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Targets and Strategies for the Mitochondrial Assault on Cancer

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Mitochondria: The Anti- cancer Target for the Third Millennium

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Abstract

Mitochondria-directed anti-cancer agents (“mitocans”) represent a novel approach to cancer therapy. To optimize their effectiveness researchers need to identify appropriate targets and mechanisms of action, and to adopt a molecular design and/or delivery strategy ensuring that the drugs act at the mitochondrial level. Here we review: (i) the major options available for mitochondrial targeting: so far most studies have taken advantage of the high mitochondrial transmembrane potential; (ii) one set of possible targets: membrane channels exploited as transducers of a death signal; (iii) the induction of redox stress at mitochondria as a promising approach to cancerous cell destruction.

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Abbreviations

AIF:

Apoptosis-Inducing Factor

ALS:

Amyotrophic Lateral Sclerosis

ANT:

Adenine Nucleotide Translocator (exchanger)

ATR:

Atractyloside

BGK:

Bongkrekate

BLM:

Black Lipid Membrane (planar bilayer)

CAT:

Catalase

ChTx:

Charybdotoxin

CNS:

Central Nervous System

COX:

Cyclooxigenase

CSA:

Cyclosporin A

Cyp D:

Cyclophilin D

Δψ:

mitochondrial transmembrane electrical potential

EndoG:

Endonuclease G

eNOS:

endothelial NO Synthase

ER:

Endoplasmic Reticulum

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GSK:

Glycogen Synthase Kinase

HIF:

Hypoxia-Inducible Factor

HK:

Hexokinase

HPC:

Hypoxic preconditioning

HSP:

Heat Shock Protein

IbTx:

Iberiotoxin

IMM:

Inner Mitochondrial Membrane

I/R:

Ischemia/Reperfusion

MAC:

Mitochondrial Apoptosis-induced Channel

MCU:

Mitochondrial Ca2+ Uniporter

MEF:

Mouse Embryonic Fibroblast

MgTx:

Margatoxin

mitoVES:

mitochondria-targeted Vitamin E Succinate

MPTP:

Mitochondrial Permeability Transition Pore

mtBzR:

mitochondrial Benodiazepine Receptor

OMM:

Outer Mitochondrial membrane

PE:

PhosphatidylEthanolamine

PEG:

PolyEthyleneGlycol

PHDs:

Prolyl Hydroxylase Domain enzymes

PM:

Plasma Membrane

PPi:

Pyrophosphate

PTX:

Paclitaxel

RIPK1:

Receptor-Interacting serine/threonine-Protein Kinase 1

ROS:

Reactive Oxygen Species

ShK:

Stichodactyla toxin

SOD:

Superoxide Dismutase

SR:

Sarcoplasmic Reticulum

TNF:

Tumour Necrosis Factor

TPP:

Triphenylphosphonium

TRAIL:

TNF-Related Apoptosis-Inducing Ligand

TRAP-1:

Tumour necrosis factor Receptor-Associated Protein-1

TSPO:

Translocator Protein

VDAC:

Voltage-Dependent Anion Channel (mitochondrial porin)

WT:

Wild Type

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Acknowledgements

The authors are grateful to the funding agencies supporting their work. The following are specifically acknowledged: an Italian Association for Cancer Research grant (to I.S. n. 11814), Progetti di Rilevante Interesse Nazionale (PRIN) grants (20107Z8XBW_004 to M.Z. and 2010CSJX4F_005 to I.S.), a Fondazione Cassa di Risparmio di Padova e Rovigo (CARIPARO) grant (to M.Z.).

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Authors and Affiliations

  1. CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, Viale Giuseppe Colombo 3, 35131, Padova, Italy

    Lucia Biasutto & Mario Zoratti

  2. Department of Biology, University of Padova, Padova, Italy

    Ildikò Szabò

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  1. Lucia Biasutto
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  2. Ildikò Szabò
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  3. Mario Zoratti
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Correspondence to Mario Zoratti .

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Editors and Affiliations

  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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Biasutto, L., Szabò, I., Zoratti, M. (2014). Targets and Strategies for the Mitochondrial Assault on Cancer. 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_9

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