Proton pump inhibitors for the treatment of cancer in companion animals

The treatment of cancer presents a clinical challenge both in human and veterinary medicine. Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects. A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell. The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis. Human clinical trials have prompted to consider this as a viable and safe option for the treatment of cancer in companion animals. Preliminary animal studies suggest that the same positive outcome could be achievable. The purpose of this review is to support investigations into the use of PPIs for cancer treatment cancer in companion animals by considering the evidence available in both human and veterinary medicine

Effects of extracellular pH reductions on [3H]D-aspartate and [3H]noradrenaline release by presynaptic nerve terminals isolated from rat cerebral cortex.

We analyzed the effects of extracellular pH reductions on the release of [(3)H]D: -aspartate ([(3)H]D: -ASP) and [(3)H]noradrenaline ([(3)H]NA) from cerebrocortical synaptosomes isolated from rats. Synaptosomes were superfused with standard medium at a physiologic pH of 7.4 and with acidified medium with a pH of 6.00, 5.50, or 5.0. Medium acidification produced pH-dependent stimulation of [(3)H]D: -ASP release. The increase amounted to 202 +/- 12.6% when the pH was reduced to 5.5. The [(3)H]D: -ASP release evoked by low pH (5.50) was still observed in the absence of Ca(2+) ions, but it was abolished by DL: -threo-beta-benzyloxyaspartate (DL: -TBOA) (100 microM), which inhibits neuronal glutamate/aspartate transport. Exposure to 5-(N,N-hexamethylene)-amiloride (EIPA) (30-100 microM), a selective inhibitor of Na(+)/H(+) exchange, caused concentration-dependent stimulation of [(3)H]D: -ASP release; the increase observed with EIPA 30 microM was 160 +/- 12%. The EIPA-induced release was not dependent on the presence of Ca(2+) ions in the medium, but it was abolished when synaptosomes were pretreated with 100 microM DL: -TBOA. Reduction of the extracellular pH (5.50-5.0) also stimulated the release of [(3)H]NA from rat cortical synaptosomes. Exposure to medium with a pH of 5.50 increased basal release by 136 +/- 9.5%. The release-stimulating effect of this medium was calcium-independent and abolished by 3 muM desipramine (DMI). [(3)H]NA release was also stimulated by EIPA. The increase induced by a concentration of 30 muM amounted to 136 +/- 9.50%, and this effect was calcium-independent and abolished by pretreatment with DMI (3 muM). These findings suggest that reduction of the extracellular pH stimulates release of [(3)H]D-ASP and [(3)H]NA by reversing neurotransmitter transport in the nerve terminal. This reversal might be activated by increased cytosolic concentrations of the transmitters caused by reduction of the pH gradient between the cytoplasm and the synaptic vesicles that take up the transmitters. This hypothesis is confirmed by the results of experiments conducted with EIPA. Selective blockade of Na(+)/H(+) exchange with this compound induces accumulation of H(+) in the nerve terminals and intracellular acidification, which leads to calcium-independent, transporter-mediated release of [(3)H]D: -ASP and [(3)H]NA