Chalcone derivatives inhibit human platelet aggregation and inhibit growth in human bladder cancer cells
Journal
Biological and Pharmaceutical Bulletin
Journal Volume
37
Journal Issue
7
Pages
1191-1198
Date Issued
2014
Author(s)
Abstract
In an effort to develop potent cyclooxygenase-1 (COX-1) inhibitors used as anticancer agent, a series of 2′,5′-dimethoxychalcones was screened to evaluate their antiplatelet effect on human washed platelets suspension. Compound 2 exhibited potent inhibition of human washed platelet aggregation induced by collagen, significantly inhibited collagen- and arachidonic acid-induced thromboxane B2 release, and revealed inhibitory effect on COX-1 activity. Molecular docking studies showed that 1, 2, and 4 were bound in the active site of COX-1. These indicated that the antiplatelet effect of these compounds were mainly mediated through the suppression of COX-1 activity and reduced the thromboxane formation. To investigate the mechanistic action of COX-1 inhibitor enhanced the cytotoxic effect against human bladder cancer cells, NTUB1, we assessed the cytotoxic effect of 2 against NTUB1. Treatment of NTUB1 cells with various concentrations of 2 led to a concentration-dependent increase of cell death and decrease of reactive oxygen species levels. The flow-cytometric analysis showed that 2 induced a G1 phase cell cycle arrest but did not accompany an appreciable sub-G1 phase in NTUB1 cells. In addition, compound 2 increased p21 and p27 expressions and did not inhibit the expression of COX-1 in NTUB1 cells. Our results suggested that 2 enhanced cell growth inhibition or antiproliferative activity in NTUB1 cells through G1 arrest by COX-1 independent mechanism. ? 2014 The Pharmaceutical Society of Japan.
Subjects
Antiplatelet; Bladder cancer; Chalcone; Cyclooxygenase-1 (COX-1); Cytotoxicity; G1 cell cycle arrest
SDGs
Other Subjects
2',5' dimethoxychalcone derivative; chalcone derivative; collagen; cyclooxygenase 1; protein p21; protein p27; reactive oxygen metabolite; thromboxane B2; unclassified drug; antineoplastic agent; antithrombocytic agent; chalcone; cyclooxygenase 1; reactive oxygen metabolite; article; bladder cancer; cancer cell; cancer cell line; cancer inhibition; cell cycle arrest; cell cycle G1 phase; concentration response; controlled study; drug cytotoxicity; drug screening; drug structure; enzyme activity; flow cytometry; human; human cell; molecular docking; NTUB1 cell line; prostaglandin release; protein expression; thrombocyte aggregation inhibition; analogs and derivatives; cell proliferation; cell survival; chemical structure; chemistry; dose response; drug effects; G1 phase cell cycle checkpoint; metabolism; molecular dynamics; thrombocyte aggregation; tumor cell line; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chalcone; Cyclooxygenase 1; Dose-Response Relationship, Drug; Flow Cytometry; G1 Phase Cell Cycle Checkpoints; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Platelet Aggregation; Platelet Aggregation Inhibitors; Reactive Oxygen Species
Publisher
Pharmaceutical Society of Japan
Type
journal article