. Several classes of small-molecules that activate the p53 pathway have been discovered using various approaches. Here, we identified harmine (β-carboline alkaloid) as a novel activator of p53 signaling involved in inhibition of angiogenesis and tumor growth. Harmine induced p53 phosphorylation and disrupted the p53-MDM2 interaction. Harmine also prevented p53 degradation in the presence of cycloheximide and activated nuclear accumulation of p53 followed by increasing its transcriptional activity in endothelial cells. Moreover, harmine not only induced endothelial cell cycle arrest and apoptosis, but also suppressed endothelial cell migration and tube formation as well as induction of neovascularity in a mouse corneal micropocket assay. Finally, harmine inhibited tumor growth by reducing tumor angiogenesis, as demonstrated by a xenograft tumor model. Our results suggested a novel mechanism and bioactivity of harmine, which inhibited tumor growth by activating the p53 signaling pathway and blocking angiogenesis in endothelial cells.

Topics: Angiogenesis Inhibitors; Animals; Aorta; Apoptosis; Blotting, Western; Cell Cycle; Cell Movement; Cell Proliferation; Cells, Cultured; Comet Assay; Fluorescent Antibody Technique; Hallucinogens; Harmine; Human Umbilical Vein Endothelial Cells; Humans; Immunoprecipitation; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mice, Nude; Neovascularization, Pathologic; Phosphorylation; Proto-Oncogene Proteins c-mdm2; Rats; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Harmine is a beta-carboline alkaloid from the plant Peganum harmala. We evaluated the anti-metastatic activity of harmine using in vivo mouse lung metastasis and in vitro models. Lung metastasis was induced using B16F-10 melanoma cells in C57BL/6 mice by three different modalities of administration: simultaneous, prophylactic, and after tumor development. Harmine significantly inhibited tumor nodule formation in the lung tissue and decreased various biochemical parameters associated with lung metastasis. Higher expression levels of pro-metastatic genes such as matrix metalloproteinase-9 (MMP-9), extracellular signal[en]regulated kinase (ERK), and vascular endothelial factors (VEGFs), all of which play important roles in cancer cell migration and invasion, were observed in the metastatic group compared with normal, but were all down-regulated by treatment with harmine. Harmine was also able to inhibit tumor cell proliferation, invasion, and migration in vitro. In conclusion, harmine exerts anti-metastatic activity and this effect could be linked to the metastasis-related signaling pathway that includes ERK, VEGF, and MMPs.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Migration Assays; Cell Movement; Cell Proliferation; Cell Survival; Cytokines; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Harmine; Injections, Intraperitoneal; Lung; Lung Neoplasms; Male; Matrix Metalloproteinase 9; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Signal Transduction; Survival Analysis; Vascular Endothelial Growth Factor A

The beta-carboline alkaloids are naturally existing plant substances. It is known that these alkaloids have a wide spectrum of neuropharmacological, psychopharmacological, and antitumor effects. Therefore, they have been traditionally used in oriental medicine for the treatment of various diseases including cancers and malaria. In this study, harmol and harmalol, which are beta-carboline alkaloids, were examined for their antitumor effect on human lung carcinoma cell lines, and structure-activity relationship was also investigated. H596, H226, and A549 cells were treated with harmol and harmalol, respectively. Apoptosis was induced by harmol only in H596 cells. In contrast, harmalol had negligible cytotoxicity in three cell lines. Harmol induced caspase-3, caspase-8, and caspase-9 activities and caspase-3 activities accompanied by cleavage of poly-(ADP-ribose)-polymerase. Furthermore, harmol treatment decreased the native Bid protein, and induced the release of cytochrome c from mitochondria to cytosol. The apoptosis induced by harmol was completely inhibited by caspase-8 inhibitor and partially inhibited by caspase-9 inhibitor. The antagonistic antibody ZB4 blocked Fas ligand-induced apoptosis, but had no effect on harmol-induced apoptosis. Harmol had no significant effect on the expression of Fas. In conclusion, our results showed that the harmol could cause apoptosis-inducing effects in human lung H596 cells through caspase-8-dependent pathway but independent of Fas/Fas ligand interaction.

Topics: Adenocarcinoma; Apoptosis; Carcinoma, Adenosquamous; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Caspase 3; Caspase 8; Caspase 9; Cell Line, Tumor; Enzyme Activation; Fas Ligand Protein; fas Receptor; Harmaline; Harmine; Humans; Lung Neoplasms; Neoplasm Proteins