Pyruvate‐lactate exchange and glucose uptake in human prostate cancer cell models. A study in xenografts and suspensions by hyperpolarized [1‐¹³C]pyruvate MRS and [¹⁸F]FDG‐PET

Abstract

Reprogramming of energy metabolism in the development of prostate cancer can be exploited for a better diagnosis and treatment of the disease. The goal of this study was to determine whether differences in glucose and pyruvate metabolism of human prostate cancer cells with dissimilar aggressivenesses can be detected using hyperpolarized [1‐13C]pyruvate MRS and [18F]FDG‐PET imaging, and to evaluate whether these measures correlate. For this purpose, we compared murine xenografts of human prostate cancer LNCaP cells with those of more aggressive PC3 cells. [1‐13C]pyruvate was hyperpolarized by dissolution dynamic nuclear polarization (dDNP) and [1‐13C]pyruvate to lactate conversion was followed by 13C MRS. Subsequently [18F]FDG uptake was investigated by static and dynamic PET measurements. Standard uptake values (SUVs) for [18F]FDG were significantly higher for xenografts of PC3 compared with those of LNCaP. However, we did not observe a difference in the average apparent rate constant kpl of 13C label exchange from pyruvate to lactate between the tumor variants. A significant negative correlation was found between SUVs from [18F]FDG PET measurements and kpl values for the xenografts of both tumor types. The kpl rate constant may be influenced by various factors, and studies with a range of prostate cancer cells in suspension suggest that LDH inhibition by pyruvate may be one of these. Our results indicate that glucose and pyruvate metabolism in the prostate cancer cell models differs from that in other tumor models and that [18F]FDG‐PET can serve as a valuable complementary tool in dDNP studies of aggressive prostate cancer with [1‐13C]pyruvate.

Resistance to Androgen Deprivation Leads to Altered Metabolism in Human and Murine Prostate Cancer Cell and Tumor Models

“…Finally, we demonstrated that PC-3 cells converted HP 13 C-pyruvate to lactate at a higher rate than LNCaP cells, consistent with results from Zacharias et al who examined PC-3 xenografts using HP 13 C-pyruvate MRI [39]. However, recent work by van Heijster et al [40] did not reveal a significant difference using the same cell lines, which could be attributed to the much higher concentration of hyperpolarized pyruvate used in our study. Further, we have shown in an inducible model of castration resistance that ADPC tumors are much less glycolytic than CRPC tumors and can be monitored noninvasively using HP [1- 13 C]pyruvate based on a significant increase in the HP 13 C -lactate/ 13 C -pyruvate ratio.…”

Harnessing Lactate Metabolism for Radiosensitization

“…These characteristics are important considerations for future studies and increasingly support identifying tumor types in which harnessing radiosensitizing properties through lactate metabolism inhibition has the greatest therapeutic benefit. For example, additional imaging techniques, such as 13 C magnetic resonance spectroscopy, can better provide dynamic imaging of lactate metabolic reprogramming (115)(116)(117). A recent clinical trial explored deescalation of radiation to 30 Gy for patients with human papillomavirus-associated oropharyngeal tumors who had no hypoxia at baseline using dynamic fluorine-18-labeled fluoromisonidazole PET or resolution of hypoxia during intratreatment PET; while patients with persistent hypoxia received 70 Gy (118).…”

Dynamic Nuclear Polarization of Silicon Carbide Micro- and Nanoparticles

“…Dissolution DNP has been used to investigate metabolic pathways and to study enzymatic activities. Small hyperpolarized 13 C-labeled substrates, such as 1- 13 C-pyruvic acid or 1- 13 C-fumarate, have been successfully used to detect aberrant metabolism in cell suspensions, animal models, and human tumors. − However, the hyperpolarized state is relatively short-lived, and the polarization will restore to thermal equilibrium with the relaxation time constant T 1 . The majority of hyperpolarized 13 C-labeled molecules have a T 1 in the order of 1 min or less .…”