Strobl J S, Melkoumian Z, Peterson V A, Hylton H
Department of Pharmacology & Toxicology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown 26506, USA.
Breast Cancer Res Treat. 1998 Sep;51(1):83-95. doi: 10.1023/a:1006046604062.
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.
对能与σ位点结合的抗精神病药物进行了测试，以检验其抑制MCF - 7人乳腺癌细胞生长及使其对辐射敏感的能力。在暴露于匹莫齐特（0.6微摩尔）、氟哌啶醇（10微摩尔）和σ配体DTG（1,3 - 二（2 - 甲苯基）胍，20微摩尔）的细胞中，细胞生长受到约50%的抑制，但暴露于缺乏σ结合活性的抗精神病药物氯氮平或选择性σ1结合配体右美沙芬的细胞中未出现生长抑制。在克隆存活试验中，匹莫齐特（2.5微摩尔）增强了MCF - 7细胞对γ辐射的敏感性，但氟哌啶醇（3.6微摩尔）未起到增强作用。在给予5或8 Gy剂量的γ辐射后，匹莫齐特显著降低了MCF - 7细胞的克隆存活率，且使1%存活所需的辐射剂量（存活增强率，SER）降低了一半。正常的WI - 38人胚肺细胞暴露于匹莫齐特后对γ辐射的敏感性并未增加。匹莫齐特（2.5微摩尔）激活了MCF - 7细胞中早期凋亡变化，这可通过Hoechst 33342染料摄取检测到，10微摩尔匹莫齐特激活了完整的凋亡途径，导致24小时内超过90%的细胞死亡。单独暴露于γ辐射（8 Gy）的MCF - 7细胞出现巨细胞形成、有丝分裂停滞以及有限程度的凋亡和坏死。与单独接受辐射或匹莫齐特处理的培养物相比，在辐射与匹莫齐特联合处理50小时内，细胞数量急剧减少。我们得出结论，匹莫齐特通过一种氟哌啶醇不具备的机制增强了MCF - 7细胞对辐射诱导的细胞杀伤的敏感性，但表明由于σ2位点富集导致的MCF - 7细胞中匹莫齐特浓度可能是放射增敏作用的靶点。
