Identification of organoselenium compounds that possess chemopreventive properties in human prostate cancer LNCaP cells.

The process of cancer development consists of three sequential stages termed initiation, promotion, and progression. Oxidative stress damages DNA and introduces mutations into oncogenes or tumor suppressor genes, thus contributing to cancer development. Cancer chemoprevention is defined to prevent or delay the development of cancer by the use of natural or synthetic substances. In the present study, we synthesized a series of organoselenium compounds and evaluated their possible chemopreventive properties in human prostate cancer LNCaP cells. Among 42 organoselenium compounds tested, two compounds, 3-selena-1-dethiacephem 13 and 3-selena-1-dethiacephem 14 strongly activated the Nrf2/ARE (antioxidant response element) signaling and thus markedly increased expression of heme oxygenase-1 (HO-1), a phase II antioxidant enzyme. Translocation of Nrf2 to the nucleus preceded HO-1 protein induction by two compounds. The intracellular ROS level was strongly reduced immediately after treatment with these compounds, showing that they are potent antioxidants. Finally, both compounds inhibited cell growth via cell cycle arrest. Our findings suggest that compounds 13 and 14 could not only attenuate oxidative stress through Nrf2/ARE activation and direct ROS scavenging but also inhibit cell growth. Thus, these compounds possess the potential as pharmacological agents for chemoprevention of human prostate cancer.

[1]  Y. Akao,et al.  Preconditioning by sesquiterpene lactone enhances H2O2-induced Nrf2/ARE activation. , 2008, Biochemical and biophysical research communications.

[2]  I. Thompson,et al.  SELECT: the selenium and vitamin E cancer prevention trial. , 2003, Urologic oncology.

[3]  Snehasis Jana,et al.  Role of phase II drug metabolizing enzymes in cancer chemoprevention. , 2009, Current drug metabolism.

[4]  H. Mukhtar,et al.  Chemoprevention of Prostate Cancer through Dietary Agents: Progress and Promise , 2007, Cancer Epidemiology Biomarkers & Prevention.

[5]  R. Cole,et al.  Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[6]  K. Itoh,et al.  Ebselen, a seleno-organic antioxidant, as an electrophile. , 2006, Chemical research in toxicology.

[7]  H. Pitot.  The natural history of neoplastic development: The relation of experimental models to human cancer , 1982, Cancer.

[8]  J. Crowley,et al.  Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). , 2009, JAMA.

[9]  R. Hayes,et al.  Serum selenium and risk of prostate cancer in U.S. blacks and whites , 2003, International journal of cancer.

[10]  M. McMahon,et al.  Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. , 2001, Cancer letters.

[11]  E. Cadenas,et al.  A novel biologically active seleno-organic compound--I. Glutathione peroxidase-like activity in vitro and antioxidant capacity of PZ 51 (Ebselen). , 1984, Biochemical pharmacology.

[12]  W. Willett,et al.  PREDIAGNOSTIC SERUM SELENIUM AND RISK OF CANCER , 1983, The Lancet.

[13]  M. Humar,et al.  Carbon Monoxide Releasing Molecule-2 Inhibits Pancreatic Stellate Cell Proliferation by Activating p38 Mitogen-Activated Protein Kinase/Heme Oxygenase-1 Signaling , 2010, Molecular Pharmacology.

[14]  S. Ripatti,et al.  Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. , 1998, Journal of the National Cancer Institute.

[15]  Jawed Alam,et al.  Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. , 2003, The Biochemical journal.

[16]  R. Weale,et al.  FIVE YEARS' GRACE. , 1964, Lancet.

[17]  T. Satoh,et al.  Protective effects on neuronal cells of mouse afforded by ebselen against oxidative stress at multiple steps , 2004, Neuroscience Letters.

[18]  A. Murakami,et al.  Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes , 2004, FEBS letters.

[19]  H. Mukhtar,et al.  Cancer chemoprevention through dietary antioxidants: progress and promise. , 2008, Antioxidants & redox signaling.

[20]  Y. Kan,et al.  Identification of the NF-E2-related Factor-2-dependent Genes Conferring Protection against Oxidative Stress in Primary Cortical Astrocytes Using Oligonucleotide Microarray Analysis* , 2003, The Journal of Biological Chemistry.

[21]  Eun-sook Kim,et al.  Ebselen attenuates cisplatin-induced ROS generation through Nrf2 activation in auditory cells , 2009, Hearing Research.

[22]  K. Itoh,et al.  A Sulforaphane Analogue That Potently Activates the Nrf2-dependent Detoxification Pathway* , 2002, The Journal of Biological Chemistry.

[23]  G. Jeong,et al.  Isoliquiritigenin 2'-methyl ether induces growth inhibition and apoptosis in oral cancer cells via heme oxygenase-1. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[24]  C. B. Pickett,et al.  The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. , 2004, Free radical biology & medicine.

[25]  H. Choi,et al.  Heme oxygenase-1 induced by aprotinin inhibits vascular smooth muscle cell proliferation through cell cycle arrest in hypertensive rats. , 2009, The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology.

[26]  Y. Surh,et al.  Cancer chemoprevention with dietary phytochemicals , 2003, Nature Reviews Cancer.

[27]  M. Koketsu,et al.  Synthesis of 3-selena-1-dethiacephems and selenazepines via iodocyclization. , 2008, Organic letters.