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Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemia (T-ALL), a neoplasm derived from T cell lineage-committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated...

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Autores principales: Chang, Yoon Soo, Gills, Joell J., Kawabata, Shigeru, Onozawa, Masahiro, Della Gatta, Giusy, Ferrando, Adolfo A., Aplan, Peter D., Dennis, Phillip A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609462/
https://www.ncbi.nlm.nih.gov/pubmed/37800623
http://dx.doi.org/10.3892/ijo.2023.5576
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author Chang, Yoon Soo
Gills, Joell J.
Kawabata, Shigeru
Onozawa, Masahiro
Della Gatta, Giusy
Ferrando, Adolfo A.
Aplan, Peter D.
Dennis, Phillip A.
author_facet Chang, Yoon Soo
Gills, Joell J.
Kawabata, Shigeru
Onozawa, Masahiro
Della Gatta, Giusy
Ferrando, Adolfo A.
Aplan, Peter D.
Dennis, Phillip A.
author_sort Chang, Yoon Soo
collection PubMed
description T cell acute lymphoblastic leukemia (T-ALL), a neoplasm derived from T cell lineage-committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated by γ-secretase. γ-secretase inhibitors (GSIs) are a NOTCH-targeted therapy for T-ALL. However, their clinical application has not been successful due to adverse events (primarily gastrointestinal toxicity), limited efficacy, and drug resistance caused by several mechanisms, including activation of the AKT/mTOR pathway. Nelfinavir is an human immunodeficiency virus 1 aspartic protease inhibitor and has been repurposed as an anticancer drug. It acts by inducing endoplasmic reticulum (ER) stress and inhibiting the AKT/mTOR pathway. Thus, it was hypothesized that nelfinavir might inhibit the NOTCH pathway via γ-secretase inhibition and blockade of aspartic protease presenilin, which would make nelfinavir effective against NOTCH-associated T-ALL. The present study assessed the efficacy of nelfinavir against T-ALL cells and investigated mechanisms of action in vitro and in preclinical treatment studies using a SCL-LMO1 transgenic mouse model. Nelfinavir blocks presenilin 1 processing and inhibits γ-secretase activity as well as the NOTCH1 pathway, thus suppressing T-ALL cell viability. Additionally, microarray analysis of nelfinavir-treated T-ALL cells showed that nelfinavir upregulated mRNA levels of CHAC1 (glutathione-specific γ-glutamylcyclotransferase 1, a negative regulator of NOTCH) and sestrin 2 (SESN2; a negative regulator of mTOR). As both factors are upregulated by ER stress, this confirmed that nelfinavir induced ER stress in T-ALL cells. Moreover, nelfinavir suppressed NOTCH1 mRNA expression in microarray analyses. These findings suggest that nelfinavir inhibited the NOTCH1 pathway by downregulating NOTCH1 mRNA expression, upregulating CHAC1 and suppressing γ-secretase via presenilin 1 inhibition and the mTOR pathway by upregulating SESN2 via ER stress induction. Further, nelfinavir exhibited therapeutic efficacy against T-ALL in an SCL-LMO1 transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T-ALL.
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spelling pubmed-106094622023-10-28 Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia Chang, Yoon Soo Gills, Joell J. Kawabata, Shigeru Onozawa, Masahiro Della Gatta, Giusy Ferrando, Adolfo A. Aplan, Peter D. Dennis, Phillip A. Int J Oncol Articles T cell acute lymphoblastic leukemia (T-ALL), a neoplasm derived from T cell lineage-committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated by γ-secretase. γ-secretase inhibitors (GSIs) are a NOTCH-targeted therapy for T-ALL. However, their clinical application has not been successful due to adverse events (primarily gastrointestinal toxicity), limited efficacy, and drug resistance caused by several mechanisms, including activation of the AKT/mTOR pathway. Nelfinavir is an human immunodeficiency virus 1 aspartic protease inhibitor and has been repurposed as an anticancer drug. It acts by inducing endoplasmic reticulum (ER) stress and inhibiting the AKT/mTOR pathway. Thus, it was hypothesized that nelfinavir might inhibit the NOTCH pathway via γ-secretase inhibition and blockade of aspartic protease presenilin, which would make nelfinavir effective against NOTCH-associated T-ALL. The present study assessed the efficacy of nelfinavir against T-ALL cells and investigated mechanisms of action in vitro and in preclinical treatment studies using a SCL-LMO1 transgenic mouse model. Nelfinavir blocks presenilin 1 processing and inhibits γ-secretase activity as well as the NOTCH1 pathway, thus suppressing T-ALL cell viability. Additionally, microarray analysis of nelfinavir-treated T-ALL cells showed that nelfinavir upregulated mRNA levels of CHAC1 (glutathione-specific γ-glutamylcyclotransferase 1, a negative regulator of NOTCH) and sestrin 2 (SESN2; a negative regulator of mTOR). As both factors are upregulated by ER stress, this confirmed that nelfinavir induced ER stress in T-ALL cells. Moreover, nelfinavir suppressed NOTCH1 mRNA expression in microarray analyses. These findings suggest that nelfinavir inhibited the NOTCH1 pathway by downregulating NOTCH1 mRNA expression, upregulating CHAC1 and suppressing γ-secretase via presenilin 1 inhibition and the mTOR pathway by upregulating SESN2 via ER stress induction. Further, nelfinavir exhibited therapeutic efficacy against T-ALL in an SCL-LMO1 transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T-ALL. D.A. Spandidos 2023-10-02 /pmc/articles/PMC10609462/ /pubmed/37800623 http://dx.doi.org/10.3892/ijo.2023.5576 Text en Copyright: © Chang et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Chang, Yoon Soo
Gills, Joell J.
Kawabata, Shigeru
Onozawa, Masahiro
Della Gatta, Giusy
Ferrando, Adolfo A.
Aplan, Peter D.
Dennis, Phillip A.
Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia
title Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia
title_full Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia
title_fullStr Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia
title_full_unstemmed Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia
title_short Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia
title_sort inhibition of the notch and mtor pathways by nelfinavir as a novel treatment for t cell acute lymphoblastic leukemia
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609462/
https://www.ncbi.nlm.nih.gov/pubmed/37800623
http://dx.doi.org/10.3892/ijo.2023.5576
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