Advertisement

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

  • Mohammed Albatany
  • Susan Meakin
  • Robert Bartha
PRECLINICAL STUDIES
  • 6 Downloads

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.

Keywords

Brain cancer Glioblastoma multiforme (GBM) Apoptosis pH Quercetin MRI CEST 

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

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

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.

References

  1. 1.
    Kanu OO, Mehta A, Di C, Lin N, Bortoff K, Bigner DD, Yan H, Adamson DC (2009) Glioblastoma multiforme: a review of therapeutic targets. Expert Opin Ther Targets 13(6):701–718.  https://doi.org/10.1517/14728220902942348 CrossRefPubMedGoogle Scholar
  2. 2.
    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507.  https://doi.org/10.1056/NEJMra0708126 CrossRefPubMedGoogle Scholar
  3. 3.
    Sagiyama K, Mashimo T, Togao O, Vemireddy V, Hatanpaa KJ, Maher EA, Mickey BE, Pan E, Sherry AD, Bachoo RM, Takahashi M (2014) In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma. Proc Natl Acad Sci U S A 111(12):4542–4547.  https://doi.org/10.1073/pnas.1323855111 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Easaw JC, Mason WP, Perry J, Laperriere N, Eisenstat DD, Del Maestro R, Belanger K, Fulton D, Macdonald D, Canadian Glioblastoma Recommendations C (2011) Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme. Curr Oncol 18(3):e126–e136CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Gerweck LE, Seetharaman K (1996) Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res 56(6):1194–1198PubMedGoogle Scholar
  6. 6.
    Stubbs M, Bhujwalla ZM, Tozer GM, Rodrigues LM, Maxwell RJ, Morgan R, Howe FA, Griffiths JR (1992) An assessment of 31P MRS as a method of measuring pH in rat tumours. NMR Biomed 5(6):351–359CrossRefPubMedGoogle Scholar
  7. 7.
    Ha DH, Choi S, Oh JY, Yoon SK, Kang MJ, Kim KU (2013) Application of 31P MR spectroscopy to the brain tumors. Korean J Radiol 14(3):477–486.  https://doi.org/10.3348/kjr.2013.14.3.477 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cichocka M, Kozub J, Urbanik A (2015) PH Measurements of the Brain Using Phosphorus Magnetic Resonance Spectroscopy (31PMRS) in Healthy Men – Comparison of Two Analysis Methods. Pol J Radiol.  https://doi.org/10.12659/PJR.895178
  9. 9.
    Oberhaensli RD, Galloway GJ, Hilton-Jones D, Bore PJ, Styles P, Rajagopalan B, Taylor DJ, Radda GK (1987) The study of human organs by phosphorus-31 topical magnetic resonance spectroscopy. Br J Radiol 60(712):367–373.  https://doi.org/10.1259/0007-1285-60-712-367 CrossRefPubMedGoogle Scholar
  10. 10.
    Maintz D, Heindel W, Kugel H, Jaeger R, Lackner KJ (2002) Phosphorus-31 MR spectroscopy of normal adult human brain and brain tumours. NMR Biomed 15(1):18–27CrossRefPubMedGoogle Scholar
  11. 11.
    Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899.  https://doi.org/10.1038/nrc1478 CrossRefPubMedGoogle Scholar
  12. 12.
    Huber V, De Milito A, Harguindey S, Reshkin SJ, Wahl ML, Rauch C, Chiesi A, Pouyssegur J, Gatenby RA, Rivoltini L, Fais S (2010) Proton dynamics in cancer. J Transl Med 8:57.  https://doi.org/10.1186/1479-5876-8-57 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Neri D, Supuran CT (2011) Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 10(10):767–777.  https://doi.org/10.1038/nrd3554 CrossRefPubMedGoogle Scholar
  14. 14.
    Webb BA, Chimenti M, Jacobson MP, Barber DL (2011) Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer 11(9):671–677.  https://doi.org/10.1038/nrc3110 CrossRefPubMedGoogle Scholar
