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

BioMed Research International
Hang GaoHuajun Zhao

Abstract

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 (IC50 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 d...Continue Reading

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Citations

Mar 11, 2021·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Yu TianDinglun Zhou
Jun 26, 2021·Cancer Control : Journal of the Moffitt Cancer Center·Fang-Liang HuangChia-Ling Li
Jul 29, 2021·Journal of Drug Targeting·Yingying LiGuangxi Zhai

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Methods Mentioned

BETA
electrophoresis
protein concentration assay
PCR
Histone Acetylation
acetylation
histones acetylation
ubiquitination

Software Mentioned

Graph Pad
modfit
GraphPad Prism

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