The present study evaluated the effect of the
angiotensin converting enzyme (
ACE) inhibitor captopril on
estrogen (ER) and
progesterone (PR) receptor concentration and on proliferation in two lines of human
mammary ductal carcinoma cells in culture: T-47D (ER+/PR+) and Hs578T (ER-/PR-). The incorporation of [3H]
thymidine, validated by cell count, served as an index of proliferation. Compared to control cells, T-47D cells incubated for 48 hrs in 1, 2, or 5 mM
captopril (but not in 0.5 mM) exhibited a reduction in ER from 130 +/- 6 to 32 +/- 32 fmol/mg cytosolic
protein, and an increase in PR from 1780 +/- 120 to 2740 +/- 400 fmol/ mg
protein (p < 0.05). Western analysis confirmed these
drug-induced changes in the concentration of immunoreactive receptor
proteins.
Captopril also induced the appearance of low but detectable PR in the Hs578T cells at concentrations as low as 50 microM.
Captopril inhibited the incorporation of [3H]
thymidine by both cell types during a 48 hr incubation, although Hs578T cells were 2-3 times more resistant than were T-47D cells. This
cytostatic effect of
captopril was not due to cytotoxicity as indicated by 51Cr release, and was not accompanied by significant changes in cell cycle distribution as determined by flow cytometry. The incorporation of [3H]
uridine (
RNA synthesis) and [14C]
alanine (
protein synthesis) also were inhibited by
captopril, suggesting a general antimetabolic effect of the
drug in the
ductal carcinoma cells. These are novel actions of a common
antihypertensive agent. In contrast, the nonthiol
ACE inhibitor lisinopril, and
penicillamine, a
thiol compound with virtually no ACE inhibitory activity, had no effect on any of these endpoints.