Sorafenib Alters Interstitial Proton and Sodium Levels in the Tumor Microenvironment: A ¹H/²³Na Spectroscopic Imaging...

Cellular metabolism is inextricably linked to transmembrane levels of proton (H⁺), sodium (Na⁺), and potassium (K⁺) ions. Although reduced sodium-potassium pump (Na⁺-K⁺ ATPase) activity in tumors directly disturbs transmembrane Na⁺ and K⁺ levels, this dysfunction is a result of upregulated aerobic glycolysis generating excessive cytosolic H⁺ (and lactate) which are extruded to acidify the interstitial space. These oncogene-directed metabolic changes, affecting intracellular Na⁺ and H⁺, can be further exacerbated by upregulation of ion exchangers/transporters. As Na⁺/H⁺ imbalances impact tumor invasion, chromosomal rearrangements, proliferation rate, angiogenesis, and immune function, measuring interstitial H⁺ (H⁺ _o) or pH (pH_o) and interstitial Na⁺ (Na⁺ _o) could provide unique insights into cancer hallmarks. We obtained proton (¹H) and sodium (²³Na) magnetic resonance spectroscopic imaging (MRSI) data to map pH_o and Na⁺ _o in a human-derived glioblastoma model (U87) in vivo with sorafenib (protein kinase inhibitor) treatment and a placebo. In U87 tumors, sorafenib slowed tumor growth compared to placebo and restored transmembrane H⁺ and Na⁺ levels. Placebo tumors maintained an interstitial space that was less salty and more acidic, similar to naive U87 tumors, implying a proliferative state. However, sorafenib-treated tumors had interstitial space that became more salty and less acidic, comparable to normal tissue. Importantly, these interstitial ionic changes occurred prior to tumor growth changes. These results imply that glioblastoma therapies, which may perturb transmembrane ions by different mechanisms (e.g., ion pumping, exchange, and/or transport), can be tracked by merging ¹H with ²³Na MRSI to measure treatment effectiveness.