On the role of ROS and antioxidants in cancer progression Martin O. Bergö Dept. Biosciences and Nutrition Karolinska Institutet Martin Bergö Reactive oxygen species pools in cancer • OH • O – 2 H O 2 2 Pro-tumorigenic Oxidative stress signaling DNA damage Tumor initiation Tumor progression The dogma on dietary antioxidants and cancer Free radicals (ROS) cause DNA damage ...thus; antioxidants, which that can lead to cancer...   neutralize ROS, must protect against cancer   UV   O ·− O ·− 2 2 DNA-damage CANCER > Billion $ industry Cancer patients heavy users A research question Do antioxidants protect against cancer? Clinical trials show inconsistent results •   Linxian General Population Nutrition Intervention Trial. J. Natl. Cancer Inst. 1993 •   Alpha-Tocopherol/Beta-Carotene Cancer Prevention Study (ATBC) N. Engl. J. Med. 1994 •   Carotene and Retinol Efficacy Trial (CARET) Cancer Res. 1996 •   Physicians’ Health Study I (PHS I) N. Engl. J. Med. 1996 •   Women’s Health Study. J. Natl. Cancer Inst. 1999 •   EUROSCAN study. J. Natl. Cancer Inst. 2000 •   Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) Archives Int. Med. 2004 •   Heart Outcomes Prevention Evaluation – The Ongoing Outcomes (HOPE-TOO) Study J. Am. Med. Assoc. 2005 •   Physicians’ Health Study II (PHS II) J. Am. Med. Assoc. 2005 •   Selenium and Vitamin E Cancer Prevention Trial (SELECT) J. Am. Med. Assoc. 2011 Three trials had to be stopped early due to more cancer in the antioxidant groups Sharper questions Do antioxidants protect against cancer? Would antioxidants protect a Would antioxidants affect the tumor-free person from cancer progression of an existing in the future? tumor? Tumor initiation Tumor progression Defining the impact of antioxidants on tumor progression: lung cancer Genetic models switch Kras2LSL/+ Kras2G12D/+ Cre-adenovirus or lentivirus Jackson et al. (2001) Genes & Dev. Study design: antioxidant added after tumor initiation NN--aacceettyyllccyysstteeiinnee ((NNAACC)) 11gg//LL iinn ddrriinnkkiinngg wwaatteerr Vitamin E 0.1 och 0.5 g/kg in chow Start NAC 7 weeks Survival 0 weeks 6 weeks 12 weeks Birth AdCre End Antioxidants increased KRAS- and BRAF-induced lung tumor progression Short-term: 12 weeks after Cre-adenovirus inhalation Antioxidants reduced survival in mice with B-RAFV600E-induced lung tumors