Culture by the Neuroleptic Agents Pimozide and Thioridazine Inhibition of Human Breast Cancer Cell Proliferation in Tissue

Permanent cell culture lines derived from human breast cancer tissue are important experimental models in the study of human breast cancer cell proliferation. In the present work, pimozide, thioridazine, W-13, and W-12 were shown to inhibit MCF-7 human breast cancer cell growth. The 50% inhibition concentration values determined in two proliferation assays, | 'Hjthymidine incorporation and cell number, were in close agree ment for each compound tested. The order of potency for growth inhibi tion in the presence of 2% stripped calf serum was pimozide (K¡ 2 ß\t) > thioridazine (K, 5 UM)> W-13 (K, 15 UM)> W-12 (K, 39 /IM). Similar concentrations of these compounds blocked estradiol-induced growth of MCF-7 cells, but estrogen receptor (ER) interactions do not seem to be involved. Pimozide and thioridazine had no effect on the estradiol binding properties of the MCF-7 ER, nor did pimozide interfere with the induction of progesterone receptors by estradiol. Furthermore, pimozide also inhib ited incorporation of [3H]thymidine into MCF-7 cells stimulated by polypeptide hormones in serum-free medium. The A, for pimozide in serum-free medium alone, 0.46 JIM, was similar to that determined in the presence of insulin (0.42 /IM), insulin-like growth factor I (0.54 MM). and epidermal growth factor (0.43 /IM).The effects of pimozide on breast cancer cell growth were not limited to the MCF-7 cell line. Pimozide also blocked cell growth and [3H|thymidine incorporation into the ER-positive T47D and ZR75-1B human breast cancer cell lines and the ER-negative human breast cancer cell line, MDA-MB-231. Although numerous mech anisms of action of pimozide and thioridazine have been identified, both drugs are calmodulin antagonists at drug concentrations that inhibit breast cancer cell growth in vitro. Inhibition of MCF-7 cell growth by the selective calmodulin antagonists W-13 and W-12 is consistent with a role for calmodulin antagonism in the broad growth-inhibitory properties of pimozide. We conclude that pimozide and thioridazine may be useful in the control of estradioland polypeptide hormone-induced growth of ER-positive and ER-negative human breast tumors.