title: 7-Chloro-6-piperidin-1-yl-quinoline-5,8-dione (PT-262), a novel ROCK inhibitor blocks cytoskeleton function and cell migration.
abstract: The 5,8-quinolinediones are precursors for producing multiple types of bioactive products. In this study, we investigated a new compound derived from 5,8-quinolinediones, 7-chloro-6-piperidin-1-yl-quinoline-5,8-dione (designated as PT-262), which markedly induced cytoskeleton remodeling and migration inhibition in lung carcinoma cells. Comparison with various cytoskeleton inhibitors, including paclitaxel, colchicine and phallacidin, the cell morphology following treatment with PT-262 was similar to phallacidin on the cell elongation and abnormal actin polymerization. However, PT-262 did not directly bind to actin filaments. ROCK (Rho-associated coiled-coil forming protein kinase) is a downstream effector of RhoA to mediate the phosphorylation of myosin light chain (MLC) and cytoskeleton reorganization. The RhoA-ROCK-MLC pathway has been shown to promote cancer cell migration and metastasis. Interestingly, PT-262 was more effective on inhibiting ROCK kinase activities than specific ROCK inhibitors Y-27632 and H-1152. PT-262 induced cytoskeleton remodeling and migration inhibition in A549 lung carcinoma cells. The total MLC and phosphorylated MLC proteins and stress fibers were blocked after treatment with PT-262. Nonetheless, the RhoA protein and GTPase activity were not altered by PT-262. A computational model suggests that PT-262 interacts with the ATP-binding site of ROCK protein. Together, these findings demonstrate that PT-262 is a new ROCK inhibitor.
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, Taiwan.
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Tsai
authors.forename: Huei-Fang
authors.initials: HF
authors.lastname: Liu
authors.forename: Kai-Cheng
authors.initials: KC
authors.lastname: Hsu
authors.forename: Jinn-Moon
authors.initials: JM
authors.lastname: Yang
authors.forename: Chinpiao
authors.initials: C
authors.lastname: Chen
authors.forename: Kuang-Kai
authors.initials: KK
authors.lastname: Liu
authors.forename: Tzu-Sheng
authors.initials: TS
authors.lastname: Hsu
authors.forename: Jui-I
authors.initials: JI
authors.lastname: Chao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003599:Cytoskeleton / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D018625:Microscopy, Atomic Force; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology*; D034741:RNA, Small Interfering; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: C533600:7-chloro-6-piperidin-1-ylquinoline-5,8-dione; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D011809:Quinones; D034741:RNA, Small Interfering; D054460:rho-Associated Kinases