phenanthrenes and Lymphoma--Non-Hodgkin

The anti-tumor properties of novel derivatives prepared from Aconitum C(20)-diterpenoid alkaloid, which show the least toxicity among the Aconitum alkaloids, were investigated in the Non-Hodgkin's lymphoma cell line Raji cells. Two novel Aconitum C(20)-diterpenoid alkaloid derivatives, 11-m-Trifluorometylbenzoyl (Mb)-pseudokobuisne and 11-Anisoyl (As)-pseudokobusine, showed significant suppressive effects and their 50% inhibitory concentrations were 2.2 μg/ml and 2.4 μg/ml against Raji cells, respectively. Both compounds have the same structure except for a functional group in the C-11 position. One of the active compounds, 11-Mb-pseudokobusine, clearly inhibited the phosphorylation of extracellular signal-regulated kinase, induced enhanced phosphoinositide 3 kinase phosphorylation and led to the subsequent accumulation of G1 and/or sub G1 phase in Raji cells. In addition, no significant suppressive effects on the growth of human CD34(+) hematopoietic stem/progenitor cells (HSPC) were observed by 11-Mb-pseudokobusine which showed a strong suppressive activity on the growth of Raji cells, whereas 11-As-pseudokobusine also a showed significantly suppressive effect on the growth of HSPC. Therefore, the atisine type structure characteristic of C(20)-diterpenoid alkaloids plays a very important role in the pharmacological properties. In particular, the C-11 residues are an important component for the anti-tumor properties and for the lower toxicity to hematopoiesis.

Topics: Aconitum; Alkaloids; Blotting, Western; Bridged-Ring Compounds; Butadienes; Carbon; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 2; Diterpenes; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; G1 Phase; Hematopoietic Stem Cells; Humans; Lymphoma, Non-Hodgkin; Nitriles; Phenanthrenes; Phytotherapy; Structure-Activity Relationship

To investigate the antiproliferative effect of triptolide on B-NHL cell line Raji cells, to study its effect on lymph node metastasis in patients with non-Hodgkin's lymphoma (NHL) in vitro, and to explore the underlying mechanism regulating SDF-1/CXCR4 axis.. The effects of triptolide on the growth of Raji cells were studied by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) assay. The effects of triptolide on SDF-1 mRNA expression in lymph node stromal cells from patients with NHL were determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The effects of triptolide on CXCR4 expression on lymphoma cells freshly isolated from the lymph nodes of these patients were studied by flow cytometric analysis. Chemotaxis assays were performed to observe the effects of triptolide on migration of primary lymphoma cells towards recombinant human SDF-1 alpha (rhSDF-1 alpha) or cultured lymph node stromal cells in vitro.. Triptolide inhibited the proliferation of B-NHL cell line Raji cells in a dose- and time-dependent manner with a 24-h IC50 value of 43.06 nmol/L and a 36-h IC50 value of 25.08 nmol/L. The expression of SDF-1alpha mRNA in lymph node stromal cells obtained from patients with NHL was decreased after treatment by triptolide at concentrations of 25 and 50 nmol/L for 24 h. Flow cytometry analysis showed that the CXCR4 expression on primary lymphoma cells were downregulated gradually in a dose-dependent manner following triptolide treatment. Chemotaxis assays revealed that the migration of freshly isolated lymphoma cells towards either rhSDF-1 or cultured lymph node stromal cells was markedly inhibited by the addition of triptolide in vitro, and the inhibition was dose-dependent.. Triptolide can inhibit the proliferation of B-NHL cell line Raji cells. Moreover, triptolide is able to inhibit the migration of lymphoma cells via lymph nodes in vitro. The potential antitumor mechanisms of triptolide are related to the antiproliferative effect and the blockage of SDF-1/CXCR4 axis.

Topics: Antineoplastic Agents, Alkylating; Cell Line, Tumor; Cell Proliferation; Chemokine CXCL12; Chemotaxis; Diterpenes; Dose-Response Relationship, Drug; Epoxy Compounds; Humans; Lymph Nodes; Lymphatic Metastasis; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Phenanthrenes; Plants, Medicinal; Receptors, CXCR4; RNA, Messenger; Stromal Cells; Tripterygium

Topics: Age Factors; Animals; Antigens, Bacterial; Antilymphocyte Serum; Benz(a)Anthracenes; Benzopyrenes; Bordetella pertussis; Carcinogens; Cell-Free System; Croton Oil; Endotoxins; Freund's Adjuvant; Graft Rejection; Hemolytic Plaque Technique; Hydrocarbons; Immune Sera; Immunosuppressive Agents; Leukemia, Experimental; Lymphoma, Non-Hodgkin; Methods; Methylcholanthrene; Mice; Mice, Inbred Strains; Neoplasm Regression, Spontaneous; Neoplasm Transplantation; Neoplasms, Experimental; Phenanthrenes; Salmonella typhi; Spleen; Time Factors; Transplantation Immunology; Transplantation, Homologous