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, alpha-tocopheryl succinate (alpha-TOS), has come into focus due to its anticancer properties. alpha-TOS behaves in a very different way than its redox-active counterpart, alpha-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, alpha-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 alpha-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 alpha-TOS was combined with immunological agents. alpha-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. alpha-TOS and TRAIL in combination with dendritic cells induce INF-gamma 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.