title: Chalcone derivatives inhibit human platelet aggregation and inhibit growth in human bladder cancer cells.
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.
authors.affiliation: Faculty of Pharmacy, College of Pharmacy, Kaohsiung Medical University.
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Wu
authors.forename: Kai-Wei
authors.initials: KW
authors.lastname: Lin
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Teng
authors.forename: A-Mei
authors.initials: AM
authors.lastname: Huang
authors.forename: Yu-Chian
authors.initials: YC
authors.lastname: Chen
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Yen
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Wu
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010975:Platelet Aggregation Inhibitors; D017382:Reactive Oxygen Species; D002599:Chalcone; D051545:Cyclooxygenase 1