dihydropyridines and Melanoma

An inflammatory tumor microenvironment fosters tumor growth, angiogenesis and metastatic progression. Platelet-activating factor (PAF) is an inflammatory biolipid produced from membrane glycerophospholipids. Through the activity of its G-protein coupled receptor, PAF triggers a variety of pathological reactions including tumor neo-angiogenesis. Several groups have demonstrated that inhibiting PAF-PAF receptor pathway at the level of a ligand or receptor results in an effective inhibition of experimental tumor growth and metastasis. In particular, our group has recently demonstrated that PAF receptor antagonists can effectively inhibit the metastatic potential of human melanoma cells in nude mice. Furthermore, we showed that PAF stimulated the phosphorylation of CREB and ATF-1 in metastatic melanoma cells, which resulted in overexpression of MMP-2 and MT1-MMP. Our data indicate that PAF acts as a promoter of melanoma metastasis in vivo. Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that these cells are better equipped to respond to PAF within the tumor microenvironment when compared to their non-metastatic counterparts.

Topics: Animals; Cyclic AMP Response Element-Binding Protein; Dihydropyridines; Humans; Inflammation; Lung Neoplasms; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Melanoma; Neovascularization, Pathologic; Platelet Activating Factor; Platelet Membrane Glycoproteins; Proteins; Receptors, G-Protein-Coupled; Signal Transduction

Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine aalog (

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Dihydropyridines; Drug Design; Humans; Melanoma; Mitosis; Molecular Structure; Structure-Activity Relationship; Thiones; Tubulin Modulators; Tumor Cells, Cultured

Six new 1,4-dihydropyridine derivatives were evaluated in vitro for antimicrobial and cytotoxic effects and in vivo for antineoplastic activity. These compounds inhibited the growth of most of Gram-positive and Gram-negative bacteria at concentrations of 50 and 100 micrograms/ml. Concentrations effective against fungi were somewhat lower (25-50 micrograms/ml). The growth of mycobacteria was inhibited at concentrations of 3.1-25 micrograms/ml. Compound IV inhibited the growth of pathogenic mycobacteria including M. tuberculosis resistant to SM and INH at 3.1 or 6.2 micrograms/ml. In cytotoxicity assays, compound II, IV and V appeared the most active. However, none of the 1,4-dihydropyridine derivatives affected the survival time of mice with P388 and L1210 leukemias or melanoma B16. The growth of subcutaneous tumors of sarcoma 180 was inhibited by compounds I, III, IV and V. The effect was dose related.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Bacteria; Dihydropyridines; Drug Evaluation, Preclinical; Fungi; Leukemia L1210; Leukemia P388; Melanoma; Mice; Pyridines; Species Specificity; Structure-Activity Relationship