title: Reduction of metastasis using a non-volatile buffer.
abstract: The tumor microenvironment is acidic as a consequence of upregulated glycolysis and poor perfusion and this acidity, in turn, promotes invasion and metastasis. We have recently demonstrated that chronic consumption of sodium bicarbonate increased tumor pH and reduced spontaneous and experimental metastases. This occurred without affecting systemic pH, which was compensated. Additionally, these prior data did not rule out the possibility that bicarbonate was working though effects on carbonic anhydrase, and not as a buffer per se. Here, we present evidence that chronic ingestion of a non-volatile buffer, 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA) with a pK                         (a) of 6.9 also reduced metastasis in an experimental PC3M prostate cancer mouse model. Animals (n = 30) were injected with luciferase expressing PC3M prostate cancer cells either subcutaneously (s.c., n = 10) or intravenously (i.v., n = 20). Four days prior to inoculations, half of the animals for each experiment were provided drinking water containing 200 mM IEPA buffer. Animals were imaged weekly to follow metastasis, and these data showed that animals treated with IEPA had significantly fewer experimental lung metastasis compared to control groups (P < 0.04). Consistent with prior work, the pH of treated tumors was elevated compared to controls. IEPA is observable by in vivo magnetic resonance spectroscopy and this was used to measure the presence of IEPA in the bladder, confirming that it was orally available. The results of this study indicate that metastasis can be reduced by non-volatile buffers as well as bicarbonate and thus the effect appears to be due to pH buffering per se.
authors.affiliation: Department of Cancer Imaging Research, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL 33612, USA. arig.ibrahimhashim@moffitt.org
authors.forename: Arig
authors.initials: A
authors.lastname: Ibrahim Hashim
authors.forename: Heather H
authors.initials: HH
authors.lastname: Cornnell
authors.forename: Maria de Lourdes
authors.initials: Mde L
authors.lastname: Coelho Ribeiro
authors.forename: Dominique
authors.initials: D
authors.lastname: Abrahams
authors.forename: Jessica
authors.initials: J
authors.lastname: Cunningham
authors.forename: Mark
authors.initials: M
authors.lastname: Lloyd
authors.forename: Gary V
authors.initials: GV
authors.lastname: Martinez
authors.forename: Robert A
authors.initials: RA
authors.lastname: Gatenby
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000627:therapeutic use*; D008163:Luminescent Measurements; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011422:Propionates / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: C434425:2-imidazole-1-yl-3-ethoxycarbonylpropionic acid; D007093:Imidazoles; D011422:Propionates