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Molecules 2018, 23(6), 1394; https://doi.org/10.3390/molecules23061394

Anti-Tumorigenic Activity of Chrysin from Oroxylum indicum via Non-Genotoxic p53 Activation through the ATM-Chk2 Pathway

1
Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan
2
Department of Innovative Therapeutic Sciences, Cooperative Major in Nanopharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan
3
Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University; Nagoya 467-8603, Japan
4
The Kochi Prefectural Makino Botanical Garden, Kochi 781-8125, Japan
5
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kawasaki 210-9501, Japan
These authors share the first authorship of this paper.
*
Authors to whom correspondence should be addressed.
Received: 28 May 2018 / Revised: 6 June 2018 / Accepted: 7 June 2018 / Published: 8 June 2018
(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)
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Abstract

The p53 tumor suppressor plays critical roles in cell cycle regulation and apoptotic cell death in response to various cellular stresses, thereby preventing cancer development. Therefore, the activation of p53 through small molecules is an attractive therapeutic strategy for the treatment of cancers retaining wild-type p53. We used a library of 700 Myanmar wild plant extracts to identify small molecules that induce p53 transcriptional activity. A cell-based screening method with a p53-responsive luciferase-reporter assay system revealed that an ethanol extract of Oroxylum indicum bark increased p53 transcriptional activity. Chrysin was isolated and identified as the active ingredient in the O. indicum bark extract. A treatment with chrysin increased p53 protein expression and the p53-mediated expression of downstream target genes, and decreased cell viability in MCF7 cells, but not in p53-knockdown MCF7 cells. We also found that chrysin activated the ATM-Chk2 pathway in the absence of DNA damage. Hence, the inactivation of the ATM-Chk2 pathway suppressed p53 activation induced by chrysin. These results suggest the potential of chrysin as an anti-cancer drug through the activation of p53 without DNA damage. View Full-Text
Keywords: Oroxylum indicum; chrysin; p53; ATM; Chk2; flavonoid Oroxylum indicum; chrysin; p53; ATM; Chk2; flavonoid
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Nagasaka, M.; Hashimoto, R.; Inoue, Y.; Ishiuchi, K.; Matsuno, M.; Itoh, Y.; Tokugawa, M.; Ohoka, N.; Morishita, D.; Mizukami, H.; Makino, T.; Hayashi, H. Anti-Tumorigenic Activity of Chrysin from Oroxylum indicum via Non-Genotoxic p53 Activation through the ATM-Chk2 Pathway. Molecules 2018, 23, 1394.

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