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Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia

Acute T lymphocytic leukemia (T-ALL) is an aggressive hematologic resulting from the malignant transformation of T-cell progenitors. Drug resistance and relapse are major difficulties in the treatment of T-ALL. Here, we report the antitumor potency of NL-101, a compound that combines the nitrogen mu...

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Detalles Bibliográficos
Autores principales: Gao, Hang, Lou, Siyue, Hong, Huanwu, Ge, Qiufu, Zhao, Huajun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042524/
https://www.ncbi.nlm.nih.gov/pubmed/32149078
http://dx.doi.org/10.1155/2020/1520651
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author Gao, Hang
Lou, Siyue
Hong, Huanwu
Ge, Qiufu
Zhao, Huajun
author_facet Gao, Hang
Lou, Siyue
Hong, Huanwu
Ge, Qiufu
Zhao, Huajun
author_sort Gao, Hang
collection PubMed
description Acute T lymphocytic leukemia (T-ALL) is an aggressive hematologic resulting from the malignant transformation of T-cell progenitors. Drug resistance and relapse are major difficulties in the treatment of T-ALL. Here, we report the antitumor potency of NL-101, a compound that combines the nitrogen mustard group of bendamustine with the hydroxamic acid group of vorinostat. We found NL-101 exhibited efficient antiproliferative activity in T-ALL cell lines (IC(50) 1.59–1.89 μM), accompanied by cell cycle arrest and apoptosis, as evidenced by the increased expression of Cyclin E1, CDK2, and CDK4 proteins and cleavage of PARP. In addition, this bendamustine-derived drug showed both a HDACi effect as demonstrated by histone hyperacetylation and p21 transcription and a DNA-damaging effect as shown by an increase in γ-H2AX. Intriguingly, we found that NL-101-induced autophagy in T-ALL cells through inhibiting Akt-mTOR signaling pathway, as indicated by an increase in LC3-I to LC3-II conversion and decrease of p62. Furthermore, inhibition of autophagy by 3-methyladenine increased apoptotic cell death by NL-101, suggesting a prosurvival role of autophagy. In summary, our finding provides rationale for investigation of NL-101 as a DNA/HDAC dual targeting drug in T-ALL, either as a single agent or in combination with autophagy inhibitors.
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spelling pubmed-70425242020-03-08 Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia Gao, Hang Lou, Siyue Hong, Huanwu Ge, Qiufu Zhao, Huajun Biomed Res Int Research Article Acute T lymphocytic leukemia (T-ALL) is an aggressive hematologic resulting from the malignant transformation of T-cell progenitors. Drug resistance and relapse are major difficulties in the treatment of T-ALL. Here, we report the antitumor potency of NL-101, a compound that combines the nitrogen mustard group of bendamustine with the hydroxamic acid group of vorinostat. We found NL-101 exhibited efficient antiproliferative activity in T-ALL cell lines (IC(50) 1.59–1.89 μM), accompanied by cell cycle arrest and apoptosis, as evidenced by the increased expression of Cyclin E1, CDK2, and CDK4 proteins and cleavage of PARP. In addition, this bendamustine-derived drug showed both a HDACi effect as demonstrated by histone hyperacetylation and p21 transcription and a DNA-damaging effect as shown by an increase in γ-H2AX. Intriguingly, we found that NL-101-induced autophagy in T-ALL cells through inhibiting Akt-mTOR signaling pathway, as indicated by an increase in LC3-I to LC3-II conversion and decrease of p62. Furthermore, inhibition of autophagy by 3-methyladenine increased apoptotic cell death by NL-101, suggesting a prosurvival role of autophagy. In summary, our finding provides rationale for investigation of NL-101 as a DNA/HDAC dual targeting drug in T-ALL, either as a single agent or in combination with autophagy inhibitors. Hindawi 2020-02-14 /pmc/articles/PMC7042524/ /pubmed/32149078 http://dx.doi.org/10.1155/2020/1520651 Text en Copyright © 2020 Hang Gao et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Gao, Hang
Lou, Siyue
Hong, Huanwu
Ge, Qiufu
Zhao, Huajun
Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia
title Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia
title_full Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia
title_fullStr Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia
title_full_unstemmed Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia
title_short Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia
title_sort autophagy inhibition potentiates the anticancer effects of a bendamustine derivative nl-101 in acute t lymphocytic leukemia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042524/
https://www.ncbi.nlm.nih.gov/pubmed/32149078
http://dx.doi.org/10.1155/2020/1520651
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