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The Monocarboxylate transporter inhibitor Quercetin induces intracellular acidification in a mouse model of Glioblastoma Multiforme: in-vivo detection using magnetic resonance imaging

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Summary

The response of tumor intracellular pH to a pharmacological challenge could help identify aggressive cancer. Chemical exchange saturation transfer (CEST) is an MRI contrast mechanism that is dependent on intracellular pH (pHi). pHi is important in the maintenance of normal cell function and is normally maintained within a narrow range by the activity of transporters located at the plasma membrane. In cancer, changes in pHi have been correlated with both cell proliferation and cell death. Quercetin is a bioflavonoid and monocarboxylate transporter (MCT) inhibitor. Since MCTs plays a significant role in maintaining pH balance in the tumor microenvironment, we hypothesized that systemically administered quercetin could selectively acidify brain tumors. The goals of the current study were to determine whether CEST MRI measurements sensitive to tumor pH could detect acidification after quercetin injection and to measure the magnitude of the pH change (ΔpH). Using a 9.4 T MRI, amine and amide concentration independent detection (AACID) CEST spectra were acquired in six mice approximately 15 ± 1 days after implanting 105 U87 human glioblastoma multiforme cells in the brain, before and after administration of quercetin (dose: 200 mg/kg) by intraperitoneal injection. Three additional mice were studied as controls and received only vehicle dimethyl sulfoxide (DMSO) injection. Repeated measures t-test was used to compare AACID changes in tumor and contralateral tissue regions of interest. Two hours after quercetin injection there was a significant increase in tumor AACID by 0.07 ± 0.03 corresponding to a 0.27 decrease in pHi, and no change in AACID in contralateral tissue. There was also a small average increase in AACID in tumors within the three mice injected with DMSO only. The use of the natural compound quercetin in combination with pH weighted MRI represents a unique approach to cancer detection that does not require injection of an imaging contrast agent.

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Abbreviations

GBM:

glioblastoma multiforme

pHi :

intracellular pH

pHe :

extracellular pH

PBS:

phosphate buffered saline

CEST:

chemical exchange saturation transfer

MCT:

monocarboxylate transporter

DMSO:

Dimethyl sulfoxide

RF:

radiofrequency

MTRasym :

asymmetric magnetization transfer ratio

MT:

magnetization transfer

AACID:

amine and amide concentration-independent detection

FSE:

fast spin-echo

WASSR:

water saturation shift referencing

ROI:

region of interest

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Acknowledgements

Funding for this study was provided by the Ontario Institute of Cancer Research (OICR) Smarter Imaging Program and the Canadian Institutes of Health Research (CIHR). MRI facilities were supported by Brain Canada and the Canada First Research Excellence Fund (BrainsCAN). Thanks to Misan University-Ministry of Higher Education and Scientific Research, Iraq.

Funding

This study was funded by the Ontario Institute of Cancer Research (OICR) Smarter Imaging Program (grant number 00807).

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Authors and Affiliations

  1. Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario, 1151 Richmond Street, London, ON, N6A 3K7, Canada

    Mohammed Albatany & Robert Bartha

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

    Mohammed Albatany & Robert Bartha

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

    Susan Meakin

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  1. Mohammed Albatany
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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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Albatany, M., Meakin, S. & Bartha, R. The Monocarboxylate transporter inhibitor Quercetin induces intracellular acidification in a mouse model of Glioblastoma Multiforme: in-vivo detection using magnetic resonance imaging. Invest New Drugs 37, 595–601 (2019). https://doi.org/10.1007/s10637-018-0644-3

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