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Lysosome-targeted ruthenium(II) complex encapsulated with pluronic® F-127 induces oncosis in A549 cells

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Abstract

Transition metal complexes with characteristics of unique packaging in nanoparticles and remarkable cancer cell cytotoxicity have emerged as potential alternatives to platinum-based antitumor drugs. Here we report the synthesis, characterization, and antitumor activities of three new Ruthenium complexes that introduce 5-fluorouracil-derived ligands. Notably, encapsulation of one such metal complex, Ru3, within pluronic® F-127 micelles (Ru3-M) significantly enhanced Ru3 cytotoxicity toward A549 cells by a factor of four. To determine the mechanisms underlying Ru3-M cytotoxicity, additional in vitro experiments were conducted that revealed A549 cell treatment with lysosome-targeting Ru3-M triggered oxidative stress, induced mitochondrial membrane potential depolarization, and drastically reduced intracellular ATP levels. Taken together, these results demonstrated that Ru3-M killed cells mainly via a non-apoptotic pathway known as oncosis, as evidenced by observed Ru3-M-induced cellular morphological changes including cytosolic flushing, cell swelling, and cytoplasmic vacuolation. In turn, these changes together caused cytoskeletal collapse and activation of porimin and calpain1 proteins with known oncotic functions that distinguished this oncotic process from other cell death processes. In summary, Ru3-M is a potential anticancer agent that kills A549 cells via a novel mechanism involving Ru(II) complex triggering of cell death via oncosis.

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Acknowledgements

This work was supported by the Discipline Construction Project of Guangdong Medical University (4SG23004G), Dongguan Science and Technology of Social Development Program (20211800905082), the Key Scientific Research Projects of Colleges and Universities in Guangdong Province (2020ZDZX2031), and Medical Industry Innovation Project of Guangdong Medical University (4SG22305P).

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  1. Nanlian Pan, Yuqing Zhang and Minying Huang contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Guangdong Medical University, Dongguan, 523808, China

    Nanlian Pan, Yuqing Zhang, Minying Huang, Zhijun Liang, Yao Gong, Yuling Li, Ciling Wu & Jing Sun

  2. Department of Pharmacy, Dongguan People’s Hospital, Dongguan, 523059, China

    Nanlian Pan

  3. Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, 523808, China

    Zunnan Huang

  4. The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China

    Xide Chen & Jing Sun

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  1. Nanlian Pan
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Pan, N., Zhang, Y., Huang, M. et al. Lysosome-targeted ruthenium(II) complex encapsulated with pluronic® F-127 induces oncosis in A549 cells. J Biol Inorg Chem (2024). https://doi.org/10.1007/s00775-023-02039-5

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