Vitamin E Analogues and Immune Response in Cancer Treatment

Abstract

Chemotherapeutic drugs induce both proliferation arrest and apoptosis; however, some cancer cells escape drug toxicity and become resistant. The suppression of the immune system by chemotherapeutic agents and radiation promotes the development and propagation of various malignancies via "mimicry-induced" autoimmunity, and maintain a cytokine milieu that favors proliferation by inhibiting apoptosis. A novel, efficient approach is based on a synergistic effect of different anticancer agents with different modes of action. Recently, a redox-silent analogue of vitamin E, a-tocopheryl succinate (a-TOS), has come into focus due to its anticancer properties. a-TOS behaves in a very different way than its redox-active counterpart, a-tocopherol, since it promotes cell death. It exerts pleiotrophic responses in malignant cells leading to cell cycle arrest, differentiation, and apoptosis. Apart from its role in killing cancer cells via apoptosis, a-TOS affects expression of genes involved in cell proliferation and cell death in a "subapoptotic" manner. For example, it modulates the cell cycle machinery, resulting in cell cycle arrest. The ability of a-TOS to induce a prolonged S phase contributes to sensitization of cancer cells to drugs destabilizing DNA during replication. A cooperative antitumor effect was observed also when a-TOS was combined with immunological agents. a-TOS and TRAIL synergize to kill cancer cells either by upregulating TRAIL death receptors or by amplifying the mitochondrial apoptotic pathway without being toxic to normal cells. a-TOS and TRAIL in combination with dendritic cells induce INF-? production by CD4+ and CD8+ T lymphocytes, resulting in a significant tumor growth inhibition or in complete tumor regression. These findings are indicative of a novel strategy for cancer treatment that involves enhanced immune system surveillance.