Reversed metabolic reprogramming as a measure of cancer treatment efficacy in rat C6 glioma model


Autoři: Keshav Datta aff001;  Mette H. Lauritzen aff002;  Milton Merchant aff003;  Taichang Jang aff003;  Shie-Chau Liu aff002;  Ralph Hurd aff002;  Lawrence Recht aff003;  Daniel M. Spielman aff001
Působiště autorů: Department of Electrical Engineering, Stanford University, Stanford, California, United States of America aff001;  Department of Radiology, Stanford University, Stanford, California, United States of America aff002;  Department of Neurology, Stanford University, Stanford, California, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225313

Souhrn

Background

Metabolism in tumor shifts from oxidative phosphorylation to inefficient glycolysis resulting in overproduction of lactate (Warburg effect), and cancers may be effectively treated if this imbalance were corrected. The aim of this longitudinal study of glioblastoma in a rat model was to determine whether the ratio of lactate (surrogate marker for glycolysis) to bicarbonate (for oxidative phosphorylation), as measured via in vivo magnetic resonance imaging of hyperpolarized 13C-labeled pyruvate accurately predicts survival.

Methods

C6 Glioma implanted male Wistar rats (N = 26) were treated with an anti-vascular endothelial growth factor antibody B20.4.1.1 in a preliminary study to assess the efficacy of the drug. In a subsequent longitudinal survival study, magnetic resonance spectroscopic imaging (MRSI) was used to estimate [1-13C]Lactate and [1-13C]Bicarbonate in tumor and contralateral normal appearing brain of glioma implanted rats (N = 13) after injection of hyperpolarized [1-13C]Pyruvate at baseline and 48 hours post-treatment with B20.4.1.1.

Results

A survival of ~25% of B20.4.1.1 treated rats was noted in the preliminary study. In the longitudinal imaging experiment, changes in 13C Lactate, 13C Bicarbonate and tumor size measured at baseline and 48 hours post-treatment did not correlate with survival. 13C Lactate to 13C Bicarbonate ratio increased in all the 6 animals that succumbed to the tumor whereas the ratio decreased in 6 of the 7 animals that survived past the 70-day observation period.

Conclusions

13C Lactate to 13C Bicarbonate ratio (Lac/Bic) at 48 hours post-treatment is highly predictive of survival (p = 0.003). These results suggest a potential role for the 13C Lac/Bic ratio serving as a valuable measure of tumor metabolism and predicting therapeutic response.

Klíčová slova:

Bicarbonates – Cancer treatment – Drug metabolism – Euthanasia – Glioma – Glucose metabolism – Magnetic resonance imaging – Metabolites


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2019 Číslo 12