Anti-Cancer Drugs: The mitochondrial paradox

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.
  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

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.

References

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
    Aemercer@liverpool.ac.uk
    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)

Copyright

© 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.

Metrics

  • 2,158
    views
  • 206
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Sophie L Penman
  2. Rebecca L Jensen
  3. Robyn T Kiy
  4. Amy E Chadwick
(2020)
Anti-Cancer Drugs: The mitochondrial paradox
eLife 9:e59140.
https://doi.org/10.7554/eLife.59140

Further reading

    1. Biochemistry and Chemical Biology
    2. Plant Biology
    Henning Mühlenbeck, Yuko Tsutsui ... Cyril Zipfel
    Research Article

    Transmembrane signaling by plant receptor kinases (RKs) has long been thought to involve reciprocal trans-phosphorylation of their intracellular kinase domains. The fact that many of these are pseudokinase domains, however, suggests that additional mechanisms must govern RK signaling activation. Non-catalytic signaling mechanisms of protein kinase domains have been described in metazoans, but information is scarce for plants. Recently, a non-catalytic function was reported for the leucine-rich repeat (LRR)-RK subfamily XIIa member EFR (elongation factor Tu receptor) and phosphorylation-dependent conformational changes were proposed to regulate signaling of RKs with non-RD kinase domains. Here, using EFR as a model, we describe a non-catalytic activation mechanism for LRR-RKs with non-RD kinase domains. EFR is an active kinase, but a kinase-dead variant retains the ability to enhance catalytic activity of its co-receptor kinase BAK1/SERK3 (brassinosteroid insensitive 1-associated kinase 1/somatic embryogenesis receptor kinase 3). Applying hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis and designing homology-based intragenic suppressor mutations, we provide evidence that the EFR kinase domain must adopt its active conformation in order to activate BAK1 allosterically, likely by supporting αC-helix positioning in BAK1. Our results suggest a conformational toggle model for signaling, in which BAK1 first phosphorylates EFR in the activation loop to stabilize its active conformation, allowing EFR in turn to allosterically activate BAK1.

    1. Biochemistry and Chemical Biology
    2. Neuroscience
    Katarzyna Marta Zoltowska, Utpal Das ... Lucía Chávez-Gutiérrez
    Research Article

    Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17–42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.