Abstract
Mitochondria play a key role in the energy generation of cells. Here, we reassess the opportunities to fight cancer by manipulating the expression of mitochondrial DNA (mtDNA). The mtDNA encodes 13 polypeptides that are all critical for oxidative phosphorylation. Most cancers, if not all, use glycolysis as main bioenergetic pathway, despite the presence of oxygen. This is known as the Warburg effect and leads to disturbance of the mitocytoplasmic energy balance. Cytosolic ATP levels are kept high by the increased glycolysis, limiting the demand for ATP from mitochondria. The restricted ADP-ATP exchange across the mitochondrial membranes results in a high ATP/ADP ratio within the organelles and a high mitochondrial membrane potential. Together, these increase the cancer cell’s resistance to apoptosis. Although the increased glycolysis may enhance the survival of cancer cells, several lines of evidence suggest that mitochondrial activity remains indispensable for proliferation. Specific inhibition of mitochondrial protein synthesis, e.g. with doxycycline, results in a mitonuclear protein imbalance, decreasing the apoptotic threshold and preventing proliferation of various cancer types in vivo. The anti-cancer effects are achieved at serum levels that are present in patients treated with the antibiotic to combat infections. There is good evidence to consider further clinical investigations with doxycycline to substantiate its beneficial effects on cancer.
Highlights
Mitochondria, antibiotics and cancer In mammalian cells, the mitochondrial genome is a circular molecule encoding indispensable genetic information
A small number of genes has been preserved on mitochondrial DNA (mtDNA): 24 genes coding for the two rRNA and 22 tRNA species engaged in mitochondrial protein synthesis, and 13 genes coding for subunits of the mitochondrial ATP generating enzyme complexes of the oxidative phosphorylation system [2]
Synchronization of cancer cells as an opportunity in various treatment scenarios We have shown that inhibition of mitochondrial protein synthesis with doxycycline leads to proliferation arrest in the G1-phase of the cell cycle [9]
Summary
Mitochondria, antibiotics and cancer In mammalian cells, the mitochondrial genome (mtDNA) is a circular molecule encoding indispensable genetic information. In the 1980s, we found that tetracyclines cause a proliferation arrest of tumor cells in vitro as well as in vivo [8,9]. Lee and colleagues [6] showed that actinonin inhibited tumor cell growth in vitro and in vivo. Through interruption of the synthesis of mature mitochondrial proteins, actinonin and tetracyclines cause a dilution of functional oxphos complexes as a consequence of cell
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