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

ABSTRACT: 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.

SUBMITTER: Pierroz V

PROVIDER: S-EPMC5032677 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Effective delivery of luminescent probes for cell imaging requires both cell membrane permeation and directing to discrete target organelles. Combined, these requirements can present a significant challenge for metal complex luminophores, that have excellent properties as imaging probes but typically show poor membrane permeability. Here, we report on highly luminescent Ruthenium polypyridyl complexes based on the parent; [Ru(dpp)2(x-ATAP)](PF6)2 structure, where dpp is 4,7-diphenyl-1,10-phenanthroline and x-ATAP is 5-amino-1,10-phenanthroline with pendant alkyl-acetylthio chains of varying length; where x is 6; 5-Amido-1,10-phenanthroline-(6-acetylthio-hexanyl). 8; 5-Amido-1,10-phenanthroline-(8-acetylthio-octanyl). 11; 5-Amido-1,10-phenanthroline-(11-acetylthio-undecanyl); and 16; 5-Amido-1,10-phenanthroline-(16-acetylthio-hexadecanyl). Soluble in organic media, the alkyl-acetylthiolated complexes form nanoaggregates of low polydispersity in aqueous solution. From dynamic light scattering the nanoaggregate diameter was measured as 189 nm and 135 nm for 5 × 10-6 M aqueous solutions of [Ru(dpp)2(N∧N)](PF6)2 with the hexadecanoyl and hexanyl tails respectivly. The nanoaggregate exhibited dual exponential emission decays with kinetics that matched closely those of the [Ru(dpp)2(16-ATAP)]2+ incorporated into the membrane of a DPPC liposome. Cell permeability and distribution of [Ru(dpp)2(11-ATAP)]2+ or [Ru(dpp)2(16-ATAP)]2+ were evaluated in detail in live HeLa and CHO cell lines and it was found from aqueous media, that the nanoaggregate complexes spontaneously cross the membrane of mammalian cells. This process seems, on the basis of temperature dependent studies to be activated. Fluorescence imaging of live cells reveal that the complexes localize highly specifically within organelles and that organelle localization changes dramatically in switching the pendent alkyl chains from C16 to C11 as well as on cell line identity. Our data suggests that building metal complexes capable of self-assembling into nano-dimensional vesicles in this way may be a useful means of promoting cell membrane permeability and driving selective targeting that is facile and relatively low cost compared to use of biomolecular vectors.

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

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Dataset Information

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

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OmicsDI is part of the ELIXIR infrastructure

Tweets

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