Mechanism of Action and Therapeutic Potential of Novel Adamantyl Retinoid-Related Molecules

Cancer costs the life of over 6 M human beings from around the world every year. More than 1.3 million new cases are predicted to be diagnosed only in the USA during 2005 with over 570,000 deaths estimated. A better understanding of the molecular basis of carcinogenesis has facilitated progress towards improving early detection and prevention as well as the development of more efficient and specific treatments against certain types of cancer. However, very few successful anticancer agents exist today and aggressive tumors are still incurable. Retinoids are natural and synthetic derivatives of vitamin A, which have shown promise for the prevention and treatment of cancer because of their cell growth inhibition and differentiation activities. Unfortunately, their clinical use has been stalled by significant toxicity caused by the broad biological responses mediated by the nuclear retinoid receptors. Synthetic retinoid-related molecules containing an adamantyl group have been shown to induce apoptosis and show promising anticancer activity in animal models, therefore representing optimal leads for the development of novel retinoid-like anticancer drugs. These compounds induce apoptosis via the mithochondrial pathway and seem to function independently of nuclear retinoid receptor activity. In contrast, they have an effect on various cytosolic signaling pathways, including activation of stress kinases (cJun N-terminal kinase and p38 kinase) and inhibition of survival kinases (I κB kinase).