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Mitochondria as therapeutic targets for cancer chemotherapy

Abstract

Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged α-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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Abbreviations

ADD70:

AIF-derived decoy of heat shock protein 70

AIF:

apoptosis-inducing factor

Akt:

v-akt murine thymoma viral oncogene homolog

ANT:

adenine nucleotide translocator

Bad:

Bcl-2 antagonist of cell death

Bak:

Bcl-2 antagonist/killer

Bax:

Bcl-2-associated X protein

Bcl-2:

B-cell lymphoma protein 2

Bcl-XL:

B-cell lymphoma X protein, long splicing isoform

BH:

Bcl-2 homology domain

Bid:

BH3 interacting domain death agonist

Bim:

Bcl-2-interacting mediator of cell death

CD437:

6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid

CsA:

cyclosporin A

CypD:

cyclophilin D

cyt c:

cytochrome c

ΔΨm:

mitochondrial transmembrane potential

ErbB-2:

v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2

GSAO:

4-(N-(S-lutathionylacetyl)amino)phenylarsenoxide

HSP70:

heat shock 70 kDa protein

IAP:

inhibitor of apoptosis protein

IM:

mitochondrial inner membrane

MEF:

mouse embryonic fibroblasts

MOMP:

mitochondrial outer membrane permeabilization

Noxa:

synonym of PMAIP1 (phorbol-12-myristate-13-acetate-induced protein 1)

OM:

mitochondrial outer membrane

PBR:

peripheral-type benzodiazepine receptor

PK11195:

1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide

Ppif:

peptidyl-prolyl cis-trans isomerase F

PTPC:

permeability transition pore complex

Puma/Bbc3:

p53-upregulated modulator of apoptosis/Bcl-2-binding component 3

Ras:

rat sarcoma viral oncogene homolog

ROS:

reactive oxygen species

Smac/DIABLO:

second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point

VDAC:

voltage-dependent anion channel

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Acknowledgements

This work was supported by a Special Grant from the Ligue Nationale contre le Cancer, European Union (projects RIGHT and Trans-Death) and Ministère pour la Recherche. LG receives a fellowship from Region 92.

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Galluzzi, L., Larochette, N., Zamzami, N. et al. Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 25, 4812–4830 (2006). https://doi.org/10.1038/sj.onc.1209598

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