Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum-Resistant Metastatic CRC and CRPC Cell Models |
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Authors: | Ariadna Lázaro Cristina Balcells Dr Josefina Quirante Prof Josefa Badia Prof Laura Baldomà Dr Jas S Ward Prof Kari Rissanen Dr Mercè Font-Bardia Prof Laura Rodríguez Dr Margarita Crespo Prof Marta Cascante |
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Institution: | 1. Dpt de Química Inorgànica i Orgànica, Secció de Química Inorgànica, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1–11, 08028 Barcelona, Spain;2. Dpt. of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain;3. Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27–31, 08028 Barcelona, Spain;4. Dpt de Bioquímica i Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27–31, 08028 Barcelona, Spain;5. Dpt of Chemistry, Nanoscience Center, University of Jyvaskyla, P.O. Box 35, Jyvaskyla, 40014 Finland;6. Unitat de difracció de RX, CCiTUB, Universitat de Barcelona, Solé i Sabarís 1–3, 08028 Barcelona, Spain |
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Abstract: | Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N′)PtIV compounds derived from amine–imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs. |
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Keywords: | anticancer drugs biological activity chemotherapeutic resistance luminescence platinum |
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