Further aspects of doxycycline therapy in COVID-19.

Dear Editor,

In their work, Conforti et al urge experts to broadly investigate the combination of doxycycline and hydroxychloroquine in treating coronavirus disease (COVID‐19). The tetracycline antibiotic doxycycline is a nontoxic inhibitor of mitochondrial biogenesis and cellular respiration besides other known pleiotropic properties. Now that the World Health Organization has just halted hydroxychloroquine trials for COVID‐19 because of safety reasons, the time has come to find auxiliary compounds so as to give additional benefit to doxycycline.

We also need to take into account that quite a lot of similarities in metabolic pathways of virally infected and cancer cells have been observed. Viruses usually target mitochondria as cellular power houses and various interplays have been detected between viruses and mitochondrial dynamics. Most viruses require aerobic glycolysis as the energy source for replication and its inhibition could attenuate this process.

Vitamin C is a broad‐spectrum antiviral agent and an inhibitor of aerobic glycolysis. The combined administration of doxycycline with vitamin C resulted in a robust eradication of cancer stem cells (CSCs) in in vitro experiments by blocking mitochondrial protein translation and ATP production from glycolysis. The addition of azithromycin further boosted CSC clearance.

Sargiacomo et al also proposed the use of doxycycline or azithromycin in COVID‐19. Their concept assumes that SARS‐CoV‐2 prefers chronologically aged, senescent lung cells for binding and replication causing stormy inflammation and subsequent fibrosis, suggesting the application of senolytic drugs such as doxycycline to prevent fibrotic transformation.

I believe that a combined approach regarding CSC elimination may be transmissible into antiviral therapy. Supplementation of doxycycline with the amplifier vitamin C may result in mitochondrial damage of virally compromised cells, the attenuation of immune response by the inhibition of glycolysis in pro‐inflammatory immune cells, and a stronger suppression on postinflammatory fibrosis than with doxycycline alone.

In vitro very low concentration of doxycycline is able to block mitochondria, and this antiinflammatory dose is approved up to a 12‐month use in rosacea so a prolonged course together with vitamin C may also be an inexpensive, safe, and promising approach in antiviral prophylaxis and treatment.