The cell death response to gamma-radiation in MCF-7 cells is enhanced by a neuroleptic drug, pimozide.
Neuroleptic drugs that bind sigma sites were tested for their ability to inhibit growth and radiosensitize MCF-7 human breast cancer cells. Inhibition of growth by approximately 50% occurred in cells exposed to pimozide (0.6 microM), haloperidol (10 microM), and the sigma ligand DTG (1,3-di(2-tolyl)guanidine, 20 microM), but no growth inhibition occurred in cells exposed to clozapine, a neuroleptic drug lacking sigma binding activity, or dextromethorphan, a selective sigma 1 binding ligand. Pimozide (2.5 microM), but not haloperidol (3.6 microM), enhanced the sensitivity of MCF-7 cells to gamma radiation in clonogenic survival assays. Pimozide significantly decreased MCF-7 clonogenic survival following a 5 or 8 Gy dose of gamma radiation, and the dose of radiation required for 1% survival (survival enhancement ratio, SER) was decreased by a factor of 2. Exposure of normal WI-38 human embryonic lung cells to pimozide did not increase their sensitivity to gamma radiation. Pimozide (2.5 microM) activated early apoptotic changes in MCF-7 cells that were detected by the uptake of Hoechst 33342 dye, and 10 microM pimozide activated a complete apoptotic pathway resulting in the death of > 90% of the cells within 24 hours. MCF-7 cells exposed to gamma radiation alone (8 Gy) showed giant cell formation, mitotic arrest, and a limited degree of apoptosis and necrosis. Within 50 hours of treatment with a combination of radiation and pimozide, cell numbers were sharply reduced compared with cultures exposed to either radiation or pimozide alone. We conclude that pimozide augmented the sensitivity of MCF-7 cells to radiation-induced cell killing through a mechanism not shared by haloperidol, but suggest that concentration of pimozide in MCF-7 cells as a result of an enrichment of sigma 2 sites might target the radiosensitization.
Strobl
J S
JS
Department of Pharmacology & Toxicology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown 26506, USA.
Melkoumian
Z
Z
Peterson
V A
VA
Hylton
H
H
D014150:Antipsychotic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005434:Flow Cytometry; D005720:Gamma Rays; D006146:Guanidines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D010868:Pimozide / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D014150:Antipsychotic Agents; D006146:Guanidines; D011838:Radiation-Sensitizing Agents; D010868:Pimozide; D006220:Haloperidol