Antioxidants in Cancer and Cardiovascular Diseases

1. Antioxidants in Cancer and Cardiovascular Diseases การประชุมวิชาการ ครั้งที่ 21 ประจำปี 2548 คณะแพทยศาสตร์ มหาวิทยาลัยขอนแก่น วันที่ 11- 14 ตุลาคม 2548 วีรพล คู่คงวิริยพันธุ์ Ph.D. ภาควิชาเภสัชวิทยา คณะแพทยศาสตร์ มหาวิทยาลัยขอนแก่น

2. Theme of presentation - Roles of antioxidant system in the body - Constitution of body antioxidant system - Epidemiological studies & clinical trials of antioxidant vitamins - Reflection of the failure of the clinical trials - New classes of drugs with novel antioxidant effect

3. Potential sources of reactive species Essential roles of reactive species in the body: • -Cellular signaling molecules: H2O2 • -Defense mediators against invading organisms: O2o-, HClO • -Intercellular mediator (autocoid): NO

4. S k i n B u r n s H e a r t S o l a r r a d i a t i o n C o r o n a r y t h r o m b o s i s P s o r i a s i s B r a i n D e r m a t i t i s T r a u m a , s t r o k e P a r k i n s o n L u n g N e u r o t o x i n s A s t h m a J o i n t s D e m e n t i a R h e u m a t o i d a r t h r i t i s A R D S F r e e r a d i c a l s G a s t r o i n t e s t i n a l t r a c t K i d n e y D i a b e t e s T r a n s p l a n t a t i o n P a n c r e a t i t i s G l o m e r u l o n e p h r i t i s E n d o t o x i n l i v e r i n j u r y I s c h e a m i c b o w e l M u l t i o r g a n E y e I n f l a m m a t o r y - i m m u n e i n j u r y C a t a r a c t o g e n e s i s I s c h a e m i a - r e f l o w s t a t e s R e t i n o p a t h y o f p r e m a t u r i t y D r u g t o x i c i t y D e g e n e r a t i v e r e t i n a l d a m a g e V e s s e l s I r o n o v e r l o a d A r t h e r o s c l e r o s i s E r y t h r o c y t e s A l c o h o l t o x i c i t y F a n c o n i a n e m i a N u t r i t i o n a l d e f i c e i n c i e s M a l a r i a, thalassemia R a d i a t i o n A g i n g C a n c e r s A m y l o i d d i s e a s e Excessive or uncontrollable production of reactive species ensues biomolecular damages, cell injury, cell dysfunction/death & organ failure

5. Enzyme antioxidants: SOD, CAT, Gpx, GR, TrxR, Prx Non-enzyme antioxidants: GSH, ascorbate, vitamin E beta-carotene, urate, bilirubin, ferritin High use of O2 and glucose Activation: iNOS, XO, NAD(P)H oxidase, High Fe/ascorbate High peroxidizable fatty acids Redox cycling chemicals Antioxidant defenses • Antioxidant agents: • Remove free radicals and other reactive species • enzymatic method: SOD, CAT, etc • radical scavenger, ascorbate, vitamin E • Minimize the availability of pro-oxidants: metal chelators; transferrin, ceruloplasmin • Protect biomolecule against damage: chaperon protein; heat shock proteins

6. Antioxidant compounds

7. Antioxidant & accessory enzymes Enzyme Location Substrate / Action Cu/Zn SOD Cytosol O2º- Mn-SOD Mitochondria O2º- EC-SOD Extracellular O2º- GSH-peroxidase (Gpx) Cytosol H2O2, lipid peroxides Catalase (CAT) Cytosol H2O2 Glutathione reductase (GR) Cytosol Oxidized GSH Glutathione-S-transferase Cytosol Organic peroxides Peroxiredoxin (Prx) Cytosol/mitochondria H2O2, lipid peroxides, ONOO- Thioredoxin reductase (TrxR) Cytosol/mitochondria Oxidized Trx, H2O2, vitamin C

8. Interplay between vitamin C and vitamin E Glutathione antoxidant system Thioredoxin system

9. Vitamin E consumption and the risk of coronary disease in women A prospective study of the intake of vitamins C, E, and A and the risk of breast cancer Study in 87,245 female nurses by assessing dietary consumption. Stampfer et al. New Engl J Med 1993;328:1444-9. Epidemiology of chemoprevention by vitamins Study in 89,494 healthy women. Vitamin intake was assessed from foods. Hunter et al. New Engl J Med 1993; 329:234-240

10. Epidemiology of chemoprevention by vitamin C 85118 female nurses with 16 years follow-up. Nurse Health Study: Osganian et al. J Am Coll Cardiol 2003;42:246-52.

