Topiramate induces acute intracellular acidification in glioblastoma.
Reversal of the intracellular/extracellular pH gradient is a hallmark of malignant tumors and is an important consideration in evaluating tumor growth potential and the effectiveness of anticancer therapies. Glioblastoma multiforme (GBM) brain tumors have increased expression of the carbonic anhydrase (CA) isozymes CAII, CAIX and CAXII that contribute to the altered regulation of intracellular pH (pHi). The anti-epileptic drug topiramate (TPM) inhibits CA action and may acidify the tumor intracellular compartment. In-vivo detection of acute tumor acidification could aid in cancer diagnosis and monitoring treatment response. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) has been used to measure tissue pH. Using a recently developed CEST-MRI method called amine/amide concentration independent detection (AACID), we have previously shown intracellular acidification caused by single dose of lonidamine. The current study aims to evaluate the intracellular acidification induced by a single dose of the clinically approved drug TPM. Brain tumors were induced in NU/NU mice by injecting 105U87 human glioblastoma multiforme cells into the right frontal lobe. Using a 9.4T MRI scanner AACID measurements were acquired, before and after administration of TPM (dose: 120 mg/kg, intraperitoneal), 15 ± 2 days after tumor cell implantation. TPM administration induced acute intracellular acidification (average ± SD: baseline AACID = 1.14 ± 0.05; post AACID = 1.19 ± 0.05, paired ttest p = 0.02) in implanted brain tumors. In contrast, contralateral tissue showed no change in AACID value. These results suggest that topiramate can rapidly induce a tumor specific physiological change detectable by AACID CEST. This pH challenge paradigm could be exploited to aid in tumor detection and monitoring treatment response.
Department of Medical Biophysics, University of Western Ontario, London, ON, N6A 3K7, Canada.|Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, N6A 5B7, Canada.
Kamini
K
Marathe
Department of Medical Biophysics, University of Western Ontario, London, ON, N6A 3K7, Canada.|Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, N6A 5B7, Canada.
Nevin
N
McVicar
Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, N6A 5B7, Canada.
Alex
A
Li
Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, N6A 5B7, Canada.
Miranda
M
Bellyou
Department of Biochemistry, University of Western Ontario, London, ON, N6A 3K7, Canada.
Susan
S
Meakin
Department of Medical Biophysics, University of Western Ontario, London, ON, N6A 3K7, Canada. rbartha@robarts.ca.|Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, N6A 5B7, Canada. rbartha@robarts.ca.|Robarts Research Institute, University of Western Ontario, 1151 Richmond Street, London, ON, N6A 5B7, Canada. rbartha@robarts.ca.
Robert
0000-0002-7118-9096
R
Bartha
D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000473:pathology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000077236:Topiramate; D023041:Xenograft Model Antitumor Assays
D051858:Forkhead Transcription Factors; D018696:Neuroprotective Agents; C090140:Whn protein; D000077236:Topiramate; D005632:Fructose; D002256:Carbonic Anhydrases
AACID; CEST; Carbonic anhydrase inhibitor; Chemical exchange saturation transfer; Intracellular pH; Magnetic resonance imaging; Topiramate; Tumor