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

Abstract

An increase in hyperpolarized (HP) [1‐13C]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 [1‐13C]lactate conversion rate in the kidney, liver, and heart. In general, increased HP [1‐13C]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 [1‐13C]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 [1‐13C]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 [1‐13C]lactate conversion rate increased. In radiation therapy, the HP [1‐13C]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 [1‐13C]lactate conversion rate (Kpl) was observed to be offset by two opposite effects: a decrease on radiation therapy and an increase caused by metformin treatment. Although HP [1‐13C]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 [1‐13C]pyruvate MRS for response monitoring of cancer treatment should be carried out with caution when metformin is used as an adjuvant cancer therapy.

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

“…Metformin is known to reduce the cytoplasmic redox state as estimated from the increased lactate/pyruvate ratio. To this end, metformin stimulates lactate production and increases the hyperpolarized [1-13 C]lactate conversion rate in the kidney, liver, and heart [ 83 ]. On the other hand, the effects of metformin on the mitochondrial redox state, are concentration-dependent and biphasic.…”

“…In cancer cells, the upregulation and stabilization of HIF1α contributes to the Warburg effect. HIF1α transactivates genes related to the increase of glucose uptake, glycolysis, and lactate production, including PDKs, and causes cancer cells to rely on glycolysis for energy, rather than on oxidative metabolism [ 83 ]. The reduction in oxidative phosphorylation decreases superoxide production by the respiratory chain, resulting in the inhibition of pro-apoptotic signaling pathways.…”

“…A recent study provided evidence that metformin can enhance lactate production in cancer cells. Indeed, metformin was shown to increase the hyperpolarized [1-13 C]lactate conversion rate in an animal model of breast cancer [ 83 ]. The hyperpolarized [1-13 C]lactate production has been suggested as a biomarker for cancer occurrence as well as for monitoring tumor response to therapy.…”

“…Actually, the study by Choi and coworkers suggests that the in vivo administration of metformin may challenge this paradigm. Indeed, metformin revealed to be effective as an adjuvant treatment combined with radiation therapy and increased the tumor suppression effect compared to radiation therapy alone, nevertheless it enhanced the hyperpolarized [1-13 C]lactate production [ 83 ].…”

Hyperpolarized δ-[1- 13C]gluconolactone imaging visualizes response to TERT or GABPB1 targeting therapy for glioblastoma

“…However, these metabolic alterations are not specific to TERT. Indeed, changes in treatment, and PI3K inhibition [13][14][15][16][17] and 1 H-MRS total lactate levels are also affected by the presence of necrotic regions in GBM 18 . We, therefore, wanted to develop additional complementary imaging methods that can further help assess TERT expression and inhibition and enhance the specificity of our imaging.…”