A novel cyclometallated Pt(II)-ferrocene complex induces nuclear FOXO3a localization and apoptosis and synergizes with cisplatin to inhibit lung cancer cell proliferation.
Cisplatin is a platinum-based compound that acts as an alkylating agent and is used to treat a variety of malignant tumors including lung cancer. As cisplatin has significant limitations in the clinic, alternative platinum compounds such as cycloplatinated complexes have been considered as attractive anti-tumor agents. Here, we report the antiproliferative activity of a novel diastereomerically pure cycloplatinated complex (Sp,1S,2R)-[Pt{(κ(2)-C,N)[(η(5)-C5H3)-CH[double bond, length as m-dash]N-CH(Me)-CH(OH)-C6H5]Fe(η(5)-C5H5)}Cl(DMSO)] 6a, against A549 non-small cell lung cancer. Mechanistic studies revealed that compound 6a induces nuclear translocation of a FOXO3a reporter protein as well as endogenous FOXO3a in U2OS and A549 cells, respectively. Accordingly, treatment of A549 cells with compound 6a activates the intrinsic caspase pathway and dramatically increases the percentage of apoptotic cells. Furthermore, 6a displays a synergistic antiproliferative effect when applied together with cisplatin. Compound 6a is also active in other cancer cell lines including NCI-H460 large cell lung cancer cells. Importantly, antiproliferative activity of the platinacycle 6a on the non-tumor and non-proliferating 3T3-L1 cell line is weaker than in all cancer cell lines tested.
Department of Biochemistry and Molecular Biology, Faculty of Biology, and IBUB, Universitat de Barcelona, Unit Associated with CSIC Diagonal 645, E-08028-Barcelona, Spain. martacascante@ub.edu.
Roldán
R
Cortés
Míriam
M
Tarrado-Castellarnau
Daniel
D
Talancón
Concepción
C
López
Wolfgang
W
Link
Daniel
D
Ruiz
Josep Joan
JJ
Centelles
Josefina
J
Quirante
Marta
M
Cascante
D041721:3T3-L1 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005296:Ferrous Compounds / Q000737:chemistry / Q000494:pharmacology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000075163:Metallocenes; D051379:Mice; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects
D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D005296:Ferrous Compounds; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D000075163:Metallocenes; D009944:Organoplatinum Compounds; C004998:ferrocene