Involvement of oncogenic tyrosine kinase NPM-ALK in trifluoperazine-induced cell cycle arrest and apoptosis in ALK+ anaplastic large cell lymphoma

Abstract

ABSTRACTObjectives: Trifluoperazine (TFP) has potential anticancer activity that was demonstrated in different types of cancer cells. However, little is known about its effects in the T-cell ALK+ anaplastic large cell lymphoma (ALCL). In this study, we investigated the effects of TFP in this aggressive type of cancer.Methods: The cytotoxicities of TFP on DEL and SUP-M2 cells were measured by trypan blue staining. The effects of TFP on cell cycle and apoptosis in DEL and SUP-M2 cells were determined by flow cytometry. The underlying anticancer mechanism of TFP was investigated by real-time PCR, Western Blotting, and nucleophosmin-ALK (NPM-ALK) tyrosine kinase assay in DEL cells.Results: Our results show that TFP did not significantly affect cell viability of human normal lymphocytes, whereas it reduced the cell viability of the ALK+ T-cell lymphoma cells, DEL and SUP-M2, in concentration- and time-dependent manners. TFP also induced cell cycle arrest at G0/G1 phase, and caused cell apoptosis in these cells. These effects could be explained by the involvement of NPM-ALK and its downstream cell survival regulatory proteins.Conclusions: Our results demonstrate for the first time that TFP is capable of inducing degradation and inhibition of kinase activity of NPM-ALK, as well as the increased level of phospho-NPM-ALK, leading to the inhibition of cell growth in ALK+ ALCL cells. TFP may have a potential to be utilized to treat this aggressive lymphoma.