Methyl-p-hydroxyphenyllactate (
MeHPLA) is a
bioflavonoid and/or
tyrosine metabolite which may regulate cellular growth and proliferation through interactions with nuclear type II sites. Our current studies suggest that type II sites may function as
MeHPLA receptors which are localized on the nuclear matrix, and occupancy of this binding site by
MeHPLA directly correlates with the inhibition of normal and malignant cell proliferation. This
ligand is inactivated by
MeHPLA esterase in mammary
tumors, resulting in a deficiency in
MeHPLA, high quantities of unoccupied type II sites, and uncontrolled cellular proliferation. For these reasons we synthesized 2,6-bis((3,4-dihydroxyphenyl)methylene)-cyclohexanone (
BDHPC) and 2,6-bis((3-methoxy-4-hydroxyphenyl)-methylene)cyclohexanone (
BMHPC) for assessment as nuclear type II site and cell growth antagonists. These two
esterase stable
cyclohexanone derivatives, which bind to nuclear type II sites with high affinity (Kd 1-7 nM), mimic
MeHPLA as cell growth-regulating agents. Dose-dependent occupancy of type II sites in MCF-7 human cells by
BDHPC and
BMHPC directly correlated with the inhibition of cell proliferation, and administration of
BDHPC by
silastic implant inhibited mouse mammary
tumor growth in vivo. These findings demonstrate that
esterase-stable type II antagonists such as
BDHPC and
BMHPC inhibit
mammary cancer cell proliferation in vitro and in vivo and support earlier studies demonstrating that
MeHPLA and functionally related compounds may regulate malignant cell proliferation at the level of this binding site.