Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel.
Int J Oncol. 2010 Oct;37(4):1043-51. doi: 10.3892/ijo_00000756.
Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor. Despite some recent improvement in the treatment of this malignancy, life expectancy of GBM patients remains extremely low. Therefore, continuous efforts to develop new treatment modalities are mandatory. A novel approach to cancer treatment is the use of targeted treatments, alone and in combination with other therapies. In this study, we evaluated the effects of novel combinations of conventional anti-cancer treatments (temozolomide or irradiation) with the targeted drug, imatinib, or with psychotropic drugs, belonging to the selective serotonin reuptake inhibitors (SSRIs) and phenothiazine subclasses, as well as combination of imatinib with psychotropic agents, on a human U87 glioblastoma cell line. The combination of temozolomide with imatinib or the psychotropic drugs resulted in an additive anti-proliferative effect, while the combination of irradiation and the psychotropic agents resulted in a less than additive effect on cell proliferation. A marked synergistic anti-proliferative effect of imatinib combined with the psychotropic drugs fluoxetine, sertraline or perphenazine was demonstrated. None of the single or combined treatments led to a reduction in the expression of phosphorylated MAP kinase. However, a marked synergistic reduction in the expression of the key regulatory molecule, pAKT, was detected, following the combined treatment of the cells with the imatinib/psychotropics combination. This down-regulation of pAKT may mediate the synergistic anti-proliferative interaction of imatinib with the psychotropic agents. Although the concentrations of the psychotropic agents used in this and other in vitro studies were beyond the clinically relevant blood levels in humans, recent studies have demonstrated anti-proliferative effects in vivo, using sertraline in a human colon cancer model. Thus, it seems that further in vivo studies combining imatinib with psychotropic agents, especially fluoxetine and sertraline, are warranted.
多形性胶质母细胞瘤（GBM）是一种高度侵袭性的恶性脑肿瘤。尽管这种恶性肿瘤的治疗最近有所改善，但 GBM 患者的预期寿命仍然极低。因此，必须不断努力开发新的治疗方法。癌症治疗的一种新方法是使用靶向治疗，单独使用或与其他疗法联合使用。在这项研究中，我们评估了新型组合常规抗癌治疗（替莫唑胺或放疗）与靶向药物伊马替尼，或与精神药物（属于选择性 5-羟色胺再摄取抑制剂（SSRIs）和吩噻嗪亚类），以及伊马替尼与精神药物联合使用对人 U87 胶质母细胞瘤细胞系的影响。替莫唑胺与伊马替尼或精神药物联合使用具有相加的抗增殖作用，而放疗与精神药物联合使用对细胞增殖的作用则小于相加作用。伊马替尼与精神药物氟西汀、舍曲林或奋乃静联合使用具有明显的协同抗增殖作用。单独或联合治疗均未导致磷酸化 MAP 激酶表达减少。然而，在用伊马替尼/精神药物联合处理细胞后，检测到关键调节分子 pAKT 的表达明显协同降低。pAKT 的这种下调可能介导了伊马替尼与精神药物的协同抗增殖相互作用。尽管在这项研究和其他体外研究中使用的精神药物的浓度超过了人类临床相关的血液水平，但最近的研究表明，在使用舍曲林的人类结肠癌模型中，具有抗增殖作用。因此，似乎有必要进一步进行体内研究，将伊马替尼与精神药物联合使用，尤其是氟西汀和舍曲林。
