title: Effect of a potent cyclooxygenase inhibitor, 5-ethyl-4-methoxy-2-phenylquinoline (KTC-5), on human platelets.
abstract: Because the metabolites of arachidonic acid participate in many physiopathological responses, including inflammation and platelet aggregation, cyclooxygenase inhibitors are important in the treatment of associated diseases. A biologically active compound, 5-ethyl-4-methoxy-2-phenylquinoline (KTC-5), selectively and concentration dependently inhibited aggregation of platelets from man and ATP release caused by arachidonic acid (200 microM) and collagen (10 microg mL(-1)) without affecting the aggregation caused by thrombin (0.1 U mL(-1)) and U46619 (2 microM). The IC50 value (drug concentration inhibiting maximum response by 50%) of KTC-5 for aggregation induced by arachidonic acid and collagen was 0.11+/-0.04 microM and 0.20+/-0.03 microM, respectively. This inhibitory effect of KTC-5 was reversible and time dependent. KTC-5 specifically inhibited intracellular calcium mobilization initiated by arachidonic acid or collagen without affecting that caused by thrombin or U46619 in human platelets. Furthermore, KTC-5 inhibited thromboxane B2 and prostaglandin D2 formation provoked by arachidonic acid. The IC50 value of KTC-5 for arachidonic-acid-induced thromboxane B2 formation was 0.07+/-0.02 microM. Based on these observations, the data indicated that KTC-5 potently inhibited human platelet aggregation and ATP release mainly via the inhibition of the cyclooxygenase-1 activity. Moreover, KTC-5 inhibited lipopolysaccharide-induced prostaglandin E2 formation in RAW264.7 cells in the presence of external arachidonic acid with an IC50 value of 0.17+/-0.06 microM. Immunoblot analysis showed that KTC-5 did not affect the cyclooxygenase-2 expression in the presence of lipopolysaccharide on RAW264.7 cells. This result indicated that KTC-5 affects the activity of cyclooxygenase-2. According to these data, we concluded that KTC-5 is a cyclooxygenase inhibitor for both subtypes.
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Chang-Hui
authors.initials: CH
authors.lastname: Liao
authors.forename: Cho-Hwa
authors.initials: CH
authors.lastname: Liao
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chang
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
authors.forename: Shen-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D016718:Arachidonic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology*; D018929:Cell Culture Techniques; D003094:Collagen / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D010974:Platelet Aggregation / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*
chemical_list: C470481:5-ethyl-4-methoxy-2-phenylquinoline; D016861:Cyclooxygenase Inhibitors; D011804:Quinolines; D016718:Arachidonic Acid; D000255:Adenosine Triphosphate; D003094:Collagen