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.