Offset of apparent hyperpolarized 13 C lactate flux by the use of adjuvant metformin in ionizing radiation therapy in vivo

Abstract

An increase in hyperpolarized (HP) [1-¹³ C]lactate production has been suggested as a biomarker for cancer occurrence as well as for response monitoring of cancer treatment. Recently, the use of metformin has been suggested as an anticancer or adjuvant treatment. By regulating the cytosolic NAD⁺ /NADH redox state, metformin stimulates lactate production and increases the HP [1-¹³ C]lactate conversion rate in the kidney, liver, and heart. In general, increased HP [1-¹³ C]lactate is regarded as a sign of cancer occurrence or tumor growth. Thus, the relationship between the tumor suppression effect of metformin and the change in metabolism monitored by HP [1-¹³ C]pyruvate MRS in cancer treatment needs to be investigated. The present study was performed using a brain metastasis animal model with MDA-MB-231(BR)-Luc breast cancer cells. HP [1-¹³ C]pyruvate MRS, T₂ -weighted MRI, and bioluminescence imaging were performed in groups treated with metformin or adjuvant metformin and radiation therapy. Metformin treatment alone did not display a tumor suppression effect, and the HP [1-¹³ C]lactate conversion rate increased. In radiation therapy, the HP [1-¹³ C]lactate conversion rate decreased with tumor suppression, with a p-value of 0.028. In the adjuvant metformin and radiation treatment, the tumor suppression effect increased, with a p-value of 0.001. However, the apparent HP [1-¹³ C]lactate conversion rate (K_pl ) was observed to be offset by two opposite effects: a decrease on radiation therapy and an increase caused by metformin treatment. Although HP [1-¹³ C]pyruvate MRS could not evaluate the tumor suppression effect of adjuvant metformin and radiation therapy due to the offset phenomenon, metabolic changes following only metformin pre-treatment could be monitored. Therefore, our results indicate that the interpretation of HP [1-¹³ C]pyruvate MRS for response monitoring of cancer treatment should be carried out with caution when metformin is used as an adjuvant cancer therapy.

Keywords: 13C pyruvate; MRS; NAD+/NADH redox; cancer metabolism; dynamic nuclear polarization; hyperpolarization; metformin; therapeutic response.