Fischer Annette, Müller Dieter, Zimmermann-Kordmann Martin, Kleuser Burkhard, Mickeleit Michael, Laabs Stephan, Löwe Werner, Cantagrel Frédéric, Reutter Werner, Danker Kerstin
Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Institut für Biochemie und Molekularbiologie, Arnimallee 22, 14195 Berlin-Dahlem, Germany.
Chembiochem. 2006 Mar;7(3):441-9. doi: 10.1002/cbic.200500336.
The search for specific anticancer drugs that do not interfere with DNA synthesis or influence the cytoskeleton has led to the development of modified phospholipids with antiproliferative properties. These compounds cause remodeling of the structure and function of plasma membranes. Recently, we described novel compounds, the glycosidated phospholipids, that surprisingly inhibit cell proliferation. These compounds contain alpha-D-glucose in the sn-2 position of the glycerol backbone of phosphatidylcholine (PC) and platelet-activating factor (PAF), which gives rise to 2-glucophosphatidylcholine (Glc-PC) and 1-O-octadecyl-2-O-alpha-d-glucopyranosyl-sn-2-glycero-3-phosphatidylcholine (Glc-PAF), respectively. Glc-PC and Glc-PAF inhibit the growth of HaCaT cells at nontoxic concentrations. Here we report the introduction of myo-inositol, in place of alpha-D-glucose, in the sn-2 position of the glycerol backbone; this leads to two diastereomeric 1-O-octadecyl-2-O-(2-(myo-inositolyl)-ethyl)-sn-glycero-3-(R/S)-phosphatidylcholines (Ino-C2-PAF). The inositol-containing PAF enhances the antiproliferative capacity (IC(50)=1.8 microM) and reduces the cytotoxicity relative to Glc-PAF (LC(50)=15 microM). Through biological assays, we showed that, in HaCaT cells, Ino-C2-PAF causes upregulation of the keratinocyte-specific differentiation marker involucrin, increases the activity of the differentiation marker transglutaminase, and induces apoptosis at nontoxic concentrations. Ino-C2-PAF therefore seems to be a promising candidate for development as an antiproliferative drug for the treatment of hyperproliferative diseases of the skin.
寻找不干扰DNA合成或影响细胞骨架的特异性抗癌药物，已促使具有抗增殖特性的修饰磷脂得以开发。这些化合物会引起质膜结构和功能的重塑。最近，我们描述了一类新型化合物——糖基化磷脂，令人惊讶的是，它们能抑制细胞增殖。这些化合物在磷脂酰胆碱（PC）和血小板活化因子（PAF）甘油主链的sn-2位含有α-D-葡萄糖，分别生成2-葡萄糖磷脂酰胆碱（Glc-PC）和1-O-十八烷基-2-O-α-D-吡喃葡萄糖基-sn-2-甘油-3-磷脂酰胆碱（Glc-PAF）。Glc-PC和Glc-PAF在无毒浓度下可抑制HaCaT细胞的生长。在此我们报告，在甘油主链的sn-2位引入肌醇取代α-D-葡萄糖；这产生了两种非对映体的1-O-十八烷基-2-O-(2-(肌醇基)-乙基)-sn-甘油-3-(R/S)-磷脂酰胆碱（Ino-C2-PAF）。相对于Glc-PAF（LC(50)=15 microM），含肌醇的PAF增强了抗增殖能力（IC(50)=1.8 microM）并降低了细胞毒性。通过生物学检测，我们表明，在HaCaT细胞中，Ino-C2-PAF导致角质形成细胞特异性分化标志物内披蛋白上调，增加分化标志物转谷氨酰胺酶的活性，并在无毒浓度下诱导细胞凋亡。因此，Ino-C2-PAF似乎是一种很有前景的候选药物，可开发用于治疗皮肤过度增殖性疾病的抗增殖药物。
