Received for publication August 23, 2006.
Revised January 5, 2007.
Accepted for publication January 10, 2007.

Vitamin E analogs, a novel group of 'mitocans,' as anti-cancer agents: The importance of being redox-silent

Abstract

The search for a selective and efficient anti-cancer agent for treating all neoplastic disease has yet to deliver a universally suitable compound(s). Currently, majority of established anti-cancer drugs are either non-selective, causing considerable systemic (secondary) toxicity, or lose their efficacy due to the constant mutational change of malignant cells to become drug- resistant. Until relatively recently, a largely neglected target for potential anti-cancer agents was the mitochondrion. The concept of selective mitochondrial destabilization associated with apoptotic killing of cancer cells is starting to translate into clinically applicable cancer therapies. Vitamin E (VE) analogs, epitomized by alpha-tocopheryl succinate, belong to the group of 'mitocans' (mitochondrially targeted anti-cancer drugs), since they are selective for malignant cells, cause destabilization of their mitochondria and suppress cancer in pre-clinical models. This review focuses on our current understanding of VE analogs in the context of their pro-apoptotic/anti-cancer efficacy and suggests that their effect on mitochondria may be amplified by modulation of alternative pathways operating in parallel. We show here that the analogs of VE that cause apoptosis (which translates into their anti-cancer efficacy) generally do not possess anti-oxidant (redox) activity. Therefore, by analogy to Oscar Wilde's play 'The Importance of Being Earnest', we use the motto in the title 'The importance of being redox-silent' to emphasize an essentially novel paradigm for cancer therapy, where redox-silence is a prerequisite property for most of the anti-cancer activities described in this communication.

Key words: Apoptosis, Mechanisms of cell killing/apoptosis