Estrogen receptor (ER)-negative human
breast cancer cell lines (MDA-MB-231 and MDA-MB-435) and ER-positive derivatives of the MCF-7 cell line selected for growth in the presence of
antiestrogens (LY2 and RR) were used as in vitro models of
tamoxifen-resistant human
breast cancer in this study. The sensitivity of the
tamoxifen-sensitive (MCF-7) and
tamoxifen-resistant human
breast cancer cell growth to two noncytotoxic
neuroleptic drugs,
pimozide and
thioridazine, and the anticalmodulin agent,
W-13, were compared. Inhibition of cell growth was measured as a decrease in cell number following a 72-h incubation with
drug. Growth of the ER-negative cell lines MDA-MB-231 and MDA-MB-435 was inhibited by all three drugs. The average Ki values in these two lines were 6.3 and 3.8 microM for
pimozide and 4.1 and 15 microM for
thioridazine, respectively. Both ER-negative cell lines were more sensitive than MCF-7 cells to growth inhibition by
W-13. MCF-7 cells selected for
antiestrogen resistance were sensitive to growth inhibition by
W-13 and
thioridazine (LY2, average Ki = 10.4 microM; RR, average Ki = 5.2 microM). LY2 and RR cells were resistant to
pimozide except when treated with
estradiol (Ki = 4.6 and 7.9 microM, respectively).
Pimozide,
thioridazine and
W-13 all exerted different effects on the distribution of human
breast cancer cells within the cell cycle, suggesting that each
drug may utilize a distinct pathway for inhibition of cell growth. We conclude that all three drugs are potential noncytotoxic alternatives to
tamoxifen for the treatment of
tamoxifen-resistant human
breast cancer.