Dataset Information

Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH.

ABSTRACT: Gliomas maintain an acidic extracellular pH (pH_e), which promotes tumor growth and builds resistance to therapy. Given evidence that acidic pH_e beyond the tumor core indicates infiltration, we hypothesized that imaging the intratumoral pH_e in relation to the peritumoral pH_e 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., DOTP^8-) complexed with paramagnetic thulium (Tm³⁺), to generate pH_e maps in rat brains bearing U251 tumors. Following TmDOTP^5- infusion, T₂-weighted MRI provided delineation of the tumor boundary and BIRDS was used to image the pH_e gradient between intratumoral and peritumoral regions (?pH_e) in both untreated and temozolomide treated (40?mg/kg) rats bearing U251 tumors. Treated rats had reduced tumor volume (p?e was significantly higher in untreated compared to treated rats (p?e. Thus, BIRDS can be used to map the ?pH_e in gliomas and provide a physiological readout of the therapeutic response on the tumor microenvironment.

SUBMITTER: Rao JU

PROVIDER: S-EPMC5554228 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH.

Rao Jyotsna U JU Coman Daniel D Walsh John J JJ Ali Meser M MM Huang Yuegao Y Hyder Fahmeed F

Scientific reports 20170811 1

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 shift ...[more]

PMID: 28801587

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Project description:BACKGROUND:High-grade glioma (HGG) is a fatal human cancer. Bortezomib, a proteasome inhibitor, has been approved for the treatment of multiple myeloma but its use in glioma awaits further investigation. This study aimed to explore the chemotherapeutic effect and the underlying mechanism of bortezomib on gliomas. METHODS:U251 and U87 cell viability and proliferation were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, tumor cell spheroid growth, and colony formation assay. Cell apoptosis and cell cycle were detected by flow cytometry. Temozolomide (TMZ)-insensitive cell lines were induced by long-term TMZ treatment, and cells with stem cell characteristics were enriched with stem cell culture medium. The mRNA levels of interested genes were measured via reverse transcription-quantitative polymerase chain reaction, and protein levels were determined via Western blotting/immunofluorescent staining in cell lines and immunohistochemical staining in paraffin-embedded sections. Via inoculating U87 cells subcutaneously, glioma xenograft models in nude mice were established for drug experiments. Patient survival data were analyzed using the Kaplan-Meier method. RESULTS:Bortezomib inhibited the viability and proliferation of U251 and U87 cells in a dose- and time-dependent manner by inducing apoptosis and cell cycle arrest. Bortezomib also significantly inhibited the spheroid growth, colony formation, and stem-like cell proliferation of U251 and U87 cells. When administrated in combination, bortezomib showed synergistic effect with TMZ in vitro and sensitized glioma to TMZ treatment both in vitro and in vivo. Bortezomib reduced both the mRNA and protein levels of Forkhead Box M1 (FOXM1) and its target gene Survivin. The FOXM1-Survivin axis was markedly up-regulated in established TMZ-insensitive glioma cell lines and HGG patients. Expression levels of FOXM1 and Survivin were positively correlated with each other and both related to poor prognosis in glioma patients. CONCLUSIONS:Bortezomib was found to inhibit glioma growth and improved TMZ chemotherapy efficacy, probably via down-regulating the FOXM1-Survivin axis. Bortezomib might be a promising agent for treating malignant glioma, alone or in combination with TMZ.

Dataset Information

Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH.

Publications

Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH.

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