Antioxidants in Cancer Antioxidants in Cancer and Cardiovascular and Cardiovascular

DiseasesDiseases

วี�รพล คู่��คู่งวีรยพ�นธุ์�� Ph.D.ภาคู่วีชาเภสั�ชวีทยา

คู่ณะแพทยศาสัตร� มหาวีทยาล�ยขอนแก่�น

ก่ารประช�มวีชาก่าร คู่ร�#งท�$ 21 ประจำ&าป' 2548

คณะแพทยศาสตร์� มหาวิ�ทยาลั�ยขอนแก่�น วี�นท�$ 11- 14 ต�ลาคู่ม 2548

Theme of presentationTheme of presentation

- Roles of antioxidant system in the body

- Constitution of body antioxidant system

- Epidemiological studies & c linical trials of antioxidant vitamins

- Reflection of the failure of the clinical trials

- New classes of drugs with novel antioxidant effect

Potential sources of reactive species

Essential roles of reactive species in the body:

- Cellular signaling molecules: H2

O2

- Defense mediators against inv ading organisms: O

2

-o , HClO- Intercellular mediator (autocoi

d): NO

Free radicals

BrainTrauma, strokeParkinson NeurotoxinsDementia Joints

Rheumatoid arthritis

SkinBurnsSolar radiationPsoriasisDermatitis

Gastrointestinal tractDiabetesPancreatitisEndotoxin liver injuryIscheamic bowel

HeartCoronary thrombosis

EyeCataractogenesisRetinopathy of prematurityDegenerative retinal damageVessels

ArtherosclerosisErythrocytesFanconi anemiaMalaria, thalassemia

LungAsthmaARDS

KidneyTransplantationGlomerulonephritis

MultiorganInflammatory-immune injuryIschaemia-reflow statesDrug toxicityIron overloadAlcohol toxicityNutritional deficeinciesRadiationAgingCancerAmyloid diseases

Excessive or uncontrollable production of reactive species ensues

biomolecular damages, cell injury, cell dysfunction/death & organ failure

AntioxidantAntioxidant defenses defenses

High use of O2 and glucoseActivation: iNOS, XO, NAD(P)H oxidase, High Fe/ascorbateHigh peroxidizable fatty acidsRedox cycling chemicals

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

Enzyme antioxidants: SOD, CAT, Gpx, GR, TrxR, PrxNon-enzyme antioxidants:GSH, ascorbate, vitamin Ebeta-carotene, urate, bilirubin, ferritin

Antioxidant compoundsAntioxidant compounds

Antioxidant & accessory Antioxidant & accessory enzymes enzymes

Enzyme Location Substrate / ActionCu/Zn SOD Cytosol O2

º-

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

Interplay between vitamin C and vitamin E

Glutathione antoxidant system

Thioredoxin system

Epidemiology of chemoprevention by Epidemiology of chemoprevention by vitamins vitamins

Study in 89,494 healthy women. Vitamin intake was assessed from foods. Hunter et al. New Engl J Med 1993; 329:234-240

Vitamin C

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Re

lati

ve

ris

k

Lowest

Highest

Vitamin E

0

0.2

0.4

0.6

0.8

1

1.2

Rela

tive r

isk

Lowest

Highest

Vitamin A

0

0.2

0.4

0.6

0.8

1

1.2

Rela

tive r

isk

Lowest

Highest

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.

Vitamin E consumption and the risk of coronary disease in women

Epidemiology of chemoprevention Epidemiology of chemoprevention by vitamin Cby vitamin C

-85118 16female nurses with years follow up. H HHHHH HHHHHH H HHHHHHH : et al HHHH. 2003 ;42:246-52.

Clinical trial with seleniumClinical trial with selenium

Extending the study for another 3 year follow-upReid et al. Cancer Epidemiol Biomarkers Prev 2002;11:1285-91.

