The Monocarboxylate transporter inhibitor Quercetin induces intracellular acidification in a mouse model of Glioblastoma Multiforme: in-vivo detection using magnetic resonance imaging
- 86 Downloads
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.
KeywordsBrain cancer Glioblastoma multiforme (GBM) Apoptosis pH Quercetin MRI CEST
phosphate buffered saline
chemical exchange saturation transfer
asymmetric magnetization transfer ratio
amine and amide concentration-independent detection
water saturation shift referencing
region of interest
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.
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.
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.
- 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.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
- 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
- 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
- 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.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
- 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
- 30.Murray RK GD (2003) Membranes: structure & function. McGraw-Hill Companies, Inc:415–433Google Scholar
- 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
- 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