Steinert B W, Tang D G, Grossi I M, Umbarger L A, Honn K V
Department of Radiation Oncology, Wayne State University, Detroit, MI 48202.
Int J Cancer. 1993 Apr 22;54(1):92-101. doi: 10.1002/ijc.2910540116.
Platelet eicosanoid metabolism resulting from tumor-cell-induced platelet aggregation (TCIPA) was examined in a homologous in vitro system. Rat Walker 256 carcinosarcoma cells induced the aggregation of rat platelets via a thrombin-dependent mechanism with concomitant production of eicosanoid metabolites (e.g., 12-HETE, TXA2). TCIPA was dependent on the concentration of tumor cells inducing aggregation, as well as cyclooxygenase and lipoxygenase products. Cyclooxygenase inhibitors, but not lipoxygenase inhibitors, blocked platelet aggregation induced in vitro by a low concentration of agonist. At a high agonist concentration, neither cyclooxygenase nor lipoxygenase inhibitors alone affected platelet aggregation; however, the combined inhibition of both the cyclooxygenase and lipoxygenase pathways resulted in subsequent inhibition of platelet aggregation regardless of agonist concentration. The extent of platelet TXA2 and 12-HETE biosynthesis was likewise dependent on and correlated with agonist concentration. The inhibitors used in this study did not significantly inhibit protein kinase C activity at the doses tested. Platelet surface glycoprotein alpha IIb beta 3 play an important role in platelet aggregation. The effect of platelet cyclooxygenase and lipoxygenase inhibition in regulating alpha IIb beta 3 surface expression was examined by flow cytometric analysis. Thrombin stimulation of washed rat platelets resulted in significantly increased surface expression of platelet alpha IIb beta 3 integrin complex. The enhanced surface expression was not inhibited by a cyclooxygenase inhibitor (aspirin), a thromboxane synthase inhibitor (CGS-14854) or a thromboxane receptor antagonist (SQ 29,548), nor was it stimulated by a thromboxane A2 mimic (pinane-thromboxane A2). However, alpha IIb beta 3 expression was blocked by lipoxygenase inhibition and stereospecifically increased by the platelet lipoxygenase metabolite 12(S)-HETE. These results suggest that both the platelet lipoxygenase and cyclooxygenase pathways are important for TCIPA but that different mechanisms of action are involved.
在一个同源体外系统中检测了肿瘤细胞诱导的血小板聚集（TCIPA）所导致的血小板类花生酸代谢。大鼠沃克256癌肉瘤细胞通过凝血酶依赖性机制诱导大鼠血小板聚集，并伴随类花生酸代谢产物（如12-羟基二十碳四烯酸、血栓素A2）的产生。TCIPA取决于诱导聚集的肿瘤细胞浓度，以及环氧化酶和脂氧化酶产物。环氧化酶抑制剂而非脂氧化酶抑制剂可阻断低浓度激动剂在体外诱导的血小板聚集。在高激动剂浓度下，单独的环氧化酶抑制剂和脂氧化酶抑制剂均不影响血小板聚集；然而，联合抑制环氧化酶和脂氧化酶途径会导致随后血小板聚集受到抑制，而与激动剂浓度无关。血小板血栓素A2和12-羟基二十碳四烯酸生物合成的程度同样取决于激动剂浓度并与之相关。本研究中使用的抑制剂在测试剂量下并未显著抑制蛋白激酶C活性。血小板表面糖蛋白αIIbβ3在血小板聚集中起重要作用。通过流式细胞术分析检测了血小板环氧化酶和脂氧化酶抑制在调节αIIbβ3表面表达方面的作用。凝血酶刺激洗涤后的大鼠血小板导致血小板αIIbβ3整合素复合物的表面表达显著增加。这种增强的表面表达不受环氧化酶抑制剂（阿司匹林）、血栓素合酶抑制剂（CGS-14854）或血栓素受体拮抗剂（SQ 29548）的抑制，也不受血栓素A2模拟物（蒎烷-血栓素A2）的刺激。然而，αIIbβ3表达可被脂氧化酶抑制所阻断，并被血小板脂氧化酶代谢产物12(S)-羟基二十碳四烯酸立体特异性地增加。这些结果表明，血小板脂氧化酶和环氧化酶途径对TCIPA均很重要，但涉及不同的作用机制。