11. Selenium supplement in population in low selenium region in the East US (n =1320). Clark et al. JAMA 1996;276:1957-63. Extending the study for another 3 year follow-up Reid et al. Cancer Epidemiol Biomarkers Prev 2002;11:1285-91. Clinical trial with selenium

12. Clinical trial with b-carotene /vitamin A b-Carotene & Retinol Efficacy Trial (CARET)

13. ATBC study group. New Eng J Med 1994;330: 1029-35.

14. Meta-analysis of the ATBC/ CHAOS/ GISSI/ HOPE/ NHS Studies No beneficial effect of vitamin E (not so HOPEful) - incidence of death - myocardial infarction - Cardiovascular death - stroke The 72nd Scientific Session of the American Heart Association, Nov 12-15, 2000, New Orleans, Louisiana, USA

15. Failure of the clinical trials • Antioxidants usually interact as a cascade network to efficiently recycle antioxidants and potentiate the antioxidant actions • Pro-oxidant properties of some antioxidant compounds under certain conditions: increase of unbound iron • Accessibility of antioxidants to the target sites, providing the sufficient concentration and duration: cell type, subcellular site • Capture the reactive species without prevention of the causation is an inefficient method: • Bioavailability of antioxidant compounds after oral administration: tea catechins, curcumin & etc • Clinical endpoint is a result of complex pathological processes apart from oxidative damage.

16. Therapeutic drugs with intrinsic antioxidant activity • Angiotensin converting enzyme inhibitors (ACEI) • Angiotensin receptor antagonist • Statins • Thiazolidinediones (TZD)

18. Mechanisms for oxidant stress-induced endothelium dysfunction Cai & Harrison. Circ Res 2000;67:840-4.

19. Yusuf et al New Engl J Med 2000;342:154-60. Yusuf et al New Engl J Med 2000;342:145-53. Clinical study with ACEI

20. ACE-inhibitors

21. Clinical study with statins CARE trial: Sacks et al New Engl J Med 1996;335:1001-9.

22. Pleiotropic effects of statins Takayama et al. Circ J 2004;68:1067-75.

23. Pleiotropic effects of statins • Statins inhibit HMGCoA reductase: • Effects on lipid: inhibit cholesterol synthesis, reduce LDL • Effects independent of LDL: inhibit Rho, & Rho kinase--> intracellular transport, mRNA stabilization & gene expression • increase eNOS expression, decrease expression of NAD(P)H oxidase & ET-1, improve endothelium function • antiinflammatory, anti-proliferation,

24. Novel effects of TZD Tao et al. Circulation 2003;108:2805-11.

25. Thiazolidinediones: a novel class of antidiabetic drug • TZD acts on nuclear receptor; PPARg • transactivation of PPARg target genes to improve insulin sensitivity • Inhibit NF-kB, AP-1 to reduce expression of inflammatory genes, iNOS, ET, TNF, NAD(P)H-oxidase, improve endothelial function (?) • Non-PPAR-g pathway

26. Prospectus • - Most diseases are resulted from multi-factorial causations • - Ideal therapeutic agents should prevent or reverse the etiological processes • - Next to the ideal drugs should suppress all pathological processes related to the etiology • - As oxidative stress is likely to involve in many diseases, some new drugs acting on multiple target sites relevant to the disease processes and including suppression of oxidants formation may be of very beneficial.

29. Linxian study: clinical trial with selenium Linxian, district in the north region of China, epidemic area of easophageal & gastric cancer, low selenium in soil. Linxian study: Case-cohort: supplemented with Se, beta-carotene & vitamin E Mark et al. JNCI 2000;92:1753-63.

30. Figure 4. Effect of ator on vascular ROS production in SHR. SHR received standard chow or standard chow supplemented with ator (50 mg/kg per day) for 30 days. Figure 1. Effect of atorvastatin (ator) on the production of ROS in VSMCs. A and B, VSMCs were preincubated for 12 hr with vehicle, ator (10 mol/L), ator plus L-mevalonate (meva, 200 mol/L), or ator + 25-hydroxycholesterol (chol, 5 g/mL), followed by a 3-hr coincubation with either 1 mol/L angiotensin II (ang II, A) or 20 ng/mL EGF (B).

31. Network of antioxidant enzymes LH+O2 SOD-CAT  H2O2 GR-GPX + GSH  H2O2 / LOOH TrxR-Prx + Trx H2O2 / LOOH /ONOO-