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Pro-oxidant response and accelerated ferroptosis caused by synergetic Au(I) release in hypercarbon-centered gold(I) cluster prodrugs

Author

Listed:
  • Kui Xiao

    (Tsinghua University)

  • Niyuan Zhang

    (National Center for Nanoscience and Technology (NCNST))

  • Feifei Li

    (Tsinghua University)

  • Dayong Hou

    (National Center for Nanoscience and Technology (NCNST)
    the Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology
    Harbin Medical University)

  • Xiaoyi Zhai

    (Tsinghua University)

  • Wanhai Xu

    (the Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology
    Harbin Medical University)

  • Gelin Wang

    (Tsinghua University)

  • Hao Wang

    (National Center for Nanoscience and Technology (NCNST))

  • Liang Zhao

    (Tsinghua University)

Abstract

Medicinal applications of gold complexes have recently attracted attention due to their innovative antitumor mechanisms. In this work, two hypercoordinated carbon-centered gold clusters PAA4 and PAA5 are quantitatively synthesized by an intramolecular 6-exo-dig cyclization of polymetalated precursors. The on-bench and in vitro experimental studies demonstrate that the characteristic hypercarbon-tetragold(I) multi-center bonding in PAA4 and PAA5 not only guarantees their stability under common physiological conditions, but also facilitates a glutathione (GSH)-triggered prompt and synergetic release of active Au(I) ions in the GSH-overexpressed and acidic microenvironment of human bladder cancer EJ cells. The instantly massive release of coordination unsaturated Au(I) ions causes the efficient inhibition of thioredoxin reductases and then induces a rapid pro-oxidant response, consequently causing the occurrence of accelerated ferroptosis of EJ cells. As a result, these hypercarbon-centered gold(I) cluster prodrugs show high cytotoxicity to bladder cancer cell lines and thus exhibit a significant inhibition effect towards bladder tumors in vivo. Correlation of the synergetic domino dissociation of carbon-polymetal multi-center bonding in metal clusters with the accelerated ferroptosis of cancer cells provides a strategy for metallo-prodrugs and opens a broader prospect for the biological application of metal cluster compounds.

Suggested Citation

  • Kui Xiao & Niyuan Zhang & Feifei Li & Dayong Hou & Xiaoyi Zhai & Wanhai Xu & Gelin Wang & Hao Wang & Liang Zhao, 2022. "Pro-oxidant response and accelerated ferroptosis caused by synergetic Au(I) release in hypercarbon-centered gold(I) cluster prodrugs," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32474-y
    DOI: 10.1038/s41467-022-32474-y
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    References listed on IDEAS

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    1. Jun Yuan & Tingting Sun & Xin He & Ke An & Jun Zhu & Liang Zhao, 2016. "Synthesis of tetra- and octa-aurated heteroaryl complexes towards probing aromatic indoliums," Nature Communications, Nature, vol. 7(1), pages 1-8, September.
    2. Kui Xiao & Yu Zhao & Jun Zhu & Liang Zhao, 2019. "Hyperconjugative aromaticity and protodeauration reactivity of polyaurated indoliums," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    3. Chao Mao & Xiaoguang Liu & Yilei Zhang & Guang Lei & Yuelong Yan & Hyemin Lee & Pranavi Koppula & Shiqi Wu & Li Zhuang & Bingliang Fang & Masha V. Poyurovsky & Kellen Olszewski & Boyi Gan, 2021. "DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer," Nature, Nature, vol. 593(7860), pages 586-590, May.
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