Metabolic remodeling of malignant gliomas for enhanced sensitization during radiotherapy: an in vitro study.
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. 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 alpha-cyano-4-hydroxycinnamic 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.


CONCLUSIONS
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.
Colen
Chaim B
CB
Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Seraji-Bozorgzad
Navid
N
Marples
Brian
B
Galloway
Matthew P
MP
Sloan
Andrew E
AE
Mathupala
Saroj P
SP
D000222:Adaptation, Physiological; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003373:Coumaric Acids / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects
D003373:Coumaric Acids; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; C007175:alpha-cyano-4-hydroxycinnamate; D019344:Lactic Acid