Sensitization to cell death induced by soluble Fas ligand and agonistic antibodies with exogenous agents: A review

Abstract

Specific binding of either soluble Fas ligand extracellular domain (sFasL) or agonistic anti-Fas receptor extracellular-domain monoclonal-antibodies (FasR-mAb) can trigger apoptotic death of emerging harmful cells in the human body. However, the efficient cell-death induction through the action of these executors are often prevented by the resistance mechanisms equipped with the target cells. Hence, strengthening their cell-death inducing activity by sensitization with the help of exogenous agents will contribute to the development of advanced treatment strategies for many serious diseases caused by impaired cell death, including cancers and autoimmune diseases. This review gives an overview focusing on the sensitization of the cell-death induction via either sFasL- or FasR-mAb-primed signal transduction system with exogenous agents. In the beginning section, the structural and functional characteristics of cell-death induction using these soluble agonistic proteins were briefly introduced. In the following sections, the studies on the sensitization of Fas signaling system with the exogenous agents, classified into two groups, were investigated, based on an extensive survey of the relevant literatures. First, the sensitization with non-cytokine agents was described, where the effects of representative low molecular-weight clinical anticancer drugs were highlighted. Then, the potency of exogenous cytokine agents was depicted, while centering on the sensitization with interferon-γ. The survey revealed that the agents examined here were effective for the sensitization against various malignant tumors-derived and other types of cells by upregulating pro-apoptotic molecular machinery and/or downregulating anti-apoptotic factors. However, in the demanding instances, this strategy still remained dysfunctional in completing the target cell-killing process due to resistance mechanisms, such as overexpression of intracellular inhibitory proteins. Finally, it is proposed that the sensitization of cell-death induction with exogenous agents, combined with empowerment regarding the targeting specificity by protein engineering techniques, is a promising approach to potentiate the soluble agonists for translating them into clinical protein pharmaceuticals.