Authors:	Saaed, Mohamed Jacob, Stefan Sandjo, Louis P. Sugimoto, Yoshikazu Khalid, Hassan E. Opatz, Till Thines, Eckhard Efferth, Thomas
Title:	Cytotoxicity of the sesquiterpene lactones neoambrosin and damsin from ambrosia maritima against multidrug-resistant cancer cells
Online publication date:	17-Oct-2022
Year of first publication:	2015
Language:	english
Abstract:	Multidrug resistance is a prevailing phenomenon leading to chemotherapy treatment failure in cancer patients. In the current study two known cytotoxic pseudoguaianolide sesquiterpene lactones; neoambrosin (1) and damsin (2) that circumvent MDR were identified. The two cytotoxic compounds were isolated using column chromatography, characterized using 1D and 2D NMR, MS, and compared with literature values. The isolated compounds were investigated for their cytotoxic potential using resazurin assays and thereafter confirmed with immunoblotting and in silico studies. MDR cells overexpressing ABC transporters (P-glycoprotein, BCRP, ABCB5) did not confer cross-resistance toward (1) and (2), indicating that these compounds are not appropriate substrates for any of the three ABC transporters analyzed. Resistance mechanisms investigated also included; the loss of the functions of the TP53 and the mutated EGFR. The HCT116 p53-/- cells were sensitive to 1 but resistant to 2. It was interesting to note that resistant cells transfected with oncogenic ΔEGFR exhibited hypersensitivity CS toward (1) and (2) (degrees of resistances were 0.18 and 0.15 for (1) and (2), respectively). Immunoblotting and in silico analyses revealed that 1 and 2 silenced c-Src kinase activity. It was hypothesized that inhibition of c-Src kinase activity may explain CS in EGFR-transfected cells. In conclusion, the significant cytotoxicity of 1 and 2 against different drug-resistant tumor cell lines indicate that they may be promising candidates to treat refractory tumors.
DDC:	570 Biowissenschaften 570 Life sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 09 Chemie, Pharmazie u. Geowissensch. FB 10 Biologie
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8050
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	Frontiers in pharmacology 6
Pages or article number:	Art. 267
Publisher:	Frontiers Media
Publisher place:	Lausanne
Issue date:	2015
ISSN:	1663-9812
Publisher URL:	http://dx.doi.org/10.3389/fphar.2015.00267
Publisher DOI:	10.3389/fphar.2015.00267
Appears in collections:	DFG-OA-Publizieren (2012 - 2017)