Trifluoperazine Inhibits Mesangial Cell Proliferation by Arresting Cell Cycle-Dependent Mechanisms

BACKGROUND: It has been reported that trifluoperazine (TFP) inhibits proliferation of cancer cells, however, the effects of TFP in renal proliferation diseases are still unclear. This study examined the effects of TFP on proliferation of human renal mesangial cells and analyzed the underlying mechanisms. MATERIAL/METHODS: Cell proliferation in vivo was determined by HE staining, immunohistochemistry of proliferating cell nuclear antigen (PCNA), and Western blot analysis (Ki-67 and PCNA). Effects of different TFP concentrations and treatment duration on cell proliferation and cell cycle were analyzed using the MTT assay and flow cytometry. Expression of G(0)/G(1) phase cell cycle-related proteins and TFP-induced MAPK and PI3K/AKT signaling pathways was estimated with Western blot analysis. RESULTS: Our findings suggest that TFP inhibits cell proliferation in a dose- and time-dependent manner and decreased PCNA and Ki-67 levels in lupus MRL/lpr mice. TFP arrested the cell cycle in the G(0)/G(1) phase, down-regulating cyclin D1, CDK2, and CDK4, and up-regulating p21 expression in a dose-dependent manner. In addition, TFP inhibited p-AKT and p-JNK, possibly by suppressing the activation of PI3K/AKT and JNK/MAPK signaling pathways. TFP treatment remarkably reduced the levels of serum creatinine (Cr) in lupus mice. CONCLUSIONS: TFP exhibits inhibitory activity against mesangial cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of PI3K/AKT and JNK/MAPK signaling pathways. These results suggest the potential of TFP in treatment of mesangial proliferative diseases.