benzofurans and Lymphoma--T-Cell

A new series of benzofuran-2-yl(4,5-diydro-3,5-substituted diphenylpyrazol-1-yl) methanone derivatives 8a-x by the reaction of the benzofuran-2-carbohydrazides 7 with various chalcone derivatives 3a-x using microwave irradiation has been described. The effect of synthesized compounds 8a-v was studied against human cancer cell lines for their antiproliferative activity and reversal of multidrug resistance on human MDR1-gene transfected mouse lymphoma cells. Among the 24 compounds, the 8c and 8h showed good antiproliferative activity 8b, 8f and 8k were exhibited good MDR reversal activity. The main significance of the process is easy workup process, short reaction time and high yield of the new compounds for biological interest. However, the studies on genetically modified multidrug resistant cancer cells are costly and time consuming.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzofurans; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Lymphoma, T-Cell; Methane; Mice; Molecular Structure; Quantitative Structure-Activity Relationship; Stereoisomerism; Structure-Activity Relationship; Transfection

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a common environmental pollutant causing public concern. Its toxic effects include disruption of the immune, endocrine, and reproductive systems, impairment of fetal development, carcinogenicity, and lethality in rodents. Here, we report that TCDD induces apoptosis in two cultured human leukemic lymphoblastic T cell lines. This cell death was found not to be dependent on an aryl hydrocarbon receptor and to be inhibited by the inhibitor of tyrosine kinases and caspases. Apoptosis-linked c-Jun N-terminal kinase is rapidly activated in these cells by the treatment with TCDD. A dominant-negative mutant of c-Jun N-terminal kinase prevented cell death in the treatment with TCDD. Furthermore, TCDD decreases the Bcl-2 protein level in these cell lines. These findings will help in the understanding of the molecular mechanism underlying TCDD-mediated immunotoxicity.

Topics: Apoptosis; Aspartic Acid; Benzofurans; beta-Naphthoflavone; Calcium-Calmodulin-Dependent Protein Kinases; Cycloheximide; DNA Fragmentation; Environmental Pollutants; Enzyme Activation; Gene Expression Regulation, Neoplastic; Genistein; Humans; JNK Mitogen-Activated Protein Kinases; Lymphoma, T-Cell; Microscopy, Fluorescence; Mitogen-Activated Protein Kinases; Mutation; Polychlorinated Dibenzodioxins; Proto-Oncogene Proteins c-bcl-2; Receptors, Aryl Hydrocarbon; RNA, Messenger; Tumor Cells, Cultured

The MDRI protein is an energy-dependent transport protein responsible for the multi-drug resistance seen in many tumors. A variety of drugs have been shown to inhibit the function of this pump, including compounds known to block various ion channels. The mouse lymphoma cell line L5178Y has been transduced with the human mdrI gene. Using this cell line, we have tested a number of compounds to determine whether there is a correlation between the ability to block a specific type of ion channel, or shift membrane potential, and the ability to act as an MDR-reversing agent using the fluorescent substrates Rhodamine 123 and daunorubicin as test compounds. Our results show no apparent correlation between the ability to block a specific ion channel and reversal of MDR transport ability. We have found active MDR inhibitors in compounds that affect K+, Na+, Ca++, H+, but not Cl- channels. Our data suggest that Cl- channel activity may be distinct from MDR activity. Several immunosuppressive compounds and analogs were also tested and found to be active reversing agents. Measurements suggest a significant difference in resting membrane potential between the L5178YvMDR line and the L5178Y parental cell line used in these experiments. No correlation was found between the ability of drugs to alter membrane potential and to inhibit MDR transport activity. Our results suggest that MDR transport function may be independent of the physiological movement of ions and show that a wide variety of compounds can inhibit MDR transport.

Topics: Amino Acid Sequence; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzofurans; Biological Transport, Active; Carrier Proteins; Cell Membrane; Daunorubicin; Drug Resistance; Ethers, Cyclic; Flow Cytometry; Fluorescent Dyes; Hydrogen-Ion Concentration; Immunosuppressive Agents; Intracellular Fluid; Ion Channels; Leukemia L5178; Lymphoma, T-Cell; Membrane Glycoproteins; Membrane Potentials; Mice; Molecular Sequence Data; Potassium; Potassium Channels; Rhodamine 123; Rhodamines; Tumor Cells, Cultured