Journal
NEUROSURGERY
Volume 59, Issue 6, Pages 1313-1323Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1227/01.NEU.0000249218.65332.BF
Keywords
alpha-cyano-4-hydroxycinnamic acid; glioma therapy; lactate; magnetic resonance spectroscopy; tumor metabolism
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Funding
- NCI NIH HHS [R01 CA116257] Funding Source: Medline
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OBJECTIVE: To investigate a novel method to enhance radiosensitivity of gliomas via modification of metabolite flux immediately before radiotherapy. Malignant gliomas are highly glycolytic and produce copious amounts,of lactic acid, which is effluxed to the tumor microenvironment via lactate transporters. We hypothesized that inhibition of lactic acid efflux would alter glioma metabolite profiles, including those that are radioprotective. I H magnetic resonance spectroscopy (MRS) was used to quantify key metabolites, including those most effective for induction of low-dose radiation-induced cell death. METHODS: We inhibited lactate transport in U87-MG gliomas with cc-cyano-4-hydroxy-cinnamic acid (ACCA). Flow cytometry was used to assess induction of cell death in treated cells. Cells were analyzed by MRS after ACCA treatment. Control and treated cells were subjected to low-dose irradiation, and the surviving fractions of cells were determined by clonogenic assays. RESULTS: MRS revealed changes to intracellular lactate on treatment with ACCA. Significant decreases in the metabolites taurine, glutamate, glutathione, alanine, and glycine were observed, along with inversion of the choline/phosphocholine profile. On exposure to low-dose radiation, ACCA-pretreated U-87MG cells underwent rapid morphological changes, which were followed by apoptotic cell death. CONCLUSION: Inhibition of lactate efflux in malignant gliomas results in alterations of glycolytic metabolism, including. decreased levels of the antioxidants taurine and glutathione and enhanced radiosensitivity of ACCA-treated cells. Thus, in situ application of lactate transport inhibitors such as ACCA as a novel adjunctive therapeutic strategy against glial tumors may greatly enhance the level of radiation-induced cell killing during a combined radio- and chemotherapeutic regimen.
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