Targeting cancer lactate metabolism with synergistic combinations of synthetic catalysts and monocarboxylate transporter inhibitors

Hannah E Bridgewater, Elizabeth M Bolitho, Isolda Romero-Canelón, Peter J Sadler, James P C Coverdale

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    1 Citation (Scopus)
    36 Downloads (Pure)

    Abstract

    Synthetic anticancer catalysts offer potential for low-dose therapy and the targeting of biochemical pathways in novel ways. Chiral organo-osmium complexes, for example, can catalyse the asymmetric transfer hydrogenation of pyruvate, a key substrate for energy generation, in cells. However, small-molecule synthetic catalysts are readily poisoned and there is a need to optimise their activity before this occurs, or to avoid this occurring. We show that the activity of the synthetic organometallic redox catalyst [Os(p-cymene)(TsDPEN)] (1), which can reduce pyruvate to un-natural D-lactate in MCF7 breast cancer cells using formate as a hydride source, is significantly increased in combination with the monocarboxylate transporter (MCT) inhibitor AZD3965. AZD3965, a drug currently in clinical trials, also significantly lowers the intracellular level of glutathione and increases mitochondrial metabolism. These synergistic mechanisms of reductive stress induced by 1, blockade of lactate efflux, and oxidative stress induced by AZD3965 provide a strategy for low-dose combination therapy with novel mechanisms of action. [Abstract copyright: © 2023. The Author(s).]
    Original languageEnglish
    Pages (from-to)345–353
    Number of pages9
    JournalJournal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry
    Volume28
    Issue number3
    Early online date8 Mar 2023
    DOIs
    Publication statusPublished - Apr 2023

    Bibliographical note

    Funding Information:
    We thank the Royal Society of Chemistry (grant no. E22-1637945680) and the University of Birmingham for support. P.J.S. thanks the EPSRC (grant no. EP/P030572/) and Anglo American Platinum for support.

    Publisher Copyright:
    © 2023, The Author(s).

    Funder

    We thank the Royal Society of Chemistry (grant no. E22-1637945680) and the University of Birmingham for support. P.J.S. thanks the EPSRC (grant no. EP/P030572/) and Anglo American Platinum for support. Publisher Copyright: © 2023, The Author(s).

    Keywords

    • Organometallic
    • Catalysis
    • Osmium
    • Redox
    • Cancer
    • AZD3965
    • Lactate

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