title: Cytotoxicity of the Sesquiterpene Lactones Neoambrosin and Damsin from Ambrosia maritima Against Multidrug-Resistant Cancer Cells.
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.
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz Mainz, Germany.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Saeed
authors.affiliation: Institut für Biotechnologie und Wirkstoff-Forschung Kaiserslautern, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jacob
authors.affiliation: Department of Pharmaceutical Sciences, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina Florianópolis, Brazil ; Institute of Organic Chemistry, Johannes Gutenberg University of Mainz Mainz, Germany.
authors.forename: Louis P
authors.initials: LP
authors.lastname: Sandjo
authors.affiliation: Division of Chemotherapy, Faculty of Pharmacy, Keio University Tokyo, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
authors.affiliation: Department of Pharmacognosy, University of Khartoum Khartoum, Sudan.
authors.forename: Hassan E
authors.initials: HE
authors.lastname: Khalid
authors.affiliation: Institute of Organic Chemistry, Johannes Gutenberg University of Mainz Mainz, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Opatz
authors.affiliation: Institut für Biotechnologie und Wirkstoff-Forschung Kaiserslautern, Germany ; Institute of Biotechnology and Drug Research, Johannes Gutenberg University of Mainz Mainz, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thines
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
keywords: ABC-transporters; Asteraceae; EGFR; Src inhibition; p53; targeted chemotherapy