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

ABSTRACT

Objectives: 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.

KEYWORDS:

• Trifluoperazine
• NPM-ALK
• anaplastic large cell lymphoma
• apoptosis
• cell cycle arrest

Acknowledgements

L.H. and P.S. designed research; L.H., X.Z., J.W., S.W., H.M.A. and P.S. performed research and collected data; L.H. and P.S. interpreted, analyzed data and wrote the paper. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was sponsored by grants from the National Natural Science Foundation of China (31671309), HMA is supported by an R01 CA151533 grant from the National Cancer Institute.