DOXYCYCLINE: A TOOL TO REDUCE THE PROLIFERATION OF TUMOR CELLS AND
T-LYMPHOCYTES IN VIVO
Albert M. Kroon* and Jan-Willem Taanman
Department of Clinical and Movement Neurosciences,
Institute of Neurology, University College London, London, UK
In the 1960s, it was demonstrated, in isolated mitochondria, that the organelles contain their own DNA and a complete system for expression of this mitochondrial DNA (mtDNA). The translation of mtDNA-encoded genes could be inhibited by various antibiotics, including doxycycline. The initial skepticism with respect to the inhibitory effects of the antibacterial drugs muted when: (1) in vitro, sterile mitochondria were shown to remain sensitive to antibiotics, and (2) the structure and genetic content of mtDNA was characterized. The inhibition of these antibiotics is based on properties that mitochondrial ribosomes have in common with bacterial ribosomes, as a remnant of their common evolutionary origin.
In addition to the RNAs involved in translation, the mtDNA encodes 13 polypeptides. These are all indispensable for oxidative phosphorylation. If absent, oxygen-dependent ATP production ceases. Doxycycline inhibits mitochondrial protein synthesis effectively in vitro and in vivo at concentrations that are reached in serum with the standard dosage used to treat Lyme disease and Q fever. During clonal cell proliferation, doxycycline will reduce the energy generating capacity of the mitochondria in the daughter cells by up to 50% per cell division. After a few cell cycles, this capacity will drop below the apoptotic limit and induce programmed cell death.
Because of the shared properties of mitochondria and bacteria, we speculated that the doxycycline-driven apoptosis could be applied to diseases caused by clonal proliferation. Here, we give a historic and personal account of the experiments that convinced us that doxycycline may become an important player in the fight against these disorders, including cancer and T-cell proliferation-related diseases. Experiments in animal models have shown that T-cell lymphoma can be cured with doxycycline. In addition, retrospective clinical observations have revealed that doxycycline increases the life expectancy of patients with throat cancer. We advise to prioritize clinical trials with this inexpensive and safe drug that has been in use for more than 50 years.