HEXAHYDROCOLUPULONE AND ITS ANTITUMOR CELL-PROLIFERATION ACTIVITY IN-VITRO

The purpose of this study was to evaluate the ability of hexahydrocolu pulone (HHC) to inhibit the growth of tumor cells in vitro and to inve stigate the potential mechanism(s) involved. HHC was demonstrated to h ave 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 kr resulted in a significant decrease in the incorporation of [H-3] uridine and [H-3]leucine into RNA and protein, respectively. MCF-7 cel ls cultured in the presence of 1.5 mu M HHC for 48 hr demonstrated an increase in the amount of cells detected in G(0)/G(1) and a decrease i n the amount of cells detected in S phase. In contrast, treatment with 25 mu M HHC decreased the amount of cells detected in G(0)/G(1) and i ncreased the amount oi cells detected in S phase. HHC did not cause si ngle-stranded or double-stranded DNA breaks, interfere with topoisomer ase function, or generate free radicals. Mice injected intraperitoneal ly for 5 consecutive days with HHC to a final in vivo blood concentrat ion of 200 mu M 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 attri buted to HHC, a metabolite, and/or a combination thereof. These data s uggest that HHC inhibits tumor cell proliferation in vitro via a mecha nism(s) that may involve effects on macromolecular synthesis, precurso r metabolism/transport, and/or the cell cycle or cell cycle-dependent pathway(s). (C) 1998 Elsevier Science Inc.