Phytochemical naphtho[1,2-b] furan-4,5‑dione induced topoisomerase II-mediated DNA damage response in human non-small-cell lung cancer

Ching Ming Chien, Juan Cheng Yang, Pin Hsuan Wu, Chang Yi Wu, Guan Yu Chen, Yang-Chang Wu, Chon Kit Chou, Chih Hua Tseng, Yeh Long Chen, Li Fang Wang, Chien Chih Chiu

Research output: Contribution to journalArticle

Abstract

Background: Phytochemical naphtho[1,2-b] furan-4,5‑dione (NFD) presenting in Avicennia marina exert anti-cancer effects, but little is known regarding about DNA damage-mediated apoptosis in non-small-cell lung carcinoma (NSCLC). Purpose: To examine whether NFD-induced apoptosis of NSCLC cells is correlated with the induction of DNA damage, and to investigate its underlying mechanism. Study design: The anti-proliferative effects of NFD were assessed by MTS Assay Kit FACS assay, and in vivo nude mice xenograft assay. The DNA damage related proteins, the Bcl-2 family and pro-apoptotic factors were examined by immunofluorescence assay, q-PCR, and western blotting. The activity of NF-κB p65 in nuclear extracts was detected using a colorimetric DNA-binding ELISA assay. The inhibitory activity of topoisomerase II (TOPO II) was evaluated by molecular docking and TOPO II catalytic assay. Results: NFD exerted selective cytotoxicity against NSCLC H1299, H1437 and A549 cells rather than normal lung-embryonated cells MRC-5. Remarkably, we found that NFD activated the hull marker and modulator of DNA damage repairs such as γ-H2AX, ATM, ATR, CHK1, and CHK2 probably caused by the accumulation of intracellular reactive oxygen species (ROS) and inhibition of TOPO II activity. Furthermore, the suppression of transcription factor NF-κB by NFD resulted in significantly decreased levels of pro-survival proteins including Bcl-2 family Bcl-2, Bcl-xL and Mcl-1 and the endogenous inhibitors of apoptosis XIAP and survivin in H1299 cells. Moreover, the nude mice xenograft assay further validated the suppression of H1299 growth by NFD, which is the first report for evaluating the anti-cancer effect of NFD in vivo. Conclusion: These findings provide a novel mechanism indicating the inhibition of TOPO II activity and NF-κB signaling by NFD, leading to DNA damage and apoptosis of NSCLC tumor cells.

LanguageEnglish (US)
Pages109-119
Number of pages11
JournalPhytomedicine
Volume54
DOIs
StatePublished - Feb 15 2019

Fingerprint

Type II DNA Topoisomerase
Phytochemicals
Non-Small Cell Lung Carcinoma
DNA Damage
Apoptosis
Heterografts
Nude Mice
Avicennia
naphtho(1,2-b)furan-4,5-dione
N-formyl-13-dihydrocarminomycin
Neoplasms
DNA Repair
Fluorescent Antibody Technique
Reactive Oxygen Species
Proteins
Transcription Factors
Western Blotting
Enzyme-Linked Immunosorbent Assay
Polymerase Chain Reaction
Lung

Keywords

  • Apoptosis
  • DNA damage
  • Naphthoquinone
  • NF-Κb
  • Non-small cell lung cancer
  • Topoisomerase II activity

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine

Cite this

Phytochemical naphtho[1,2-b] furan-4,5‑dione induced topoisomerase II-mediated DNA damage response in human non-small-cell lung cancer. / Chien, Ching Ming; Yang, Juan Cheng; Wu, Pin Hsuan; Wu, Chang Yi; Chen, Guan Yu; Wu, Yang-Chang; Chou, Chon Kit; Tseng, Chih Hua; Chen, Yeh Long; Wang, Li Fang; Chiu, Chien Chih.

In: Phytomedicine, Vol. 54, 15.02.2019, p. 109-119.

Research output: Contribution to journalArticle

Chien, Ching Ming ; Yang, Juan Cheng ; Wu, Pin Hsuan ; Wu, Chang Yi ; Chen, Guan Yu ; Wu, Yang-Chang ; Chou, Chon Kit ; Tseng, Chih Hua ; Chen, Yeh Long ; Wang, Li Fang ; Chiu, Chien Chih. / Phytochemical naphtho[1,2-b] furan-4,5‑dione induced topoisomerase II-mediated DNA damage response in human non-small-cell lung cancer. In: Phytomedicine. 2019 ; Vol. 54. pp. 109-119.
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