Hait W N, Lee G L
Biochem Pharmacol. 1985 Nov 15;34(22):3973-8. doi: 10.1016/0006-2952(85)90374-0.
We have characterized the antiproliferative effects of the phenothiazines, a group of antipsychotic drugs possessing a wide range of pharmacological actions. The phenothiazines inhibited both the proliferation and clonogenicity of L1210 leukemic lymphocytes. This effect was dependent on both time of exposure and concentration of drug. Clonogenicity of cells in the logarithmic phase of growth was inhibited by greater than 99% at a concentration of drug that had no effect on cells in the plateau phase of growth. Human and murine cell lines, grown either in suspension or in monolayers, were equally susceptible. Calmodulin (CaM), purified from L1210 cells by preparative polyacrylamide gel electrophoresis, had sensitivity to inhibition by phenothiazines similar to that reported for CaM prepared from brain. The order of potency was trifluoperazine greater than or equal to fluphenazine greater than chlorpromazine greater than chlorpromazine-sulfoxide. As a class, these drugs were less potent antagonists of CaM than was the bee venom polypeptide, melittin. The antiproliferative effects of phenothiazines were similar to the anticalmodulin effects. Thus, the same order of potencies was seen for both effects; the shapes of the dose-response curves were similarly steep and the effects of excess calcium on the inhibition of both were identical. These studies add pharmacological support for CaM being a potential intracellular target for the antiproliferative effect of the phenothiazines.
我们已经对吩噻嗪类药物的抗增殖作用进行了表征，这是一类具有广泛药理作用的抗精神病药物。吩噻嗪类药物抑制了L1210白血病淋巴细胞的增殖和克隆形成能力。这种作用取决于药物的暴露时间和浓度。在对数生长期，药物浓度对处于生长平台期的细胞无影响，但却能抑制细胞克隆形成能力超过99%。无论是悬浮培养还是单层培养的人源和鼠源细胞系，对药物的敏感性相同。通过制备性聚丙烯酰胺凝胶电泳从L1210细胞中纯化得到的钙调蛋白（CaM），对吩噻嗪类药物抑制作用的敏感性与从脑中制备的CaM相似。其效力顺序为三氟拉嗪≥氟奋乃静＞氯丙嗪＞氯丙嗪亚砜。作为一类药物，它们作为CaM拮抗剂的效力低于蜂毒多肽蜂毒素。吩噻嗪类药物的抗增殖作用与抗钙调蛋白作用相似。因此，两种作用的效力顺序相同；剂量反应曲线的形状同样陡峭，过量钙对两者抑制作用的影响相同。这些研究为CaM作为吩噻嗪类药物抗增殖作用的潜在细胞内靶点提供了药理学支持。
