title: Anticancer activity of the lanthanum compound [tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772; FFC24).
abstract: 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 microM 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.
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Wilfried
authors.initials: W
authors.lastname: Körner
authors.forename: Stefan
authors.initials: S
authors.lastname: Wild
authors.forename: Nikolai Graf
authors.initials: NG
authors.lastname: von Keyserlingk
authors.forename: Leonilla
authors.initials: L
authors.lastname: Elbling
authors.forename: Haralabos
authors.initials: H
authors.lastname: Zorbas
authors.forename: Alla
authors.initials: A
authors.lastname: Korynevska
authors.forename: Siegfried
authors.initials: S
authors.lastname: Knasmüller
authors.forename: Hedwig
authors.initials: H
authors.lastname: Sutterlüty
authors.forename: Michael
authors.initials: M
authors.lastname: Micksche
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles; D001761:Bleomycin / Q000494:pharmacology; D002232:Carbocyanines; D020169:Caspases / Q000096:biosynthesis; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes; D016193:G1 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007275:Injections, Intravenous; D007364:Intercalating Agents / Q000494:pharmacology; D007811:Lanthanum / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010618:Phenanthrolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002232:Carbocyanines; D005456:Fluorescent Dyes; D007364:Intercalating Agents; D019384:Nucleic Acid Synthesis Inhibitors; D009942:Organometallic Compounds; D010618:Phenanthrolines; D016159:Tumor Suppressor Protein p53; C508982:tris(1,10-phenanthroline)lanthanum(III); D001761:Bleomycin; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D007811:Lanthanum; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases