Open AccessEffects of the potassium‐sparing diuretic amiloride on chemotherapy response in canine osteosarcoma cells
Author(s) -
Poon Andrew C.,
Inkol Jordon M.,
Luu Anita K.,
Mutsaers Anthony J.
Publication year - 2018
Publication title -
journal of veterinary internal medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.356
H-Index - 103
eISSN - 1939-1676
pISSN - 0891-6640
DOI - 10.1111/jvim.15382
Subject(s) - amiloride , medicine , pharmacology , doxorubicin , carboplatin , apoptosis , downregulation and upregulation , chemotherapy , cancer research , cisplatin , biology , chemistry , biochemistry , sodium , organic chemistry , gene
Background Osteosarcoma (OSA) is a common bone tumor of mesenchymal origin in dogs. Chemotherapy delays metastasis, yet most dogs die of this disease within 1 year of diagnosis. The high metabolic demand of cancer cells promotes proton pump upregulation, leading to acidification of the tumor microenvironment and chemoresistance. The potassium‐sparing diuretic amiloride is among a class of proton pump inhibitors prescribed for refractory heart failure treatment in dogs. Objective We hypothesized that amiloride treatment improves chemotherapy response by reducing acidification in canine OSA cells. Our objective was to assess the in vitro effects of amiloride on cell viability, apoptosis, and metabolism. Methods In vitro study. Assessments of cell viability and apoptosis were performed after single agent or combination treatment, along with calculations of pharmacological synergism using the combination index. Protein signaling during apoptosis was evaluated by Western blotting. Metabolic profiling was performed using a Seahorse bioanalyzer. Results Amiloride strongly synergized with doxorubicin in combination treatment and exhibited additive or antagonistic effects with carboplatin in canine OSA cells. Combination treatment with doxorubicin significantly upregulated p53‐mitochondrial signaling to activate apoptosis and downregulate Akt phosphorylation. Amiloride‐treated cells further exhibited metabolic switching with reductions in glycolytic capacity and maximal respiration. Conclusion and Clinical Importance Amiloride synergized with doxorubicin to potentiate apoptosis in canine OSA cells. These results justify further investigation into repurposing of amiloride as an oncology drug for the treatment of OSA in dogs.