Anticancer activity of the lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)] trithiocyanate (KP772; FFC24)

Autor(en)

Petra Heffeter, Michael Jakupec, Wilfried Körner, Stefan Wild, Nikolai Graf v. Keyserlingk, Leonilla Elbling, Haralabos Zorbas, Alla Korynevska, Siegfried Knasmüller, Hedwig Sutterlüty, Michael Micksche, Bernhard Keppler, Walter Berger

Abstrakt

Aim of this study was to investigate the anticancer properties of the new lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772; FFC24). In vitro, growth inhibition by KP772 was comparable for >60 tumour cell models with IC50 values generally in the low ¿M range. KP772 induced tumour cell apoptosis indicated by chromatin condensation, caspase substrate cleavage and mitochondrial membrane depolarisation. DNA is unlikely to represent the primary molecular target of KP772, as no significant interaction or damage of DNA was detectable both in vitro and in living cells. Moreover, we found no evidence for induction of radical species. In contrast, KP772 potently inhibited DNA synthesis paralleled by a massive block of cell cycle in G0/G1 phase and a selective decrease of cyclin B1. Although treatment with KP772 induced expression of p53 and p21Waf1, transfection of wild-type p53 into knock-out cells only marginally enhanced the cytostatic activity of KP772. In vivo, the anticancer activity of KP772 against human DLD-1 colon carcinoma xenografts was comparable to that of cisplatin and methotrexate at doses not causing significant adverse effects. With regard to toxicity, the LD50 and no-observed-adverse- effect levels (NOAEL) of KP772 in Sprague-Dawley rats were 21.6 and 7.5 mg/kg, in outbred albino mice 62 and 10 mg/kg, respectively. In summary, KP772 exerts anticancer activity via potent induction of cell cycle arrest and/or apoptosis and has promising in vivo anticancer activity against a human colon cancer xenograft. Together, these data suggest further development of KP772 as a new anticancer metal-drug. ¿ 2005 Elsevier Inc. All rights reserved.

Organisation(en)

Institut für Anorganische Chemie

Externe Organisation(en)

Medizinische Universität Wien, Ludwig-Maximilians-Universität München, Faustus Forschungs Compagnie GmbH, National Academy of Sciences of Ukraine (NASU)

Journal

Biochemical Pharmacology

Band

71

Seiten

426-440

Anzahl der Seiten

15

ISSN

0006-2952

Publikationsdatum

2006

Peer-reviewed

Ja

ÖFOS 2012

301206 Pharmakologie

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/ede4e34a-d5f5-443b-b253-e0f07a574915