On the role of ROS and antioxidants in cancer progression

52 Pages·2017·10.63 MB·English

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