Modulation of Cell Proliferation and Gene Expression by α‐Tocopheryl Phosphates: Relevance to Atherosclerosis and Inflammation

Abstract

The effect of a mixture of alpha-tocopheryl phosphate plus di-alpha-tocopheryl phosphate (TPm) was studied in vitro on two cell lines, RASMC (from rat aortic smooth muscle) and human THP-1 monocytic leukemia cells. Inhibition of cell proliferation by TPm was shown in both lines and occurred with TPm at concentrations lower than those at which alpha-tocopherol was equally inhibitory. TPm led in nonstimulated THP-1 cells to inhibition of CD36 mRNA and protein expression, to inhibition of oxidized low-density lipoprotein surface binding and oxLDL uptake. In nonstimulated THP-1 cells, alpha-tocopherol had only very weak effects on these events.

Effects of tocopherols and 2,2′-carboxyethyl hydroxychromans on phorbol-ester-stimulated neutrophils

“…α-TOC is known to inhibit PKC activity in a wide variety of cells [32][33][34] including neutrophils [5,6,35]. In human neutrophils, the activation and translocation of PKC from its inactive form found in the cytosol to the cell membrane are key events in phorbol-ester-induced signaling and are required to induce O 2 •− production [36].…”

α-tocopheryl phosphate suppresses tumor invasion concurrently with dynamic morphological changes and delocalization of cortactin from invadopodia

“…Thus, it seems that the antioxidant activities of TocP are not mainly involved in the repressive effects on tumor invasion, and the anti-invasive effect of TocP seems to be due to the effect of the parent compound Toc. It has been also shown that TocP is highly resistant to hydrolysis by both chemical and enzymatic actions, which indicates that its effect is not related to the hydrolytic conversion to free tocopherol (4,7,9,10,43). Furthermore, it was shown that TocP has a more marked potency than the non-esterified molecule in several studies (4,(8)(9)(10).…”

“…It has been also shown that TocP is highly resistant to hydrolysis by both chemical and enzymatic actions, which indicates that its effect is not related to the hydrolytic conversion to free tocopherol (4,7,9,10,43). Furthermore, it was shown that TocP has a more marked potency than the non-esterified molecule in several studies (4,(8)(9)(10). In addition, a previous study indicates that TocP forms a barrier that might inhibit the transfer of radicals from one polyunsaturated fatty acid to another, so that TocP has a potent antioxidant effect of its own, but not due to the conversion into Toc (7).…”

“…For example, TocP can reduce myocardial ischemia/reperfusion injury (5), protect against ultraviolet B-induced damage in cultured mouse skin (6), suppress lipid peroxidation and induction of erythrocyte hemolysis (7), induce cell death, inhibit cell proliferation and provoke apoptosis in osteosarcoma cells (3), down-regulate the scavenger receptor CD36 (4,8,9), and exert atheroscleroticpreventing effects (8,9). Furthermore, several studies have also indicated that TocP has been shown to be more effective than Toc in the regulation of cell properties (4,(8)(9)(10). Thus, the possibility that the active form of Toc may be TocP has been considered (4,9).…”

Factors affecting proteoglycan synthesis and structure that modify the interaction with lipoproteins

“…Phosphorylation has the potential to favorably modify the properties and actions of lipophilic drugs, which may otherwise manifest toxicity owing to their inherent high lipophilicity [68,69]. Troglitazone was designed with a 2, 4-thiazolidinedione nucleus to which a highly hydrophobic a-tocopherol moiety is added to confer anti oxidant properties [70].…”