Evaluating Acetate Metabolism for Imaging and Targeting in Multiple Myeloma

Abstract

Purpose We hypothesized that in multiple myeloma cells (MMC), high membrane biosynthesis will induce acetate uptake in vitro and in vivo. Here, we studied acetate metabolism and targeting in MMC in vitro and tested the efficacy of 11C-acetate-PET (positron emission tomography) to detect and quantitatively image myeloma treatment response in vivo. Experimental design Acetate fate tracking using 13C-edited-1H NMR (nuclear magnetic resonance) was performed to study in vitro acetate uptake and metabolism in MMC. Effects of pharmacological modulation of acetate transport or acetate incorporation into lipids on MMC cell survival and viability were assessed. Preclinical mouse MM models of subcutaneous and bone tumors were evaluated using 11C-acetate-PET/CT imaging and tissue biodistribution. Results In vitro, NMR showed significant uptake of acetate by MMC, and acetate incorporation into intracellular metabolites and membrane lipids. Inhibition of lipid synthesis and acetate transport was toxic to MMC, while sparing resident bone cells or normal B cells. In vivo, 11C-acetate uptake by PET imaging was significantly enhanced in subcutaneous and bone MMC tumors compared to unaffected bone or muscle tissue. Likewise, 11C-acetate uptake was significantly reduced in MM tumors after treatment. Conclusions Uptake of acetate from the extracellular environment was enhanced in MMC and was critical to cellular viability. 11C-acetate-PET detected the presence of myeloma cells in vivo, including uptake in intramedullary bone disease. 11C-acetate-PET also detected response to therapy in vivo. Our data suggested that acetate metabolism and incorporation into lipids was crucial to MM cell biology and that 11C-acetate-PET is a promising imaging modality for MM.

Determination of a pharmacokinetic model for [11C]-acetate in brown adipose tissue

“…In reality, the imaging voxel (4 mm 3 ) comprises many cells and blood vessels. [ 11 C]-acetate exchanges rapidly through the capillary wall [18] and is transported into the cell by monocarboxylate transporters [35]. It is then converted to [ 11 C]-acetyl-CoA by acetyl-CoA synthase.…”

VLA4-Targeted Nanoparticles Hijack Cell Adhesion–Mediated Drug Resistance to Target Refractory Myeloma Cells and Prolong Survival

“…Human myeloma cell lines (HMCL) U266, MM.1S, OPM2, RPMI8226, mouse bone marrow stromal cells (BMSC) and macrophages were obtained as previously described (25,26). DexR-8226 cells were selected by culturing RPMI8226 cells in increasing doses followed by maintenance in 20 M dexamethasone.…”

“…To obtain MM stroma, CD138-negative cells from the bone marrow of newly diagnosed or relapsing patients were selected by culturing them in adhesion as described (26) and then assigned to four experiments: viability by flow cytometry, staining with DiI prior to co-culture, coculture staining with live/dead, pre-treatment then co-culture.". Ex-vivo melphalan-resistant and osteotropic 5TGM1 were obtain by culturing whole bone marrow from a 5TMM mouse and two KaLwRij mice with subcutaneous 5TGM1 (25), and identified by GFP expression by microscopy and fluorimetry.…”

Contribution of perfusion to the 11C‐acetate signal in brown adipose tissue assessed by DCE‐MRI and 68Ga‐DOTA PET in a rat model

“…5,6 Furthermore, PET has greater sensitivity and spatial resolution than the thermography and thermometry methods currently used to measure BAT thermogenesis. 7,8 Blood acetate is quickly transported into cells via monocarboxylate transporters 9 and converted to acetyl-coenzyme A (acetyl-CoA), a substrate for the Krebs cycle and lipid synthesis. In a previous article, we proposed a four-compartment pharmacokinetic model to distinguish oxidation and lipid synthesis.…”

“…Blood acetate is quickly transported into cells via monocarboxylate transporters 9 and converted to acetyl‐coenzyme A (acetyl‐CoA), a substrate for the Krebs cycle and lipid synthesis. In a previous article, we proposed a four‐compartment pharmacokinetic model to distinguish oxidation and lipid synthesis 10 .…”