Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH

Abstract Gliomas maintain an acidic extracellular pH (pHe), which promotes tumor growth and builds resistance to therapy. Given evidence that acidic pHe beyond the tumor core indicates infiltration, we hypothesized that imaging the intratumoral pHe in relation to the peritumoral pHe can provide a no...

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Autores principales:	Jyotsna U. Rao, Daniel Coman, John J. Walsh, Meser M. Ali, Yuegao Huang, Fahmeed Hyder
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9101447783b94692a1bde5eeeb7ffa36
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spelling	oai:doaj.org-article:9101447783b94692a1bde5eeeb7ffa362021-12-02T16:07:47ZTemozolomide arrests glioma growth and normalizes intratumoral extracellular pH10.1038/s41598-017-07609-72045-2322https://doaj.org/article/9101447783b94692a1bde5eeeb7ffa362017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07609-7https://doaj.org/toc/2045-2322Abstract Gliomas maintain an acidic extracellular pH (pHe), which promotes tumor growth and builds resistance to therapy. Given evidence that acidic pHe beyond the tumor core indicates infiltration, we hypothesized that imaging the intratumoral pHe in relation to the peritumoral pHe can provide a novel readout of therapeutic influence on the tumor microenvironment. We used Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which utilizes chemical shifts of non-exchangeable protons from macrocyclic chelates (e.g., DOTP8−) complexed with paramagnetic thulium (Tm3+), to generate pHe maps in rat brains bearing U251 tumors. Following TmDOTP5− infusion, T2-weighted MRI provided delineation of the tumor boundary and BIRDS was used to image the pHe gradient between intratumoral and peritumoral regions (ΔpHe) in both untreated and temozolomide treated (40 mg/kg) rats bearing U251 tumors. Treated rats had reduced tumor volume (p < 0.01), reduced proliferation (Ki-67 staining; p < 0.03) and apoptosis induction (cleaved Caspase-3 staining; p < 0.001) when compared to untreated rats. The ΔpHe was significantly higher in untreated compared to treated rats (p < 0.002), suggesting that temozolomide, which induces apoptosis and hinders proliferation, also normalizes intratumoral pHe. Thus, BIRDS can be used to map the ΔpHe in gliomas and provide a physiological readout of the therapeutic response on the tumor microenvironment.Jyotsna U. RaoDaniel ComanJohn J. WalshMeser M. AliYuegao HuangFahmeed HyderNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jyotsna U. Rao Daniel Coman John J. Walsh Meser M. Ali Yuegao Huang Fahmeed Hyder Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH
description	Abstract Gliomas maintain an acidic extracellular pH (pHe), which promotes tumor growth and builds resistance to therapy. Given evidence that acidic pHe beyond the tumor core indicates infiltration, we hypothesized that imaging the intratumoral pHe in relation to the peritumoral pHe can provide a novel readout of therapeutic influence on the tumor microenvironment. We used Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which utilizes chemical shifts of non-exchangeable protons from macrocyclic chelates (e.g., DOTP8−) complexed with paramagnetic thulium (Tm3+), to generate pHe maps in rat brains bearing U251 tumors. Following TmDOTP5− infusion, T2-weighted MRI provided delineation of the tumor boundary and BIRDS was used to image the pHe gradient between intratumoral and peritumoral regions (ΔpHe) in both untreated and temozolomide treated (40 mg/kg) rats bearing U251 tumors. Treated rats had reduced tumor volume (p < 0.01), reduced proliferation (Ki-67 staining; p < 0.03) and apoptosis induction (cleaved Caspase-3 staining; p < 0.001) when compared to untreated rats. The ΔpHe was significantly higher in untreated compared to treated rats (p < 0.002), suggesting that temozolomide, which induces apoptosis and hinders proliferation, also normalizes intratumoral pHe. Thus, BIRDS can be used to map the ΔpHe in gliomas and provide a physiological readout of the therapeutic response on the tumor microenvironment.
format	article
author	Jyotsna U. Rao Daniel Coman John J. Walsh Meser M. Ali Yuegao Huang Fahmeed Hyder
author_facet	Jyotsna U. Rao Daniel Coman John J. Walsh Meser M. Ali Yuegao Huang Fahmeed Hyder
author_sort	Jyotsna U. Rao
title	Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH
title_short	Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH
title_full	Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH
title_fullStr	Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH
title_full_unstemmed	Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH
title_sort	temozolomide arrests glioma growth and normalizes intratumoral extracellular ph
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/9101447783b94692a1bde5eeeb7ffa36
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Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH

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