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Oxime bond-linked daunorubicin-GnRH-III bioconjugates exert antitumor activity in castration-resistant prostate cancer cells via the type I GnRH receptor

Oxime bond-linked daunorubicin-GnRH-III bioconjugates exert antitumor activity in castration-resistant prostate cancer cells via the type I GnRH receptor

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MARELLI, Marina Montagnani, Marilena MANEA, Roberta MORETTI, Monica MARZAGALLI, Patrizia LIMONTA, 2015. Oxime bond-linked daunorubicin-GnRH-III bioconjugates exert antitumor activity in castration-resistant prostate cancer cells via the type I GnRH receptor. In: International Journal of Oncology. 46(1), pp. 243-253. ISSN 1019-6439. eISSN 1791-2423

@article{Marelli2015Oxime-29509, title={Oxime bond-linked daunorubicin-GnRH-III bioconjugates exert antitumor activity in castration-resistant prostate cancer cells via the type I GnRH receptor}, year={2015}, doi={10.3892/ijo.2014.2730}, number={1}, volume={46}, issn={1019-6439}, journal={International Journal of Oncology}, pages={243--253}, author={Marelli, Marina Montagnani and Manea, Marilena and Moretti, Roberta and Marzagalli, Monica and Limonta, Patrizia} }

<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/29509"> <dcterms:abstract xml:lang="eng">It is well established that gonadotropin-releasing hormone receptors (GnRH-R) are expressed in different types of cancers, including castration-resistant prostate cancer (CRPC) and mediate the antiproliferative effect of GnRH analogs. Thus, these compounds are employed as targeting moieties to selectively deliver chemotherapeutic agents to cancer cells. GnRH-III, the decapeptide isolated from the sea lamprey brain, has lower potency than GnRH in stimulating gonadotropin secretion, but it exerts antiproliferative effects on many tumors expressing the GnRH-R. GnRH-III-based peptides are considered promising targeting moieties for the preparation of anticancer drug delivery systems. These studies were aimed at i) evaluating the antitumor activity of two cytotoxic oxime bond-linked daunorubicin (Dau)-GnRH-III derivative bioconjugates (Dau-GnRH-III, in which daunorubicin was coupled to the 8Lys in the native form of GnRH-III, and Dau-[4Lys(Ac)]-GnRH-III, in which daunorubicin was attached to the 8Lys of a GnRH-III derivative where 4Ser was replaced by an acetylated lysine) on CRPC cells; and ii) to elucidate the involvement of the classical GnRH-R (type I GnRH-R) in this antitumor activity. Our results demonstrated that both Dau-GnRH-III and Dau-[4Lys(Ac)]-GnRH-III were rapidly internalized into DU145 prostate cancer cells and exerted a significant cytostatic effect. Both bioconjugates increased the levels of the active form of caspase-3, indicating the involvement of apoptosis in their antitumor activity. The antiproliferative effect of both Dau-GnRH-III and Dau-[4Lys(Ac)]-GnRH-III was counteracted by the simultaneous treatment of the cells with Antide, an antagonist of the GnRH-R. Moreover, after silencing the type I GnRH-R the antitumor activity of both bioconjugates was completely abolished. These data demonstrate that in CRPC cells, daunorubicin-GnRH-III derivative bioconjugates: i) inhibit tumor cell proliferation, by triggering the apoptosis process; ii) exert their antitumor effect through the activation of the type I GnRH-R expressed on these cells. Cytotoxic-GnRH-III derivative may represent promising targeted chemotherapeutics for the treatment of CRPC patients.</dcterms:abstract> <dc:contributor>Limonta, Patrizia</dc:contributor> <dc:creator>Moretti, Roberta</dc:creator> <dc:creator>Marzagalli, Monica</dc:creator> <dcterms:issued>2015</dcterms:issued> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2015-01-14T14:25:31Z</dcterms:available> <dc:contributor>Manea, Marilena</dc:contributor> <dc:creator>Marelli, Marina Montagnani</dc:creator> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2015-01-14T14:25:31Z</dc:date> <dc:creator>Manea, Marilena</dc:creator> <dc:contributor>Marelli, Marina Montagnani</dc:contributor> <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/29509"/> <dc:contributor>Marzagalli, Monica</dc:contributor> <dc:contributor>Moretti, Roberta</dc:contributor> <dcterms:title>Oxime bond-linked daunorubicin-GnRH-III bioconjugates exert antitumor activity in castration-resistant prostate cancer cells via the type I GnRH receptor</dcterms:title> <dc:creator>Limonta, Patrizia</dc:creator> <dc:language>eng</dc:language> </rdf:Description> </rdf:RDF>

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