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Dual mode of cell death upon the photo-irradiation of a RuII polypyridyl complex in interphase or mitosis.
Journal article

Dual mode of cell death upon the photo-irradiation of a RuII polypyridyl complex in interphase or mitosis.

  • Pierroz V Institute of Molecular Cancer Research , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland . Email: sferrari@imcr.uzh.ch ; http://www.imcr.uzh.ch/research/Ferrari.html ; ; Tel: +41 44 635 3471 ; Department of Chemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland . Email: gilles.gasser@chem.uzh.ch ; http://www.gassergroup.com ; Fax: +41 44 635 6803 ; Tel: +41 44 635 4630.
  • Rubbiani R Department of Chemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland . Email: gilles.gasser@chem.uzh.ch ; http://www.gassergroup.com ; ; Tel: +41 44 635 4630.
  • Gentili C Institute of Molecular Cancer Research , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland . Email: sferrari@imcr.uzh.ch ; http://www.imcr.uzh.ch/research/Ferrari.html ; ; Tel: +41 44 635 3471.
  • Patra M Department of Chemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland . Email: gilles.gasser@chem.uzh.ch ; http://www.gassergroup.com ; ; Tel: +41 44 635 4630.
  • Mari C Department of Chemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland . Email: gilles.gasser@chem.uzh.ch ; http://www.gassergroup.com ; ; Tel: +41 44 635 4630.
  • Gasser G Department of Chemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland . Email: gilles.gasser@chem.uzh.ch ; http://www.gassergroup.com ; ; Tel: +41 44 635 4630.
  • Ferrari S Institute of Molecular Cancer Research , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland . Email: sferrari@imcr.uzh.ch ; http://www.imcr.uzh.ch/research/Ferrari.html ; ; Tel: +41 44 635 3471.
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  • 2016-10-07
Published in:
  • Chemical science. - 2016
English Photodynamic therapy (PDT) is an attractive, complementary medical technique to chemotherapy. Among the different photosensitizers (PSs) employed, Ru(ii) polypyridyl complexes were found to be valid substitutes to porphyrin-based or phthalocyanine-based PSs. Here, we confirm that one such complex, namely [Ru(bipy)2-dppz-7-methoxy][PF6]2 (Ru65), which localizes in the nucleus of various cancer and normal cells, displays cytotoxicity only upon UV-A irradiation. Importantly, we disclose the molecular mechanism of the UV-A mediated cytotoxic action of Ru65. We demonstrate that Ru65 intercalates in DNA and, upon light irradiation, promotes guanine oxidation, resulting in nicks in the double helix. We confirm this mechanism of action in living cells, showing that the UV-A irradiation of cells loaded with Ru65 results in a transient DNA damage response and cell death. Strikingly, the photo-irradiation of Ru65 triggered distinct mechanisms of cell death in interphase or mitotic cells. The former underwent cell cycle arrest at the G2/M phase and massive cytoplasmic vacuolation, which was paralleled by an unfolded-protein stress response, resulting in a reduction of viability and cell death through a paraptosis-like mechanism. On the other hand, the UV-A irradiation of Ru65 in cells synchronized by G2/M block-release with a selective CDK1 inhibitor led to blocking mitotic entry and rapid cell death through classic apoptotic pathways. Importantly, targeting mitotic cells with Ru65 allowed increasing its photo-toxicity by a factor of 3.6. Overall, our findings show that the use of a combination of a cell cycle inhibitor and a PS targeting the nucleus could open up new avenues in PDT.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/91546
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