Ruiter G A, Zerp S F, Bartelink H, van Blitterswijk W J, Verheij M
Department of Radiotherapy, Antoni van Leeuwenhoek Ziekenhuis/The Netherlands Cancer Institute, Amsterdam.
Cancer Res. 1999 May 15;59(10):2457-63.
Alkyl-lysophospholipids (ALPs) represent a new class of antitumor drugs that induce apoptotic cell death in a variety of tumor cell lines. Although their precise mechanism of action is unknown, ALPs primarily act on the cell membrane, where they inhibit signaling through the mitogen-activated protein kinase (MAPK) pathway. Because stimulation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway is essential for radiation-induced apoptosis in certain cell types, we tested the effect of ALPs in combination with ionizing radiation on MAPK/SAPK signaling and apoptosis induction. Here, we present data showing that three ALPs, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, hexadecylphosphocholine, and the novel compound octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate (D-21266) induce time- and dose-dependent apoptosis in the human leukemia cell lines U937 and Jurkat T but not in normal vascular endothelial cells. Moreover, in combination with radiation, ALPs strongly enhance the induction of apoptosis in both leukemic cell lines. All tested ALPs not only prevented MAPK activation, but, like radiation, stimulated the SAPK/JNK cascade within minutes. A dominant-negative mutant of c-Jun inhibited radiation- and ALP-induced apoptosis, indicating a requirement for the SAPK/JNK pathway. Our data support the view that ALPs and ionizing radiation cause an enhanced apoptotic effect by modulating the balance between the mitogenic, antiapoptotic MAPK, and the apoptotic SAPK/JNK pathways. This type of modulation of specific signal transduction pathways in tumor cells may lead to the development of new therapeutic strategies.
烷基溶血磷脂（ALPs）是一类新型抗肿瘤药物，可在多种肿瘤细胞系中诱导凋亡性细胞死亡。尽管其确切作用机制尚不清楚，但ALPs主要作用于细胞膜，在细胞膜上它们通过丝裂原活化蛋白激酶（MAPK）途径抑制信号传导。由于应激激活蛋白激酶/c-Jun氨基末端激酶（SAPK/JNK）途径的激活对于某些细胞类型中辐射诱导的凋亡至关重要，我们测试了ALPs与电离辐射联合对MAPK/SAPK信号传导和凋亡诱导的影响。在此，我们展示的数据表明，三种ALPs，1-O-十八烷基-2-O-甲基-rac-甘油-3-磷酸胆碱、十六烷基磷酸胆碱和新型化合物十八烷基-（1,1-二甲基-哌啶-4-基）-磷酸酯（D-21266）可在人白血病细胞系U937和Jurkat T中诱导时间和剂量依赖性凋亡，但在正常血管内皮细胞中则不然。此外，与辐射联合时，ALPs可强烈增强两种白血病细胞系中的凋亡诱导。所有测试的ALPs不仅可防止MAPK激活，而且与辐射一样，在数分钟内刺激SAPK/JNK级联反应。c-Jun的显性负性突变体可抑制辐射和ALP诱导的凋亡，表明需要SAPK/JNK途径。我们的数据支持这样的观点，即ALPs和电离辐射通过调节有丝分裂、抗凋亡的MAPK与凋亡的SAPK/JNK途径之间的平衡来增强凋亡效应。肿瘤细胞中这种特定信号转导途径的调节类型可能会导致新治疗策略的发展。
