Apoptosis at the interface of immunosuppressive and anticancer activities:The examples of two classes of chemical inducers, oxysterols and alkylating agents

Recent progresses in the understanding of molecular and biochemical pathway s involved in apoptotic cell death offer novel perspectives for therapeutic interventions, in particular in immunosuppressive and anti-cancer therapie s. In this review, we examine some chemical, biological, and mechanistic as pects of two classes of apoptosis chemical inducers: oxysterols and alkylat ing agents. Oxysterols represent a vast family of oxygenated derivatives of sterols. Found in both animal and vegetal kingdoms, they can be considered as ultimate products of an oxidative stress, and are chemically inert. Som e of them (7 beta-hydroxycholesterol, 25-hydroxycholesterol and 7,25-dihydr oxycholesterol) are cytotoxic at micromolar concentrations towards normal a nd tumor cells in culture, particularly lymphocytes, and reduce the growth of murine transplanted tumors. Thus, possible applications of oxysterols in medicine as immunosuppressants or as anticancer agents may be considered. Alkylating agents, on the other hand, have been widely used in cancer chemo therapy for decades. There toxicity results from their high chemical reacti vity, causing lesions to macromolecules through covalent linkage. Some repr esentative members of this class, mainly bifunctional derivatives which pos sess dichloroethyl groups, such as Chlormethine, Cyclophosphamide and Chlor abucil, express a pronounced cytotoxicity against lymphoid cells, and have therefore potent immunosuppressive properties. Because they triggers apopto sis via both common and distinct mechanisms, oxysterols and alkylating agen ts provide unique tools for exploring the initiation of this phenomenon in lymphoid cells, and may help design novel pharmacological approaches based on apoptotic modulation of these cells.