  15. 15.
    Shrode LD, Tapper H, Grinstein S (1997) Role of intracellular pH in proliferation, transformation, and apoptosis. J Bioenerg Biomembr 29(4):393–399CrossRefPubMedGoogle Scholar
  16. 16.
    Barar J, Omidi Y (2013) Dysregulated pH in tumor microenvironment checkmates Cancer therapy. Bioimpacts 3(4):149–162.  https://doi.org/10.5681/bi.2013.036 PubMedPubMedCentralGoogle Scholar
  17. 17.
    Izumi H, Torigoe T, Ishiguchi H, Uramoto H, Yoshida Y, Tanabe M, Ise T, Murakami T, Yoshida T, Nomoto M, Kohno K (2003) Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev 29(6):541–549.  https://doi.org/10.1016/s0305-7372(03)00106-3 CrossRefPubMedGoogle Scholar
  18. 18.
    Wood PJ, Sansom JM, Newell K, Tannock IF, Stratford IJ (1995) Reduction of tumour intracellular pH and enhancement of melphalan cytotoxicity by the ionophore Nigericin. Int J Cancer 60(2):264–268CrossRefPubMedGoogle Scholar
  19. 19.
    Volk C, Kempski B, Kempski OS (1997) Inhibition of lactate export by quercetin acidifies rat glial cells in vitro. Neurosci Lett 223(2):121–124CrossRefPubMedGoogle Scholar
  20. 20.
    Srivastava S, Somasagara RR, Hegde M, Nishana M, Tadi SK, Srivastava M, Choudhary B, Raghavan SC (2016) Quercetin, a natural flavonoid interacts with DNA, arrests cell cycle and causes tumor regression by activating mitochondrial pathway of apoptosis. Sci Rep 6:24049.  https://doi.org/10.1038/srep24049 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Izumi H, Takahashi M, Uramoto H, Nakayama Y, Oyama T, Wang KY, Sasaguri Y, Nishizawa S, Kohno K (2011) Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells. Cancer Sci 102(5):1007–1013.  https://doi.org/10.1111/j.1349-7006.2011.01908.x CrossRefPubMedGoogle Scholar
  22. 22.
    Perez-Escuredo J, Van Hee VF, Sboarina M, Falces J, Payen VL, Pellerin L, Sonveaux P (2016) Monocarboxylate transporters in the brain and in cancer. Biochim Biophys Acta 1863(10):2481–2497.  https://doi.org/10.1016/j.bbamcr.2016.03.013 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kim JH, Kim SH, Alfieri AA, Young CW (1984) Quercetin, an inhibitor of lactate transport and a hyperthermic sensitizer of HeLa cells. Cancer Res 44(1):102–106PubMedGoogle Scholar
  24. 24.
    McKay TB, Lyon D, Sarker-Nag A, Priyadarsini S, Asara JM, Karamichos D (2015) Quercetin attenuates lactate production and extracellular matrix secretion in keratoconus. Sci Rep 5:9003.  https://doi.org/10.1038/srep09003 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sang DP, Li RJ, Lan Q (2014) Quercetin sensitizes human glioblastoma cells to temozolomide in vitro via inhibition of Hsp27. Acta Pharmacol Sin 35(6):832–838.  https://doi.org/10.1038/aps.2014.22 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    McVicar N, Li AX, Goncalves DF, Bellyou M, Meakin SO, Prado MA, Bartha R (2014) Quantitative tissue pH measurement during cerebral ischemia using amine and amide concentration-independent detection (AACID) with MRI. J Cereb Blood Flow Metab 34(4):690–698.  https://doi.org/10.1038/jcbfm.2014.12 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zong X, Wang P, Kim SG, Jin T (2014) Sensitivity and source of amine-proton exchange and amide-proton transfer magnetic resonance imaging in cerebral ischemia. Magn Reson Med 71(1):118–132.  https://doi.org/10.1002/mrm.24639 CrossRefPubMedGoogle Scholar
  28. 28.
