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Topiramate induces acute intracellular acidification in glioblastoma

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Abstract

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 105 U87 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.

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Acknowledgments

We gratefully thank technical support of C. O’Neil. This work was funded by the Ontario Institute of Cancer Research (OICR) Smarter Imaging Program, and a Discovery Grant from the National Science and Engineering Research Council of Canada (NSERC).

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Authors and Affiliations

  1. Department of Medical Biophysics, University of Western Ontario, London, ON, N6A 3K7, Canada

    Kamini Marathe, Nevin McVicar & Robert Bartha

  2. Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, N6A 5B7, Canada

    Kamini Marathe, Nevin McVicar, Alex Li, Miranda Bellyou & Robert Bartha

  3. Department of Biochemistry, University of Western Ontario, London, ON, N6A 3K7, Canada

    Susan Meakin

  4. Robarts Research Institute, University of Western Ontario, 1151 Richmond Street, London, ON, N6A 5B7, Canada

    Robert Bartha

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  1. Kamini Marathe
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Correspondence to Robert Bartha.

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All applicable national and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Marathe, K., McVicar, N., Li, A. et al. Topiramate induces acute intracellular acidification in glioblastoma. J Neurooncol 130, 465–472 (2016). https://doi.org/10.1007/s11060-016-2258-y

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