1. Biochemistry and Chemical Biology
  2. Cancer Biology
Download icon

Anti-Cancer Drugs: The mitochondrial paradox

  1. Sophie L Penman
  2. Rebecca L Jensen
  3. Robyn T Kiy
  4. Amy E Chadwick  Is a corresponding author
  1. MRC Centre for Drug Safety Science, University of Liverpool, United Kingdom
  2. Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom
  • Cited 0
  • Views 1,583
  • Annotations
Cite this article as: eLife 2020;9:e59140 doi: 10.7554/eLife.59140


A structural motif that is found in two cancer drugs may be responsible for their ability to tackle cancers and for the side-effects caused by the drugs.

Main text

Organelles called mitochondria are often referred to as the powerhouse of a cell because they make the molecules of ATP that the cell uses as a source of energy. The toxic side-effects of some medicines are caused by the drug inadvertently disrupting the workings of mitochondria (Nadanaciva and Will, 2011). The heart is particularly susceptible to such side-effects because cardiac cells contain large numbers of mitochondria to meet the energy demands of heart tissue (Park et al., 2014; Varga et al., 2015). Understanding how this toxicity arises is important so it can be avoided when designing and developing new treatments. However, it can be diffucult to determine which part of the drug causes these toxic side-effects.

Now, in eLife, Anne Willis (University of Cambridge) and colleagues – including Zoë Stephenson as first author – report details of a chemical structure in the anti-cancer drug mubritinib, which inhibits the mitochondria of cardiac cells and causes an unintended rise in toxicity (Stephenson et al., 2020). Previous work had shown that mubritinib disrupts the phosphorylation of a protein called HER2 that is known to promote the growth of cancer cells (Nagasawa et al., 2006). However, during tests, Stephenson et al. found that increasing the concentration of mubritinib did not hinder this protein to the same degree as a drug called lapatinib, which is known to work by inhibiting HER2. This suggested that mubritinib does not directly inhibit HER2 and that another mechanism is likely to be responsible for its anti-cancer effects.

As mubritinib is known to affect pathways that are linked to cellular energy, the researchers – who are based at University of Cambridge and the University of Nottingham – decided to investigate how this drug impacted the production of ATP in cardiac cells cultured in two media: glucose and galactose. Cells cultured in galactose rely more heavily on mitochondria for ATP production than cells cultured in glucose, so are more susceptible to compounds that target this organelle (Marroquin et al., 2007). Stephenson et al. found that, following drug treatment, the cells in galactose produced less ATP and had a lower frequency of beating than the cells in glucose. This suggests that mubritinib impairs the activity of the electron transport chain which drives the synthesis of ATP (Figure 1). Further analysis revealed that mubritinib inhibits a particular structure within this chain called 'complex I'.

A structural motif in two anti-cancer drugs disrupts the production of ATP.

Mitochondria (top left) make the ATP molecules that provide cells with energy. Chains of protein complexes called electron transporters (purple; labelled I, II, III, IV and V) are embedded in the inner membrane of mitochondria. The first complex in this chain (complex I) converts NADH to NAD+ by removing an electron (middle panel), which then gets shuttled between the different complexes in the chain. This allows the complexes to actively transport protons (H+) into the space between the inner and outer membrane of the mitochondrion. The diffusion of these protons back across the inner membrane (downward black arrow) drives the enzyme that synthesizes ATP molecules. Two anti-cancer drugs, mubritinib and carboxyamidotriazole, contain a motif (top right) which inhibits complex I and consequently disrupts the production of ATP. Stephenson et al. found that inhibiting complex I in cancer cells led to reduced growth and increased death (bottom left), whereas inhibiting complex I in cardiac cells caused the cells to beat less frequently due to the reduction in ATP (bottom right).

Image credit: Sophie Penman.

Next, Stephenson et al. investigated a library of compounds which have a similar structure to mubritinib to identify the 'toxicophore' – the region of the drug that is causing the side-effects. This revealed that a region called the heterocyclic 1,3 nitrogen motif was responsible for inhibiting complex I and reducing the production of ATP (Figure 1).

The researchers then investigated the effects of an anti-cancer drug called carboxyamidotriazole that contains the same toxicophore structure. This drug is thought to block the progress of cancer by inhibiting specific ion channels that transport calcium ions into the cell (Singh et al., 2017). However, Stephenson et al. found that carboxyamidotriazole did not significantly bind to calcium channels. Instead, they discovered that the drug reduced the production of ATP in galactose media and decreased the amount of oxygen taken up by cardiac cells.

Finally, to identify whether the heterocyclic 1,3 nitrogen motif was responsible for the anti-cancer effects of both drugs, Stephenson et al. measured the growth and death rate of cancer cells following treatment. Cell lines representing five different cancer types were treated with mubritinib, carboxyamidotriazole, or structurally similar compounds which lacked the toxicophore. In each cell line they tested, the presence of the toxicophore resulted in increased levels of cell death and reduced rates of cell growth (Figure 1). This suggests that the toxicophore in these two drugs is also partially responsible for their anti-cancer effects.

These findings provide evidence of a chemical motif which increases the toxicity of cardiac cells by inadvertently targeting mitochondria. The identification of this motif could help design safer and more effective anti-cancer treatments. Furthermore, the method used in this study could be used to identify other chemical motifs which specifically disrupt the activity of mitochondria. Future research should test a larger collection of compounds containing this toxicophore to confirm whether the loss in mitochondrial activity is linked to adverse side effects. Furthermore, it is important to assess whether these effects only cause toxicity in the heart or whether other organs, such as the liver and kidney, may also be susceptible.


Article and author information

Author details

  1. Sophie L Penman

    Sophie L Penman is in the MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5326-1675
  2. Rebecca L Jensen

    Rebecca L Jensen is in the MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1134-2869
  3. Robyn T Kiy

    Robyn T Kiy is in the MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7960-7283
  4. Amy E Chadwick

    Amy E Chadwick is in the MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7399-8655

Publication history

  1. Version of Record published: June 25, 2020 (version 1)


© 2020, Penman et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 1,583
    Page views
  • 158
  • 0

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    2. Immunology and Inflammation
    Gerald Willimsky et al.
    Research Article

    Proteasome catalyzed peptide splicing (PCPS) of cancer-driving antigens could generate attractive neoepitopes to be targeted by TCR-based adoptive T cell therapy. Based on a spliced peptide prediction algorithm TCRs were generated against putative KRASG12V and RAC2P29L derived neo-splicetopes with high HLA-A*02:01 binding affinity. TCRs generated in mice with a diverse human TCR repertoire specifically recognized the respective target peptides with high efficacy. However, we failed to detect any neo-splicetope specific T cell response when testing the in vivo neo-splicetope generation and obtained no experimental evidence that the putative KRASG12V- and RAC2P29L-derived neo-splicetopes were naturally processed and presented. Furthermore, only the putative RAC2P29L-derived neo-splicetopes was generated by in vitro PCPS. The experiments pose severe questions on the notion that available algorithms or the in vitro PCPS reaction reliably simulate in vivo splicing and argue against the general applicability of an algorithm-driven 'reverse immunology' pipeline for the identification of cancer-specific neo-splicetopes.

    1. Biochemistry and Chemical Biology
    Qiang Liu et al.
    Research Article

    The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted Syndrome in human. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular simulations and mutagenesis, we further uncovered key residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive updated therapeutics for skin inflammation.