esculetin and Glioma

The coumarins 5-methoxy-6,7-methylenedioxycoumarin 1 5-(3-methyl-2-butenyloxy)-6,7-methylenedioxycoumarin 2 and 5-(2,3-dihydroxy-3-methylbutyloxy)-6,7-methylenedioxycoumarin 3 isolated from Pterocaulon species showed significant cytotoxicity against two glioma cells lines. Compound 1 presented IC(50) values of 34.6 μM and 31.6 μM against human (U138-MG) and rat (C6) glioma cells, respectively, and this compound was at least two times more potent than compounds 2 and 3. This result could be explained by the planar conformation adopted by 1 through a non-classical hydrogen bond between a hydrogen of the methoxy and the oxygen of the methylenedioxy groups. Another important finding was that the cytotoxic effect induced by 1 in glioma cells was not observed in organotypic cultures, indicating a selective cytotoxicity for tumor cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Asteraceae; Benzodioxoles; Cell Line, Tumor; Cell Survival; Central Nervous System Neoplasms; Coumarins; Cytotoxins; Glioma; Hippocampus; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Male; Organ Specificity; Rats; Rats, Wistar; Structure-Activity Relationship; Tissue Culture Techniques

When cultured malignant cells derived from rat gliomas (C6 and 9L) and human gliomas (A-172 and T98G) were treated for 4 hours with 1 to 80 microns nordihydroguaiaretic acid (NDGA) or 5,8,11,14-eicosatetraynoic acid (ETYA), a dose-dependent inhibition of deoxyribonucleic acid (DNA) synthesis occurred. In a series of three experiments for each cell line, 40 microM NDGA suppressed 3H-thymidine incorporation in the rat and human glioma lines to an average of less than 3.1% and 5.6% of control uptake (counts per minute), respectively. Incubation with a higher concentration of ETYA (80 microM) resulted in inhibition of rat and human DNA synthesis to less than 53% and 62% of control levels, respectively. This inhibition was not associated with any loss of cell viability, as judged by trypan blue exclusion studies. Prolonged incubation (for 72 hours) of the rat and human glioma cells with NDGA markedly decreased cell proliferation with no loss of cell viability. The inhibition of human glioma cell division by NDGA was rapidly reversible after incubation for 24 hours and at least partially reversible after incubation for 96 hours. It is concluded that the inhibitors of eicosanoid biosynthesis, NDGA and (to a lesser extent) ETYA, reduce in vitro cell proliferation in two glioma lines from both the rat and human. Since neither indomethacin nor acetylsalicylic acid altered DNA synthesis in these cell lines, this implicates the lipoxygenase products of arachidonic acid metabolism as important positive modulators in glioma cell division. These findings warrant further study in an in vivo system.

Topics: 5,8,11,14-Eicosatetraynoic Acid; Animals; Aspirin; Catechols; Cell Division; Cell Line; Cell Survival; DNA Replication; Glioma; Humans; Indomethacin; Kinetics; Lipoxygenase Inhibitors; Masoprocol; Pyrazoles; Rats; Tumor Cells, Cultured; Umbelliferones