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NPRL-Z-1, as a New Topoisomerase II Poison, Induces Cell Apoptosis and ROS Generation in Human Renal Carcinoma Cells
- Source :
- PLoS ONE, Vol 9, Iss 11, p e112220 (2014), PLoS ONE
- Publication Year :
- 2014
- Publisher :
- Public Library of Science (PLoS), 2014.
-
Abstract
- NPRL-Z-1 is a 4β-[(4″-benzamido)-amino]-4′-O-demethyl-epipodophyllotoxin derivative. Previous reports have shown that NPRL-Z-1 possesses anticancer activity. Here NPRL-Z-1 displayed cytotoxic effects against four human cancer cell lines (HCT 116, A549, ACHN, and A498) and exhibited potent activity in A498 human renal carcinoma cells, with an IC50 value of 2.38 µM via the MTT assay. We also found that NPRL-Z-1 induced cell cycle arrest in G1-phase and detected DNA double-strand breaks in A498 cells. NPRL-Z-1 induced ataxia telangiectasia-mutated (ATM) protein kinase phosphorylation at serine 1981, leading to the activation of DNA damage signaling pathways, including Chk2, histone H2AX, and p53/p21. By ICE assay, the data suggested that NPRL-Z-1 acted on and stabilized the topoisomerase II (TOP2)–DNA complex, leading to TOP2cc formation. NPRL-Z-1-induced DNA damage signaling and apoptotic death was also reversed by TOP2α or TOP2β knockdown. In addition, NPRL-Z-1 inhibited the Akt signaling pathway and induced reactive oxygen species (ROS) generation. These results demonstrated that NPRL-Z-1 appeared to be a novel TOP2 poison and ROS generator. Thus, NPRL-Z-1 may present a significant potential anticancer candidate against renal carcinoma.
- Subjects :
- Drug Research and Development
Cell cycle checkpoint
DNA damage
Urology
lcsh:Medicine
Apoptosis
Ataxia Telangiectasia Mutated Proteins
Stress Signaling Cascade
Cell Signaling
Antigens, Neoplasm
Molecular Cell Biology
Drug Discovery
Medicine and Health Sciences
Humans
Topoisomerase II Inhibitors
MTT assay
Poly-ADP-Ribose Binding Proteins
lcsh:Science
Protein kinase A
Apoptotic Signaling Cascade
Podophyllotoxin
Pharmacology
Multidisciplinary
biology
Akt/PKB signaling pathway
Topoisomerase
lcsh:R
Biology and Life Sciences
Cell Biology
Molecular biology
Kidney Neoplasms
Signaling Cascades
DNA-Binding Proteins
DNA Topoisomerases, Type II
Nephrology
Renal Cancer
Immunology
biology.protein
lcsh:Q
Tumor Suppressor Protein p53
Clinical Medicine
Signal transduction
Reactive Oxygen Species
DNA Damage
Signal Transduction
Research Article
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....156324b4fa09e4b3b37e32b5205ceac5