Apoptosis at the Interface of Immunosuppressive and Anticancer Activities: The Examples of Two Classes of Chemical Inducers, Oxysterols and Alkylating Agents

Pierre   L.   Bischoff; Vincent      Holl; David      Coelho; Patrick      Dufour; Bang      Luu; Denis      Weltin

doi:10.2174/0929867003374769

Abstract

Recent progresses in the understanding of molecular and biochemical pathways involved in apoptotic cell death offer novel perspec-tives for therapeutic interventions, in particular in immunosuppressive and anti-cancer therapies. In this review, we examine some chemical, biological, and mechanistic aspects of two classes of apoptosis chemical inducers oxysterols and alkylating 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. Some of them (7b-hydroxycholesterol, 25-hydroxycholesterol and 7,25-dihydroxycholesterol) are cytotoxic at micromolar concentrations towards normal and 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 chemotherapy for decades. There toxicity results from their high chemical reactivity, causing lesions to macromolecules through covalent linkage. Some representative members of this class, mainly bifunctional derivatives which possess dichloroethyl groups, such as Chlormethine, Cyclophosphamide and Chlorabucil, express a pronounced cytotoxicity against lymphoid cells, and have therefore potent immunosuppressive properties. Because they triggers apoptosis via both common and distinct mechanisms, oxysterols and alkylating agents 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.

Keywords: immunosuppressive, anticancer activities, chemical inducers, oxysterols, alkylatin agents, apoptotic death, programmed cell death PCD, necrosis, Fas, tumor necrosis factor TNF receptor TNF R, cancer chemotherapy, inhibition of cholesterol biosynthesis, antitumor effects, toxicity, nitrogen mustard, NH2 methyl bis chloroethyl methylamine mustine, caryolysine, mustine, chlormethine, mechlorethamine, cyclophosphamide, ifosfamide, chlorambucil, melphalan, glutathione S transferase GST, antioxideants, DNA dependent protein kinase, PARP inhibition