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: Chih-Chien Tsai, Huei-Fang Liu, Kai-Cheng Hsu, Jinn-Moon Yang, Chinpiao Chen, Kuang-Kai Liu, Tzu-Sheng Hsu, Jui-I Chao
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 81 Issue 7 Pg. 856-65 (Apr 01 2011) ISSN: 1873-2968 [Electronic] England
• PMID: 21276421 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• 7-chloro-6-piperidin-1-ylquinoline-5,8-dione
• Antineoplastic Agents
• Protein Kinase Inhibitors
• Quinolones
• Quinones
• RNA, Small Interfering
• rho-Associated Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Base Sequence
• Blotting, Western
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cytoskeleton (drug effects, physiology)
• Humans
• Microscopy, Atomic Force
• Protein Kinase Inhibitors (pharmacology)
• Quinolones (pharmacology)
• Quinones (pharmacology)
• RNA, Small Interfering
• rho-Associated Kinases (antagonists & inhibitors)