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Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia
Alejandro Gutierrez, … , A. Thomas Look, Jon C. Aster
Alejandro Gutierrez, … , A. Thomas Look, Jon C. Aster
Published January 9, 2014
Citation Information: J Clin Invest. 2014;124(2):644-655. https://doi.org/10.1172/JCI65093.
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Research Article Oncology Article has an altmetric score of 104

Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia

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Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug’s antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.

Authors

Alejandro Gutierrez, Li Pan, Richard W.J. Groen, Frederic Baleydier, Alex Kentsis, Jason Marineau, Ruta Grebliunaite, Elena Kozakewich, Casie Reed, Francoise Pflumio, Sandrine Poglio, Benjamin Uzan, Paul Clemons, Lynn VerPlank, Frank An, Jason Burbank, Stephanie Norton, Nicola Tolliday, Hanno Steen, Andrew P. Weng, Huipin Yuan, James E. Bradner, Constantine Mitsiades, A. Thomas Look, Jon C. Aster

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Figure 4

Activity of PPZ and related phenothiazines against mammalian T-ALL cell lines.

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Activity of PPZ and related phenothiazines against mammalian T-ALL cell ...
(A) Growth suppression of KOPT-K1 cells by the indicated phenothiazines, expressed as IC50. (B–D) Effects of compound E (GSI) and PPZ on the growth of Notch1-dependent human KOPT-K1 and DND41 T-ALL cells (B), Notch1-dependent murine 142 T-ALL cells (C), and NOTCH1-independent human SUP-T13 T-ALL cells (D). In each experiment, each condition was assayed in triplicate, and all experiments were repeated at least twice. In B–D, PPZ and compound E were used at 10 μM and 0.1 μM, respectively, while in (C) PPZ and compound E were used at 3 μM and 6 nM, respectively.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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