Biochemical and Biophysical Research Communications
Hepatic processing determines dual activity of α-tocopheryl succinate: a novel paradigm for a shift in biological activity due to pro-vitamin-to-vitamin conversion☆
Section snippets
Materials and methods
C57BL mice were used at 7–9 weeks of age. The animals (5 per group) were injected every third day with 100 μl of 100 mM α-TOS (RRR-α-TOS; Sigma) in DMSO or with 100 μl DMSO alone (control mice). Twenty-four hours following the last injection, hepatic and systemic blood was collected under a stereomicroscope as follows. A heparinised 1-ml syringe (26 g needle) was carefully inserted into the hepatic vein draining the left lobe in an anaesthetised mouse and ∼200 μl of hepatic blood was withdrawn
Results and discussion
Previous circumstantial data suggested that α-TOS may be cleaved in vivo, presumably in the liver, whereby it is converted into the redox-active α-TOH. This is largely based on studies in which higher (2- to 3-fold) levels of α-TOH were observed in the circulation of mice subjected to chronic intraperitoneal administration of α-TOS at doses, at which the pro-vitamin strongly suppressed tumour growth in pre-clinical models [3], [5]. Thus, it was apparent that disposition of α-TOS in vivo
Acknowledgment
This work was supported by grants from the Queensland Cancer Fund and the Australian Research Council to J.N.
References (26)
- et al.
Vitamin E inhibits melanoma growth in mice
Surgery
(2002) - et al.
Potentiation of anti-cancer effect by intravenous administration of vesiculated α-tocopheryl hemisuccinate on mouse melanoma in vivo
Cancer Lett.
(2003) - et al.
High cytotoxicity of α-tocopheryl hemisuccinate to cancer cells is due to failure of their antioxidative defence systems
Cancer Lett.
(2002) - et al.
α-Tocopheryl succinate induces apoptosis in HER2/erbB2-overexpressing breast cancer cells by signalling via the mitochondrial pathway
Biochem. Biophys. Res. Commun.
(2005) - et al.
Lipoprotein-associated α-tocopheryl-succinate inhibits cell growth and induces apoptosis in human MCF-7 and HBL-100 breast cancer cells
Biochim. Biophys. Acta
(2000) - et al.
Vitamin E in atherosclerosis: linking the chemical, biological and clinical aspects of the disease
Atherosclerosis
(2001) - et al.
Requirement for, promotion, or inhibition by α-tocopherol of radical-induced initiation of plasma lipoprotein lipid peroxidation
Free Rad. Biol. Med.
(1997) - et al.
Absorption, lipoprotein transport, and regulation of plasma concentrations of vitamin E in humans
J. Lipid Res.
(1993) - et al.
Hydrolysis of ester- and amide-type drugs by the purified isoenzymes of nonspecific carboxylesterase from rat liver
Biochem. Pharmacol.
(1984) - et al.
Vitamin E analogues: a new class of inducers of apoptosis with selective anti-cancer effect
Curr. Cancer Drug Targets
(2004)
Vitamin E succinate and cancer treatment: a vitamin E prototype for selective anti-tumour activity
Br. J. Cancer
Induction of apoptosis in cancer cells by α-tocopheryl succinate: molecular pathways and structural requirements
FASEB J.
Clin. Cancer Res.
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2015, Journal of Controlled ReleaseCitation Excerpt :Various approaches have been employed for the preparation of delivery systems of VE analogues, especially for well-studied α-TOS. Solubilization of α-TOS in ethanol, dimethylsulfoxide (DMSO) or oil emulsions was used for the application of the drug in mouse tumor models [20,45,46]. However, it has been reported that as few as one or two injections of the therapeutic dose of α-TAM solubilized in DMSO caused rapid death of experimental animals (Balb/c, C57Bl and FVB/N c-neu mice).
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2010, Journal of Biological ChemistryCitation Excerpt :Considering this as an alternative explanation we next asked whether the antioxidant activity of α-tocopherol was necessary to exert its protective effect. In fact, the effect reported with the redox-silent analogue α-TOS could support this idea, although caution is required when interpreting those results because this compound could be hydrolyzed in vivo yielding active α-tocopherol (25, 26). Actually, the delay observed in the protective effect of α-TOS when compared with that of α-tocopherol (Fig. 3E) could be explained if processing α-TOS to the active vitamin form is a prerequisite.
Lyophilised liposome-based formulations of α-tocopheryl succinate: Preparation and physico-chemical characterisation
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Abbreviations: NSE, non-specific esterase; α-TOH, α-tocopherol; α-TOS, α-tocopheryl succinate; α-TTP, α-tocopheryl transfer protein; VLDL, very low-density lipoprotein.