Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity

Abstract

Great hope has been given to micronutrients as anticancer agents, since they present natural compounds with beneficial effects for normal cells and tissues. One of these is vitamin E (VE), an antioxidant and an essential component of biological membranes and circulating lipoproteins. In spite of a number of epidemiological and intervention studies, little or no correlation between VE intake and incidence of cancer has been found. Recent reports have identified a redox-silent analogue of VE, alpha-tocopheryl succinate (alpha-TOS), as a potent anticancer agent with a unique structure and pharmacokinetics in vivo. alpha-TOS is highly selective for malignant cells, inducing them into apoptotic death largely via the mitochondrial route. The molecule of alpha-TOS may be modified so that analogues with higher activity are generated. Finally, alpha-TOS and similar agents are metabolised to VE, thereby yielding a compound with a secondary beneficial activity. Thus, alpha-TOS epitomises a group of novel compounds that hold substantial promise as future anticancer drugs. The reasons for this optimistic notion are discussed in the following paragraphs.

Figure 1

α-TOS inhibits colon cancer (A), and is converted to the redox-active α-TOH (B) (adapted from Weber et al, 2002). Nude mice with colon cancer xenografts were treated with the vehicle (control), α-TOH or α-TOS, by intraperitoneal injection of 100 nmol of the drug, every second day for 10 days. In the end, the tumour size was estimated (A) and the mouse plasma was analysed for the level of α-TOH (B). (C) Bases of the hypothesis are presented in this communication. After reaching the circulation, a VE analogue (epitomised in our studies by α-TOS) binds to circulating lipoproteins (LP), which carry it to the microvasculature, where it kills cancer cells (this is the ‘provitamin E effect’). Lipoproteins with bound α-TOS are cleared in the liver, where nonspecific esterase (NE) very efficiently cleaves it into α-TOH. The newly generated α-TOH is in part excreted in the bile, in part bound to the saturable α-tocopheryl-transfer protein (α-TTP), which inserts it into nascent very low-density lipoprotein. In this way, the provitamin E is converted to VE, which increases the antioxidant defences and acts as an immunosuppressive agent.