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Emerging Anti-cancer Targets in Mitochondria

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Mitochondria: The Anti- cancer Target for the Third Millennium

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Abstract

Metabolic cancer therapy should target the most aggressive and malignant tumour cells within solid tumours. Targeting of mitochondrial isocitrate dehydrogenase-2 (IDH2) by inhibitors or silencing elements would eliminate tumour cells surviving the harsh conditions of hypoxia and intermittent aglycemia as well as in progressive stages of malignancies with mutant IDH2 or IDH1, producing the oncometabolite D-2-hydroxyglutarate. Strategies for its withdrawal should also be exploited. Also, cancer-specific mitochondria-located enzymes participating in aerobic glycolysis are suitable targets of anti-cancer strategies, such as inhibition of hexokinase-2 by the small molecule 3-bromopyruvate or by post-transcriptional repression of hexokinase-2 by microRNA-143. Similarly, dichloroacetate (DCA) has been considered as a potential cancer therapeutic agent, being an efficient inhibitor of four isoforms of pyruvate dehydrogenase kinases (PDK), which by phosphorylating the E1 subunit inhibit pyruvate dehydrogenase and channel pyruvate to lactate. This, in turn, establishes the glycolytic phenotype of cancer cells. Other targets include for example the inhibitor protein of the mitochondrial ATP synthase and the facilitator of its degradation, the immediate-response factor 1 (IEX1), for which strategies dependent on the specific conditions should be exploited. However, there has been a limited number of clinical studies documenting the significance of mitochondrial targeting in cancer therapies.

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Acknowledgements

The project was supported by the Grant Agency of the Czech Republic grant P301/12/P308 to K.S.

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Authors and Affiliations

  1. Department of Membrane Transport Biophysics, Institute of Physiology, Academy of Sciences of the Czech Republic, No. 75, 142 20, Prague 4, Czech Republic

    Petr Ježek, Katarína Smolková, Aleš Dvořák & Tomáš Olejár

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  1. Petr Ježek
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  2. Katarína Smolková
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  3. Aleš Dvořák
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  4. Tomáš Olejár
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Correspondence to Petr Ježek .

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  1. School of Medical Science, Griffith University, Southport, Queensland, Australia

    Jiri Neuzil

  2. School of Medicine, National University of Singapore, Singapore, Singapore

    Shazib Pervaiz

  3. Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt, Germany

    Simone Fulda

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Ježek, P., Smolková, K., Dvořák, A., Olejár, T. (2014). Emerging Anti-cancer Targets in Mitochondria. In: Neuzil, J., Pervaiz, S., Fulda, S. (eds) Mitochondria: The Anti- cancer Target for the Third Millennium. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8984-4_10

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