Igishi T, Mikami M, Murakami K, Matsumoto S, Shigeoka Y, Nakanishi H, Yasuda K, Gutkind JS, Hitsuda Y, Shimizu E.
Enhancement of cisplatin-induced cytotoxicity by ROCK inhibitor through suppression of focal adhesion kinase-independent mechanism in lung carcinoma cells.
Int J Oncol
Intracellular signaling through Rho-associated coiled-coil forming kinase (ROCK) is a target of antimetastatic therapy and is proposed to be involved in carcinogenesis. Focal adhesion kinase (FAK) functions downstream of ROCK and participates in anti-apoptotic signaling. We hypothesized that a specific ROCK inhibitor, Y-27632, may exert a pro-apoptotic effect in combination with anticancer agents through the suppression of FAK. A549 lung carcinoma cells were treated with Y-27632 and cisplatin. The simultaneous combination did not exert any additional effect, whereas sequential treatment, in which cisplatin followed Y-27632, enhanced cytotoxicity in concentration- and time-dependent manner. Y-27632 did not suppress tyrosine phosphorylation of FAK in A549-FAK, the active form of FAK expressing A549 cells, as observed in parental cells. Nevertheless, the pretreatment of A549-FAK cells with Y-27632 still enhanced cisplatin-induced cytotoxicity. It was concluded that the ROCK inhibitor enhances cisplatin-induced cytotoxicity through FAK suppression-independent mechanism(s). These observations raise the possibility that the inhibition of the ROCK-mediated signal enhances the effect of anti-cancer agents in addition to its antimetastatic property.
Amides / pharmacology
Carcinoma / drug therapy*
Cell Line, Tumor
Cisplatin / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Focal Adhesion Kinase 1
Focal Adhesion Protein-Tyrosine Kinases
Intracellular Signaling Peptides and Proteins
Lung Neoplasms / drug therapy*
Plasmids / metabolism
Protein-Serine-Threonine Kinases / antagonists & inhibitors*
Protein-Serine-Threonine Kinases / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Pyridines / pharmacology
Tyrosine / metabolism
|Human and Animal Cells