Abstract

NPRL-Z-1 is a 4b -[(4″-benzamido)-amino]-4′-0-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 TOP2bβ 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.

Original languageEnglish
Article numbere112220
JournalPLoS One
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 5 2014

Fingerprint

DNA topoisomerase (ATP-hydrolysing)
Type II DNA Topoisomerase
Poisons
Renal Cell Carcinoma
DNA damage
DNA Damage
carcinoma
reactive oxygen species
Reactive Oxygen Species
apoptosis
Ataxia Telangiectasia Mutated Proteins
Cells
kidneys
Apoptosis
Double-Stranded DNA Breaks
DNA
G1 Phase
assays
Cell Cycle Checkpoints
histones

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

NPRL-Z-1, as a new topoisomerase II poison, induces cell apoptosis and ROS generation in human renal carcinoma cells. / Wu, Szu Ying; Pan, Shiow Lin; Xiao, Zhi Yan; Hsu, Jui Ling; Chen, Mei Chuan; Lee, Kuo Hsiung; Teng, Che Ming.

In: PLoS One, Vol. 9, No. 11, e112220, 05.11.2014.

Research output: Contribution to journalArticle

Wu, Szu Ying ; Pan, Shiow Lin ; Xiao, Zhi Yan ; Hsu, Jui Ling ; Chen, Mei Chuan ; Lee, Kuo Hsiung ; Teng, Che Ming. / NPRL-Z-1, as a new topoisomerase II poison, induces cell apoptosis and ROS generation in human renal carcinoma cells. In: PLoS One. 2014 ; Vol. 9, No. 11.
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