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Page 6 of 27 J Cancer Metastasis Treat 2019;5:5 I http://dx.doi.org/10.20517/2394-4722.2018.108

metabolism and growth through ketogenic diets, some others found no, or even pro-tumor effects. However,
all studies published to date that combined a ketogenic diet with radiotherapy have found a radiosensitizing
effect on tumor cells. Mechanisms include a selective increase in ROS and RNS production, ATP reduction
and epigenetic impairment of DNA repair through histone deacetylase inhibition by the ketone body
β-hydroxybutyrate, similar to the short chain fatty acid butyrate. The same mechanisms would not apply
to normal tissue which is metabolically flexible and even able to initiate an anti-oxidative stress response
when switching from glycolysis to mainly mitochondrial respiration fueled by fatty acids and ketone bodies.
The hypothesis is therefore that combining a ketogenic diet with radiotherapy could benefit cancer patients
in terms of larger tumor control probability for a given radiation dose without affecting or even decreasing
the probability of normal tissue toxicity. While this hypothesis has been confirmed in preclinical studies,
clinical data are limited thus far by small patient numbers, lack of control groups and lack of systematically
collecting hard clinical endpoints such as local tumor control, overall survival and radiotherapy-induced
side effects. However, there is some evidence that ketogenic diets could also benefit cancer patients in terms
of better maintaining lean body mass which would be relevant especially for frail patient population such as
those with head and neck or esophageal cancer. Given the proven safety of ketogenic diets when applied over
several weeks in cancer patients, their combination with radiotherapy (as well as other established cancer
treatments) deserves further study with a focus on important clinical endpoints.

8. Blocking the mitochondrial pyruvate carrier to inhibit lactate uptake by cancer cells and
induce tumor radiosensitization

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1
2
2
1
Cyril Corbet , Estelle Bastien , Lionel Mignion , Bénédicte F. Jordan , Arnaud Marchand ,
Patrick Chaltin , Holger M. Becker , Olivier Feron 1
3
4
1 Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels
B-1348, Belgium.
2 Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, UCLouvain, Brussels
B-1348, Belgium.
3 CISTIM Leuven, Center for Drug Design and Discovery (CD3) KU Leuven, Heverlee 3001, Belgium.
4 Division of Zoology/Membrane Transport, FB Biologie, TU Kaiserslautern, D-Kaiserslautern 67653, Germany.

Introduction: Lactate-based metabolic symbiosis between glycolytic and oxidative cancer cells is known
to facilitate tumor growth. Compounds with the capacity to block this lactate exchange thus represent
attractive therapeutic modalities to impact on tumor progression.

Experimental model: Several models, including Xenopus oocytes, 3D tumor spheroids and human
tumor xenografts in nude mice, were combined with state-of-the-art metabolomics strategies (Seahorse
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respirometry, in vitro C tracing experiments, and in vivo hyperpolarized C-pyruvate monitoring) to
characterize the mode of action of 7ACC2, an anticancer compound originally reported to block lactate
influx but not efflux.

Results: We identified 7ACC2 as a potent inhibitor of the mitochondrial pyruvate carrier (MPC) activity
which consecutively blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation.
Importantly, while both 7ACC2 and the MCT1 inhibitor AR-C155858 efficiently inhibited lactate influx,
only the former could also block compensatory oxidative glucose metabolism. Moreover, while in 3D tumor
spheroids MCT1 inhibition led to cystostatic effects, MPC activity blockade induced cytotoxic effects. This
potent growth inhibitory action associated with exacerbated 7ACC2-mediated metabolic alterations (i.e.,
blockade of lactate- and glucose-fueled TCA cycle) led to a reduction in hypoxia as proven in spheroids via
pimonidazole and carbonic anhydrase IX staining and in vivo through electron paramagnetic resonance