PMID- 33915987 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210502 IS - 2076-3921 (Print) IS - 2076-3921 (Electronic) IS - 2076-3921 (Linking) VI - 10 IP - 4 DP - 2021 Apr 1 TI - Identification of Beilschmiedia tsangii Root Extract as a Liver Cancer Cell-Normal Keratinocyte Dual-Selective NRF2 Regulator. LID - 10.3390/antiox10040544 [doi] LID - 544 AB - Transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in regulating the expression of genes participating in cellular defense mechanisms against oxidative or xenobiotic insults. However, there is increasing evidence showing that hyperactivation of NRF2 is associated with chemoresistance in several cancers, including hepatocellular carcinoma (HCC), thus making NRF2 an attractive target for cancer therapy. Another important issue in cancer medication is the adverse effects of these substances on normal cells. Here, we attempted to identify a dual-selective NRF2 regulator that exerts opposite effects on NRF2-hyperactivated HCC cells and normal keratinocytes. An antioxidant response element driven luciferase reporter assay was established in Huh7 and HaCaT cells as high-throughput screening platforms. Screening of 3,000 crude extracts from the Taiwanese Indigenous Plant Extract Library resulted in the identification of Beilschmiedia tsangii (BT) root extract as a dual-selective NRF2 regulator. Multiple compounds were found to contribute to the dual-selective effects of BT extract on NRF2 signaling in two cell lines. BT extract reduced NRF2 protein level and target gene expression levels in Huh7 cells but increased them in HaCaT cells. Furthermore, notable combinatory cytotoxic effects of BT extract and sorafenib on Huh7 cells were observed. On the contrary, sorafenib-induced inflammatory reactions in HaCaT cells were reduced by BT extract. In conclusion, our results suggest that the combination of a selective NRF2 activator and inhibitor could be a practical strategy for fine-tuning NRF2 activity for better cancer treatment and that plant extracts or partially purified fractions could be a promising source for the discovery of dual-selective NRF2 regulators. FAU - Chen, Yi-Siao AU - Chen YS AD - Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - Institute of Molecular and Genomic Medicine, National Health Research Institute, Miaoli County 35053, Taiwan. AD - Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - National Natural Product Libraries and High-Throughput Screening Core Facility, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. FAU - Chang, Hsun-Shuo AU - Chang HS AD - Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - National Natural Product Libraries and High-Throughput Screening Core Facility, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. FAU - Hsiao, Hui-Hua AU - Hsiao HH AUID- ORCID: 0000-0002-7381-1045 AD - Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan. AD - Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan. FAU - Chen, Yih-Fung AU - Chen YF AUID- ORCID: 0000-0002-5595-1319 AD - Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. FAU - Kuo, Yi-Ping AU - Kuo YP AD - Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - National Natural Product Libraries and High-Throughput Screening Core Facility, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. FAU - Yen, Feng-Lin AU - Yen FL AD - Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. FAU - Yen, Chia-Hung AU - Yen CH AUID- ORCID: 0000-0002-6939-5528 AD - Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - National Natural Product Libraries and High-Throughput Screening Core Facility, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. AD - Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan. LA - eng GR - MOST 109-2740-B-037-001, MOST 109-2314-B-037-047-MY3 and MOST 108-2314-B-037-034-MY2/Ministry of Science and Technology, Taiwan/ GR - 110AS-10.1.2-LI-L2/Livestock Research Institute, Council of Agriculture, Taiwan/ PT - Journal Article DEP - 20210401 PL - Switzerland TA - Antioxidants (Basel) JT - Antioxidants (Basel, Switzerland) JID - 101668981 PMC - PMC8066689 OTO - NOTNLM OT - NRF2 OT - adjuvant treatment OT - high-throughput screen OT - natural product COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. EDAT- 2021/05/01 06:00 MHDA- 2021/05/01 06:01 PMCR- 2021/04/01 CRDT- 2021/04/30 01:01 PHST- 2021/03/21 00:00 [received] PHST- 2021/03/30 00:00 [accepted] PHST- 2021/04/30 01:01 [entrez] PHST- 2021/05/01 06:00 [pubmed] PHST- 2021/05/01 06:01 [medline] PHST- 2021/04/01 00:00 [pmc-release] AID - antiox10040544 [pii] AID - antioxidants-10-00544 [pii] AID - 10.3390/antiox10040544 [doi] PST - epublish SO - Antioxidants (Basel). 2021 Apr 1;10(4):544. doi: 10.3390/antiox10040544.