Mitochondria as oncotarget: a comparison between the tetracycline analogs doxycycline and COL-3.

Margherita Protasoni,Jan-Willem Taanman,Albert M Kroon

doi:10.18632/oncotarget.26107

Margherita Protasoni, Jan-Willem Taanman + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.26107

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Journal: Oncotarget	Publication Date: Sep 18, 2018
Citations: 19	License type: cc-by

Affiliation: University College London

Abstract

Tetracyclines have anticancer properties in addition to their well-known antibacterial properties. It has been proposed that tetracyclines slow metastasis and angiogenesis through inhibition of matrix metalloproteinases. However, we believe that the anticancer effect of tetracyclines is due to their inhibition of mitochondrial protein synthesis, resulting in a decrease of the mitochondrial energy generating capacity. Several groups have developed analogs that are void of antibacterial action. An example is COL-3, which is currently tested for its anticancer effects in clinical trials. We have undertaken a comparative study of the tetracycline analogs COL-3 and doxycycline, which has an antibacterial function, to further investigate the role of the mitochondrial energy generating capacity in the anticancer mechanism and, thereby, evaluate the usefulness of mitochondria as an oncotarget. Our experiments with cultures of the human A549, COLO357 and HT29 cancer cells and fibroblasts indicated that COL-3 is significantly more cytotoxic than doxycycline. Mitochondrial translation assays demonstrated that COL-3 has retained its inhibitory effect on mitochondrial protein synthesis. Both drugs caused a severe decrease in the levels of mitochondrially encoded cytochrome-c oxidase subunits and cytochrome-c oxidase activity. In addition, COL-3 produced a marked drop in the level of nuclear-encoded succinate dehydrogenase subunit A and citrate synthase activity, indicating that COL-3 has multiple inhibitory effects. Contrary to COL-3, the anticancer action of doxycycline appears to be based specifically on inhibition of mitochondrial protein synthesis, which is thought to affect rapidly proliferating cancer cells more than healthy tissue. Doxycycline is likely to cause less side effects that COL-3.

Highlights

Tetracyclines are antibiotics that inhibit bacterial protein synthesis by binding to the small ribosomal subunit and blocking the attachment of aminoacyltRNAs to the A site on the ribosome
We investigated the effect of the drugs on de novo mitochondrial protein synthesis, followed by an assessment of the levels and enzymatic activity of several mitochondrial proteins over a 5-day treatment period
Toxicity for COL-3 is already apparent at concentrations that may be reached in clinical studies

Summary

Introduction

Tetracyclines are antibiotics that inhibit bacterial protein synthesis by binding to the small ribosomal subunit and blocking the attachment of aminoacyltRNAs to the A site on the ribosome. The two long edges of this skeleton show a notable difference in the distribution of polar groups, producing a preference for hydrophobic interactions on one face and for hydrogen bonding on the other. This spatial arrangement is believed to be essential for the interaction with the small ribosomal subunit [1]. Doxycycline (DC; Figure 1) is one of the most commonly prescribed tetracycline derivatives It is an inexpensive and safe drug, in use for more than 50 years to treat or prevent bacterial infections. It has optimal pharmacokinetic properties in humans and produces no bacterial resistance at a contra-indicative rate [2]

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