Autoren:	Dawood, Mona Ooko, Edna Efferth, Thomas
Titel:	Collateral sensitivity of parthenolide via NF-κB and HIF-α inhibition and epigenetic changes in drug-resistant cancer cell lines
Online-Publikationsdatum:	13-Jun-2019
Erscheinungsdatum:	2019
Sprache des Dokuments:	Englisch
Zusammenfassung/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-Sachgruppe:	570 Biowissenschaften 570 Life sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität
Organisationseinheit:	FB 09 Chemie, Pharmazie u. Geowissensch.
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-151
URN:	urn:nbn:de:hebis:77-publ-591017
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	Frontiers in pharmacology 10
Seitenzahl oder Artikelnummer:	Art. 542
Verlag:	Frontiers Media
Verlagsort:	Lausanne
Erscheinungsdatum:	2019
ISSN:	1663-9812
URL der Originalveröffentlichung:	http://dx.doi.org/10.3389/fphar.2019.00542
DOI der Originalveröffentlichung:	10.3389/fphar.2019.00542
Enthalten in den Sammlungen:	JGU-Publikationen