Molecular mechanisms of cancer prevention by selenium compounds.

Abstract

Selenium compounds that are chemopreventive in animal models inhibit cell growth and induce apoptosis in vitro, and this could explain how they reduce the outgrowth of tumor cells in vivo. Our recent work has shown that primary cultures of oral carcinoma biopsies are significantly more sensitive than normal oral mucosa cultures to induction of apoptosis by a natural selenium metabolite [selenodiglutathione (SDG)], and this is associated with induction of Fas ligand, a well-known mediator of apoptosis in other contexts, and activation of so-called stress kinase signaling pathways, particularly the Jun NH2-terminal kinase (JNK). Heme oxygenase, another marker of stress responses, is also induced by selenite and SDG. The selective activation of the Fas pathway in carcinomas could be responsible directly for their destruction by apoptosis or target them for attack by immunologic responses. In contrast, although the potent pharmacological selenium chemopreventive agent 1,4-phenylenebis(methylene)selenocyanate (p-XSC) also induces Fas ligand, heme oxygenase, and stress kinase pathways, apoptosis/Fas induction is not so strongly JNK-dependent and p-XSC does not show tumor selectivity. These differences in mechanism between SDG and p-XSC may be due to the manner in which they induce redox changes in the cells, since although the effects of SDG and p-XSC are prevented by antioxidants such as glutathione or N-acetylcysteine, hydroxyl radical scavengers such as mannitol or pyrrolidine dithiocarbamate only protect against the effects of p-XSC.

• Authors: J Fleming, A Ghose, P R Harrison
• Journal: Nutrition and cancer (Nutr Cancer) Vol. 40 Issue 1 Pg. 42-9 ( 2001) ISSN: 0163-5581 [Print] United States
• PMID: 11799922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Anticarcinogenic Agents
• Antineoplastic Agents
• FASLG protein, human
• Fas Ligand Protein
• Membrane Glycoproteins
• Organoselenium Compounds
• Selenium Compounds
• selenodiglutathione
• 1,4-phenylenebis(methylene)selenocyanate
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases
• Glutathione

Topics

• Animals
• Anticarcinogenic Agents (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Disease Models, Animal
• Fas Ligand Protein
• Glutathione (analogs & derivatives, pharmacology, therapeutic use)
• Humans
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Membrane Glycoproteins (metabolism)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Mouth Neoplasms (prevention & control)
• Organoselenium Compounds (pharmacology, therapeutic use)
• Selenium Compounds (pharmacology, therapeutic use)
• Tumor Cells, Cultured