    Zhou JY, Payen JF, Wilson DA, Traystman RJ, van Zijl PCM (2003) Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nat Med 9(8):1085–1090.  https://doi.org/10.1038/nm907 CrossRefPubMedGoogle Scholar
  29. 29.
    Zhou JLB, Wilson DA, Laterra J, van Zijl PC (2003) Amide proton transfer (APT) contrast for imaging of brain tumors. Magn Reson Med 50:1120–1126.  https://doi.org/10.1002/mrm.10651 CrossRefPubMedGoogle Scholar
  30. 30.
    Murray RK GD (2003) Membranes: structure & function. McGraw-Hill Companies, Inc:415–433Google Scholar
  31. 31.
    McVicar N, Li AX, Meakin SO, Bartha R (2015) Imaging chemical exchange saturation transfer (CEST) effects following tumor-selective acidification using lonidamine. NMR Biomed 28(5):566–575.  https://doi.org/10.1002/nbm.3287 CrossRefPubMedGoogle Scholar
  32. 32.
    Marathe K, McVicar N, Li A, Bellyou M, Meakin S, Bartha R (2016) Topiramate induces acute intracellular acidification in glioblastoma. J Neuro-Oncol 130(3):465–472.  https://doi.org/10.1007/s11060-016-2258-y CrossRefGoogle Scholar
  33. 33.
    Albatany M, Li A, Meakin S, Bartha R (2017) Dichloroacetate induced intracellular acidification in glioblastoma: in vivo detection using AACID-CEST MRI at 9.4 tesla. Journal of Neuro-oncology.  https://doi.org/10.1007/s11060-017-2664-9
  34. 34.
    Reddy NS, Nirmala P, Chidambaram N, Kumar P, Nagar A (2012) Quercetin in dimethyl benzanthracene induced breast cancer in rats. Am J Pharmacol Toxicol 7(2):68–72CrossRefGoogle Scholar
  35. 35.
    Li AX, Suchy M, Li C, Gati JS, Meakin S, Hudson RH, Menon RS, Bartha R (2011) In vivo detection of MRI-PARACEST agents in mouse brain tumors at 9.4 T. Magn Reson Med 66(1):67–72.  https://doi.org/10.1002/mrm.22772 CrossRefPubMedGoogle Scholar
  36. 36.
    Kim M, Gillen J, Landman BA, Zhou J, van Zijl PC (2009) Water saturation shift referencing (WASSR) for chemical exchange saturation transfer (CEST) experiments. Magn Reson Med 61(6):1441–1450.  https://doi.org/10.1002/mrm.21873 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Park HJ, Makepeace CM, Lyons JC, Song CW (1996) Effect of intracellular acidity and ionomycin on apoptosis in HL-60 cells. Eur J Cancer 32A(3):540–546CrossRefPubMedGoogle Scholar
  38. 38.
    Park HJ, Lyons JC, Ohtsubo T, Song CW (1999) Acidic environment causes apoptosis by increasing caspase activity. Br J Cancer 80(12):1892–1897.  https://doi.org/10.1038/sj.bjc.6690617 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Jakubowicz-Gil J, Langner E, Wertel I, Piersiak T, Rzeski W (2010) Temozolomide, quercetin and cell death in the MOGGCCM astrocytoma cell line. Chem Biol Interact 188(1):190–203.  https://doi.org/10.1016/j.cbi.2010.07.015 CrossRefPubMedGoogle Scholar
  40. 40.
    Notman R, Noro M, O'Malley B, Anwar J (2006) Molecular basis for dimethylsulfoxide (DMSO) action on lipid membranes. J Am Chem Soc 128(43):13982–13983.  https://doi.org/10.1021/ja063363t CrossRefPubMedGoogle Scholar
  41. 41.
    Zhou J, Tryggestad E, Wen Z, Lal B, Zhou T, Grossman R, Wang S, Yan K, Fu DX, Ford E, Tyler B, Blakeley J, Laterra J, van Zijl PC (2011) Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides. Nat Med 17(1):130–134.  https://doi.org/10.1038/nm.2268 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Centre for Functional and Metabolic Mapping, Robarts Research InstituteThe University of Western OntarioLondonCanada
  2. 2.Department of Medical BiophysicsThe University of Western OntarioLondonCanada
  3. 3.Department of BiochemistryThe University of Western OntarioLondonCanada

Personalised recommendations