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

UM > Institute of Chinese Medical Sciences

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	Phytochemical naphtho[1,2-b] furan-4,5‑dione induced topoisomerase II-mediated DNA damage response in human non-small-cell lung cancer
	Chien , C. M.; Yang, J. C.; Wu, P. H.; Wu, C. Y.; Chen, G. Y.; Wu, Y. C. ; Chou, C. K.; Tseng, C. H.; Chen, Y. L.; Wang, L. F.; Chiu, C. C.
	2019-02-15
Source Publication	Phytomedicine
ISSN	doi: 10.1016/j.phymed.2018.06.025.
Pages	109-119
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.
Keyword	Apoptosis DNA damage NF-Κb Naphthoquinone Non-small cell lung cancer Topoisomerase II activity.
URL	View the original
Language	英語English
The Source to Article	PB_Publication
PUB ID	54514
Document Type	Journal article
Collection	Institute of Chinese Medical Sciences
Corresponding Author	Chiu, C. C.
Recommended Citation GB/T 7714	Chien , C. M.,Yang, J. C.,Wu, P. H.,et al. Phytochemical naphtho[1,2-b] furan-4,5‑dione induced topoisomerase II-mediated DNA damage response in human non-small-cell lung cancer[J]. Phytomedicine, 2019, 109-119.
APA	Chien , C. M.., Yang, J. C.., Wu, P. H.., Wu, C. Y.., Chen, G. Y.., Wu, Y. C. ., Chou, C. K.., Tseng, C. H.., Chen, Y. L.., Wang, L. F.., & Chiu, C. C. (2019). Phytochemical naphtho[1,2-b] furan-4,5‑dione induced topoisomerase II-mediated DNA damage response in human non-small-cell lung cancer. Phytomedicine, 109-119.
MLA	Chien , C. M.,et al."Phytochemical naphtho[1,2-b] furan-4,5‑dione induced topoisomerase II-mediated DNA damage response in human non-small-cell lung cancer".Phytomedicine (2019):109-119.

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