Direct Targeting of Tumor Cell F₁F₀ ATP-Synthase by Radioiodine Angiostatin In Vitro and In Vivo

Abstract

Neurotensin (NT) receptors are overexpressed in different human tumors, such as human ductal pancreatic adenocarcinoma. New stable neurotensin analogs with high receptor affinity have been synthesized by replacing arginine residues with lysine and arginine derivatives. The aim of this study was to explore the biodistribution, tumor uptake, kidney localization, and stability characteristics of these new analogs in order to develop new diagnostic tools for exocrine pancreatic cancer. Four (111)In-labeled DTPA-chelated NT analogs and one (111)In-labeled DOTA-chelated NT analog were evaluated in NMRI nude mice bearing NT receptor-positive HT29 tumors. Experiments with a coinjection of unlabeled NT or lysine were performed to investigate receptor-mediated uptake and kidney protection, respectively. In addition, the in vivo serum stability of the most promising analog was analyzed. In the biodistribution study in mice, at 4 hours postinjection, a low percentage of the injected dose per gram (%ID/g) of tissue for all compounds was found in NT receptor-negative organs, such as the blood, spleen, pancreas, liver, muscle, and femur. A high uptake was found in the colon, intestine, kidneys, and in implanted HT29 tumors. The coinjection of excess unlabeled neurotensin significantly reduced tumor uptake, showing tumor uptake to be receptor-mediated. To a lesser extent, this was also observed for the colon, but not for other tissues. We concluded that DTPA-(Pip)Gly-Pro-(PipAm)Gly-Arg-Pro-Tyr-tBuGly-Leu-OH and the DOTA-linked counterpart have the most favorable biodistribution properties regarding tumor uptake.

Association between maternal omega‐3 polyunsaturated fatty acids supplementation and preterm delivery: A proteomic study

“…Otherwise, for example, the mitochondrial superoxide dismutase would have been highlighted. This is consistent with the hypothesis that the oxidative damage may derive from an OxPhos dysfunction both inside the mitochondria and in ectopic locations, that has been reported in plasma membranes, 41‐45 myelin sheath, rod disks, exosomes, and MV 17,46‐48 . The expression of mitochondrial components of the electron transfer chain (ETC) and F o F 1 ‐ATP synthase in ectopic sites not protected by a double membrane poses greater risks for oxidative stress generation and implies the involvement of GSS.…”

Evidence for Ectopic Aerobic ATP Production on C6 Glioma Cell Plasma Membrane

“…In fact, several authors have demonstrated that the angiostatin which binds and inhibits F o F 1 -ATP synthase on the endothelial cell surface (Chi and Pizzo 2006a), blocks tumor angiogenesis in vivo (Jung et al 2007;Moser et al 2001), inhibiting the endothelial cell migration and proliferation (Moser et al 2001).…”

Ectopic expression of the ATP synthase β subunit on the membrane of PC-3M cells supports its potential role in prostate cancer metastasis

“…Our results also suggested that ectopic ATP synthase localized to the caveolae of the cell membrane, with the F1 portion directed into the extracellular space. Some studies have also reported that other subunits of the ATP synthase, such as the α and β subunits of the F1 domain and the β-and δ-subunits of F0, can be found on the outside of the membranes of tumor cells and some types of normal cells, including hepatocytes, keratinocytes, adipocytes, endothelial cells and cardiomyocytes (21)(22)(23)(24), suggesting that translocation is possible. The enzyme may therefore be called cell surface ATP synthase or ecto-ATP synthase (ecto-ATPase, ecto-F1-ATPase), and ectopically localized ATP5B may be called ecto-ATP5B.…”