The Comparative Effects of Acid Suppressants on Healthy and Neoplastic In Vitro Mast Cells
Abstract
Mast cell tumors (MCTs) are common skin tumors in dogs and are treated surgically when possible. Because of their integral role as sentinels of immunity, release of inflammatory mediators by MCTs during activation (e.g. degranulation) can have catastrophic consequences. For example, histamine release triggers angioedema, tissue necrosis, gastrointestinal ulceration, and tumor-related death. Prior to surgery, or in the case of non- resectable tumors, adjunctive treatments with drugs that are cytotoxic to mast cells (MCs) or prevent MC release of inflammatory mediators would be of great benefit. We believe that acid suppressant medications might directly kill MCs or prevent exuberant release of histamine and other inflammatory mediators. Both histamine-2 receptor antagonists (H₂RAs) and proton pump inhibitors (PPIs) are widely used in dogs with MCTs for their ability to reduce gastric acid and theoretically reduce degranulation associated adverse events (AEs). Both of these classes of acid suppressants have been found to possess a plethora of anti-inflammatory and even cytotoxic properties regarding host immunity and reduction in neoplastic cell proliferation, survival, and metastasis. Though H₂RAs are widely used in patients with MCTs to prevent tumor side effects, PPIs likely inactivate a critical proton pump, a vacuolar ATPase, that is required for MC granule structure and viability. A vacuolar ATPase inhibitor, bafilomycin A, has powerful cytotoxic effects on MCs due to granule disruption. Because PPIs also work on vacuolar ATPase pumps, we expect that routinely available PPIs, such as esomeprazole, might have similar effects. If so, use of PPIs in dogs with MCT disease might be of greater benefit than the use of H₂RAs.
In these studies, we have shown that esomeprazole, more so than famotidine, alters healthy and neoplastic in vitro MC structure, viability, and degranulation patterns. Treatment with esomeprazole caused a visible concentration and time-dependent increase in cytoplasmic vacuolization via electron microscopy, as well as induced significant cytotoxicity (via both early and late apoptosis) in several species of neoplastic in vitro MC lines. Esomeprazole treatment, but not famotidine, also caused alterations in MC activation, as assessed by β-hexosaminidase release indicative of degranulation. An in vitro canine B cell lymphoma line was used as an agranulocytic control. The same treatment effects were either blunted or completely absent in the lymphoma line in comparison to all MC lines.
Although this work is in vitro and cannot be directly extrapolated to an in vivo model, we found the direct effects of esomeprazole on canine neoplastic MCs to be superior to those of famotidine, suggesting PPIs might be the acid suppressant of choice for canine MCT disease. Further studies are necessary investigating the mechanisms by which esomeprazole induces these treatment effects and if they are similar across other types of PPIs, as well as comparative, in vivo clinical trials investigating acid suppressant use in dogs with MCTs. Results of our work provide the framework for further investigation of efficacious use of acid suppressants in MCT disease in companion animals.
Citation
Gould, Emily Nissa (2022). The Comparative Effects of Acid Suppressants on Healthy and Neoplastic In Vitro Mast Cells. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /197190.