Selenium supplement in population in low selenium region in the East US (n =1320). Clark et al. JAMA 1996;276:1957-63.

-Carotene & Retinol Efficacy Trial(CARET)

Clinical trial with Clinical trial with -carotene -carotene /vitamin A/vitamin A

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

- Meta analysis of- Meta analysis of the ATBC/ CHAOS/ GISSI/ HOPE/ NHS Stu the ATBC/ CHAOS/ GISSI/ HOPE/ NHS Stu

diesdies

The 72nd Scientific Session of the American Heart Association, Nov 12-15, 2000, New Orleans, Louisiana, USA

No beneficial effect of vitamin E (not so HOPEful)

- incidence of death

- myocardial infarction

- Cardiovascular death

- stroke

Failure of the clinical trialsFailure of the clinical trials

Antioxidants usually interact as a cascade network to efficiently recycle antioxidants and potentiate the antioxi

dant actions

- Pro oxidant properties of some antioxidant compound s under certain conditions: increase of unbound iron

Accessibility of antioxidants to the target sites, providi ng the sufficient concentration and duration: cell type, su

bcellular site

Capture the reactive species without prevention of the causation is an inefficient method:

Bioavailability of antioxidant compounds after oral ad ministration: tea catechins, curcumin & etc

Clinical endpoint is a result of complex pathological pr ocesses apart from oxidative damage.

Therapeutic drugs with Therapeutic drugs with intrinsic intrinsic aa ntioxidant activity ntioxidant activity

Angiotensin converting enzyme inhibitors (ACEI) Angiotensin receptor antagonist Statins Thiazolidinediones (TZD)

Mechanisms for oxidant stress-induced Mechanisms for oxidant stress-induced endothelium dysfunctionendothelium dysfunction

Cai & Harrison. Circ Res 2000;67:840-4.

Clinical study with ACEIClinical study with ACEI

Yusuf et al New Engl J Med 2000;342:154-60. Yusuf et al New Engl J Med 2000;342:145-53.

ACE-inhibitorsACE-inhibitors

Clinical study with statinsClinical study with statins

CARE trial: Sacks et al New Engl J Med 1996;335:1001-9.

Pleiotropic effects of stat Pleiotropic effects of statinsins

Takayama et al. Circ J 2004;68:1067-75.

Pleiotropic effects of statins Pleiotropic effects of statins

Statins inhibit HMGCoA reductase: Effects on lipid: inhibit cholesterol synthesis, reduce LDLEffects independent of LDL: inhibit Rho, & Rho kinase--> intra

cellular transport, mRNA stabilization & gene expression increase eNOS expression, decrease expression of NAD(P)H

oxidase & ET-1, improve endothelium function antiinflammatory, anti-proliferation,

Novel effects of TZDNovel effects of TZD

Tao et al. Circulation 2003;108:2805-11.

Thiazolidinediones: a nov Thiazolidinediones: a nov el class of antidiabetic dr el class of antidiabetic dr

ugug TZD acts on nuclear receptor; PPAR transactivation of PPAR target genes to improve insulin sensitivity Inhibit NF-B, AP-1 to reduce expression of inflammatory genes, iNOS, ET, TNF, NAD(P)H-oxidase, improve endothelial function (?) Non-PPAR- pathway

ProspectusProspectus

- - 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 o xidative stress is likely to involve in many diseases, some new drugs acting on multiple target sites relevant t

o the disease processes and including suppression of oxi dants formation may be of very beneficial.

Linxian study: clinical trial with Linxian study: clinical trial with seleniumselenium

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.

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 ROSin VSMCs. A and B, VSMCs were preincubated for 12 hrwith 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 angiotensinII (ang II, A) or 20 ng/mL EGF (B).

Network of antioxidant Network of antioxidant enzymes enzymes

LH+O2

SOD-CAT H2O2

GR-GPX + GSH H2O2 / LOOH

TrxR-Prx + Trx H2O2 / LOOH /ONOO-