Activity of aaptamine and two derivatives, demethyloxyaaptamine and isoaaptamine, in cisplatin-resistant germ cell cancer
Standard
Activity of aaptamine and two derivatives, demethyloxyaaptamine and isoaaptamine, in cisplatin-resistant germ cell cancer. / Dyshlovoy, Sergey A; Venz, Simone; Shubina, Larisa K; Fedorov, Sergey N; Walther, Reinhard; Jacobsen, Christine; Stonik, Valentin A; Bokemeyer, Carsten; Balabanov, Stefan; Honecker, Friedemann.
in: J PROTEOMICS, Jahrgang 96, 16.01.2014, S. 223-39.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Activity of aaptamine and two derivatives, demethyloxyaaptamine and isoaaptamine, in cisplatin-resistant germ cell cancer
AU - Dyshlovoy, Sergey A
AU - Venz, Simone
AU - Shubina, Larisa K
AU - Fedorov, Sergey N
AU - Walther, Reinhard
AU - Jacobsen, Christine
AU - Stonik, Valentin A
AU - Bokemeyer, Carsten
AU - Balabanov, Stefan
AU - Honecker, Friedemann
N1 - Copyright © 2013 Elsevier B.V. All rights reserved.
PY - 2014/1/16
Y1 - 2014/1/16
N2 - UNLABELLED: We analyzed the effects of all three marine alkaloids aaptamine, demethyloxyaaptamine and isoaaptamine in NT2-R, a cisplatin-resistant subline of the human embryonal carcinoma cell line NT2. All aaptamines were found to be equally effective in both cell lines, excluding cross-resistance between aaptamines and cisplatin in vitro. At the inhibitory concentration (IC50), aaptamine exerted an antiproliferative effect, whereas demethyloxyaaptamine and isoaaptamine were strong inducers of apoptosis. We analyzed the changes in the proteome of NT2-R cells treated with these compounds. 16-22 proteins were found to be significantly altered, of which several were validated by Western blotting and two-dimensional Western blotting analysis. Changes in the proteome pattern frequently resulted from post-transcriptional protein modifications, i.e. phosphorylation or hypusination in the case of eIF5A. Although the lists of altered proteins were heterogeneous and compound-specific, gene ontology analyses identified rather similar profiles regarding the affected molecular functions. Ingenuity pathway analysis by IPA put the following factors in a central position of the hypothetical networks: myc and p53 for aaptamine; tumor necrosis factor (TNF) for demethyloxyaaptamine; and all three, myc, p53, and TNF for isoaaptamine. Our results represent an important step towards a better understanding of the molecular basis underlying the observed bioactivity of these promising marine compounds.BIOLOGICAL SIGNIFICANCE: We characterized the mode of action of three aaptamines, marine natural compound with anti-tumor activity, using a functional proteomics approach and the cisplatin-resistant pluripotent human embryonal carcinoma cell line NT2-R. The manuscript is of particular scientific interest, as we could reveal the similarities and differences of the modes of action. Furthermore, we were able to identify several new targets of these promising compounds. We found hypusination of eIF5A to be a prominent feature exclusively of aaptamine treatment, as this was not observed upon treatment with demethyloxyaaptamine or isoaaptamine. Our results are a step towards unraveling the mode of action of these interesting compounds.
AB - UNLABELLED: We analyzed the effects of all three marine alkaloids aaptamine, demethyloxyaaptamine and isoaaptamine in NT2-R, a cisplatin-resistant subline of the human embryonal carcinoma cell line NT2. All aaptamines were found to be equally effective in both cell lines, excluding cross-resistance between aaptamines and cisplatin in vitro. At the inhibitory concentration (IC50), aaptamine exerted an antiproliferative effect, whereas demethyloxyaaptamine and isoaaptamine were strong inducers of apoptosis. We analyzed the changes in the proteome of NT2-R cells treated with these compounds. 16-22 proteins were found to be significantly altered, of which several were validated by Western blotting and two-dimensional Western blotting analysis. Changes in the proteome pattern frequently resulted from post-transcriptional protein modifications, i.e. phosphorylation or hypusination in the case of eIF5A. Although the lists of altered proteins were heterogeneous and compound-specific, gene ontology analyses identified rather similar profiles regarding the affected molecular functions. Ingenuity pathway analysis by IPA put the following factors in a central position of the hypothetical networks: myc and p53 for aaptamine; tumor necrosis factor (TNF) for demethyloxyaaptamine; and all three, myc, p53, and TNF for isoaaptamine. Our results represent an important step towards a better understanding of the molecular basis underlying the observed bioactivity of these promising marine compounds.BIOLOGICAL SIGNIFICANCE: We characterized the mode of action of three aaptamines, marine natural compound with anti-tumor activity, using a functional proteomics approach and the cisplatin-resistant pluripotent human embryonal carcinoma cell line NT2-R. The manuscript is of particular scientific interest, as we could reveal the similarities and differences of the modes of action. Furthermore, we were able to identify several new targets of these promising compounds. We found hypusination of eIF5A to be a prominent feature exclusively of aaptamine treatment, as this was not observed upon treatment with demethyloxyaaptamine or isoaaptamine. Our results are a step towards unraveling the mode of action of these interesting compounds.
U2 - 10.1016/j.jprot.2013.11.009
DO - 10.1016/j.jprot.2013.11.009
M3 - SCORING: Journal article
C2 - 24269226
VL - 96
SP - 223
EP - 239
JO - J PROTEOMICS
JF - J PROTEOMICS
SN - 1874-3919
ER -