Hexahydrocolupulone and its antitumor cell proliferation activity in vitro.
The purpose of this study was to evaluate the ability of hexahydrocolupulone (HHC) to inhibit the growth of tumor cells in vitro and to investigate the potential mechanism(s) involved. HHC was demonstrated to have a wide spectrum of activity against a number of established human tumor cell lines, including some exhibiting drug resistance. Culturing human breast adenocarcinoma (MCF-7) cells in the presence of HHC for 18 hr resulted in a significant decrease in the incorporation of [3H]uridine and [3H]leucine into RNA and protein, respectively. MCF-7 cells cultured in the presence of 1.5 microM HHC for 48 hr demonstrated an increase in the amount of cells detected in G0/G1 and a decrease in the amount of cells detected in S phase. In contrast, treatment with 25 microM HHC decreased the amount of cells detected in G0/G1 and increased the amount of cells detected in S phase. HHC did not cause single-stranded or double-stranded DNA breaks, interfere with topoisomerase function, or generate free radicals. Mice injected intraperitoneally for 5 consecutive days with HHC to a final in vivo blood concentration of 200 microM survived and showed no obvious signs of toxicity. Mass spectroscopy analysis, crystal generation, and structure elucidation confirmed HHC purity. Consequently, all activity observed can be attributed to HHC, a metabolite, and/or a combination thereof. These data suggest that HHC inhibits tumor cell proliferation in vitro via a mechanism(s) that may involve effects on macromolecular synthesis, precursor metabolism/transport, and/or the cell cycle or cell cycle-dependent pathway(s).
Stephan
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Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455, USA.
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Nutter
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D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D018360:Crystallography, X-Ray; D003512:Cyclohexanones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D015394:Molecular Structure; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000972:Antineoplastic Agents, Phytogenic; D003512:Cyclohexanones; D046911:Macromolecular Substances; C111226:hexahydrocolupulone; C075356:colupulone