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Authors: Dawood, Mona
Ooko, Edna
Efferth, Thomas
Title: Collateral sensitivity of parthenolide via NF-κB and HIF-α inhibition and epigenetic changes in drug-resistant cancer cell lines
Online publication date: 13-Jun-2019
Language: english
Abstract: Parthenolide (PT) is a sesquiterpene lactone isolated from Tanacetum parthenium. In this study, PT showed varying cytotoxic effects against different solid tumor cell lines. HCT116 (p53+/+) colon carcinoma cells and their parental HCT116 knockout p53 cells (p53−/−) cell lines showed a resistance degree of 2.36. On the other hand, wild-type U87.MG cells or cells transfected with a deletion-activated EGFR cDNA (U87.MGΔEGFR) exhibited slight sensitivity towards PT. Multidrug-resistant MDA-MB-231-BCRP cells were even more sensitive towards PT than sensitive MDA-MB-231-pcDNA3 cells with a resistance degree of 0.07 (collateral sensitivity). To the best of our knowledge, hypersensitivity (collateral sensitivity) of BCRP-overexpressing tumor cells has been reported for the first time. We attempted to identify the mechanism of collateral sensitivity. Firstly, we found that PT bound to IKK preventing IκBα degradation and eventually inhibition of the nuclear factor kappa B (NF-κB) pathway. Down-regulation of hypoxia inducing factor 1-alpha (HIF-1α) in MDA-MB-231-BCRP resistant cells may be a second mechanism, since it is a target gene of NF-κB. Moreover, PT also showed epigenetic effect by inhibition of HDAC activity as shown using both molecular docking and HDAC activity assay. Based on COMPARE and hierarchical cluster analyses, we found gene expression profiles that predicted sensitivity or resistance of 47 tumor cell lines towards PT. Interestingly, pathway analyses of gene expression profiles revealed NF-κB and HIF signaling as top networks of these genes, cellular functions and canonical pathways influencing the activity of PT against tumor cells. In conclusion, the profound cytotoxic activity of PT against various cancer cell lines particularly against BCRP-overexpressing tumor cells suggesting PT as novel candidate compound for cancer treatment.
DDC: 570 Biowissenschaften
570 Life sciences
Institution: Johannes Gutenberg-Universität
Department: FB 09 Chemie, Pharmazie u. Geowissensch.
Place: Mainz
URN: urn:nbn:de:hebis:77-publ-591017
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: Frontiers in pharmacology
Pages or article number: Art. 542
Publisher: Frontiers Media
Publisher place: Lausanne
Issue date: 2019
ISSN: 1663-9812
Publisher URL:
Publisher DOI: 10.3389/fphar.2019.00542
Appears in collections:JGU-Publikationen

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