+ NAC - Igienisti on line

CHEMIOPREVENZIONE DEI TUMORI
Silvio De Flora
Dipartimento di Scienze della Salute
Scuola di Scienze Mediche e Farmaceutiche
Università degli Studi di Genova
GE
NUEN
SE
ATHE
NAE
UM
PREVENZIONE PRIMARIA DEI TUMORI
REGOLAMENTI
Controllo dei
fattori di rischio
ambientali
EDUCAZIONE
SANITARIA
Fattori di rischio
legati allo stile di
vita
CONTROLLO DEL RISCHIO
VALUTAZIONE DEL RISCHIO
GENOTOSSICO E CANCEROGENO
DIETA
Popolazione
generale
FARMACI
Individui ad
alto rischio
CHEMIOPREVENZIONE
VALUTAZIONE DEGLI EFFETTI
E MECCANISMI PROTETTIVI
UOMO: epidemiologia analitica, epidemiologia
molecolare, biomonitoraggio, trials clinici
METODI
ANIMALI DA LABORATORIO: valutazione di
biomarcatori intermedi, studi di cancerogenicità
SISTEMI IN VITRO: tests a breve termine
MODELLI STRUTTURA – ATTIVITA’ (SAR)
A
VITAMIN A SOURCE
C
VITAMIN C SOURCE
F
FIBER SOURCE
*
CRUCIFEROUS VEGETABLE
NCI/NIH
PIANO DI SVILUPPO PER GLI AGENTI
CHEMIOPREVENTIVI DEL CANCRO
N-Acetil-L-cisteina (NAC)
18b- Acido glicirretinico
Aspirina
Calcio
b-Carotene e altri carotenoidi
DHEA Analogo 8354
2-Difluorometilornitina (DFMO)
N-(4-Idrossifenil)retinamide (4-HPR)
Ibuprofene
Oltipraz
Piroxicam
Proscar
Sulindac
Tamoxifene
Vitamina D3 e analoghi
Vitamina E
G J. Kelloff and C.W. Boone (Eds.), J. Cell. Biochem. Suppl. 20, 1-303, 1994
PREVENTION OF LUNG TUMORS
IN MICE
NUMBER OF TUMORS/MOUSE
0.35
11.06
1.95
CONTROLS
(STANDARD DIET)
URETHANE
(STANDARD DIET)
URETHANE
(DIET WITH NAC 0.2%)
S. De Flora et al., Cancer Lett. 32, 235-241,1986
URINARY MUTAGENICITY IN A SMOKER AS RELATED TO NAC ADMINISTRATION
Revertants/24 h x 103
35
30
25
20
15
10
NAC
NAC
3
4
NAC
5
0
1
2
5
6
7
8
9
Time (days)
S. De Flora et al., J. Cell. Biochem. 58 (Suppl. 22), 33-41,1995
GENOMIC CHANGES IN MOUSE LUNG AT BIRTH
A. Izzotti et al., Mutat. Res. (Rev. Genetic Toxicol.), 544, 441-449, 2003
Lung of newborn mice / fetuses
UNTREATED
PREGNANT
MICE
NAC–TREATED
PREGNANT
MICE
8-oxo-dGuo
DNA adducts
1.9
5.0
P < 0.05
P < 0.001
0.9
NS
2.0
NS
Expression of 746 genes
MICE EXPOSED TO SMOKE AFTER BIRTH
LUNG TUMORS
UNTREATED
PREGNANT
MICE
NAC–TREATED
PREGNANT
MICE
LUNG
EMPHYSEMA
HYPERPLASIA
OF BLADDER
EPITHELIUM
16.7 %
20.4 %
6.4 %
2.1 %
61.1 %
17.0 %
R. Balansky et al., Carcinogenesis 30, 1398-1401, 2009
CHEMOPREVENTION OF CIGARETTE SMOKE–INDUCED TUMORS
R. Balansky et al., Int. J. Cancer 126, 1046-54, 2010
Sham
M
F
M+F
MCS
M
F
M+F
MCS + NAC
(current smokers)
M
F
M+F
MCS + Budesonide
(current smokers)
M
F
M+F
MCS + PEITC
(current smokers)
M
F
M+F
MCS + Budesonide
(ex–smokers)
M
F
M+F
MCS + PEITC
(ex–smokers)
M
F
M+F
P < 0.1
P < 0.05
P < 0.01
P < 0.001
0
10
20
30
40
Incidence (%)
50
60
70
0
1
2
3
4
Multiplicity (mean ± SE)
5
CHEMOPREVENTION OF CIGARETTE SMOKE–INDUCED
LUNG ADENOMAS BY NATURAL PRODUCTS
R. Balansky et al., Int. J. Cancer 131, 1991-7, 2012
BCB = black chokeberry
Sham
M
F
M+F
MCS
M
F
M+F
MCS + BCB
M
F
M+F
MCS + SB
M
F
M+F
SB = strawberry
**
**
*
0
5
*
**
10
15
*
*
20
25
Incidence (%)
30
35
0
0.25
0.50
Multiplicity (mean ± SE)
0.75
EXPRESSION OF 4858 GENES IN RAT LUNG
A. Izzotti et al., Mutat. Res. 591, 212–223, 2005
SHAM
SMOKE-FREE MICE
SMOKE-EXPOSED MICE
SAFETY
EFFICACY
NAC
OPZ
OPZ 5,6-BF
+ NAC
PEITC
I3C
PEITC
+ I3C
ECS
OPZ
NAC
5,6-BF
OPZ
+ NAC
I3C
PEITC
+ I3C
PEITC
EFFECT OF CIGARETTE SMOKE (ECS) AND CHEMOPREVENTIVE
AGENTS ON miRNA EXPRESSION IN RAT LUNG
0 .6
PCA component 2
0 .5
ECS + PEITC + I3C
0 .4
ECS + OPZ + NAC
0 .3
ECS + PEITC
0 .2
ECS + NAC
ECS + I3C
ECS + OPZ
0 .1
ECS
ECS + BF
0
NAC
-0 .1
BF
SHAM
NAC + OPZ
PEITC
-0 .2
OPZ
-0 .4
-0 .3
PEITC + I3C
- 0 .2
- 0 .1
0
0 .1
0.2
0 .3
0 .4
0 .5
0.6
0 .7
0 .8
PCA component 1
A. Izzotti et al, Cancer Prev. Res. 3, 62–72, 2010
MECHANISMS OF CANCER CHEMOPREVENTIVE AGENTS
S. De Flora and C. Ramel, Mutat. Res., 202, 285–306, 1988
S. De Flora and L.R. Ferguson, Mutat. Res., 591, 8–15, 2005
3. Inhibition of tumor promotion
PRIMARY PREVENTION
1. Inhibition of mutation and cancer initiation in the extracellular environment or in
nontarget cells
1.1. Inhibition of uptake of mutagens/carcinogens
1.1.1. Inhibition of penetration
1.1.2. Removal from the organism
1.2. Inhibition of the endogenous formation of mutagens
and carcinogens
1.2.1. Inhibition of the nitrosation reaction
1.2.2. Modification of the intestinal microbial flora
1.3. Complexation, dilution and/or deactivation of
mutagens/carcinogens outside cells
1.3.1. By physical or mechanical means
1.3.2. By chemical reaction
1.3.3. By enzyme–catalyzed reaction
1.4. Favoring absorption of protective agents
1.5. Stimulation of trapping and detoxification in nontarget cells
3.1. Inhibition of genotoxic effects (see 1 and 2)
3.2. Antioxidant activity and scavenging of free radicals
3.3. Antiinflammatory activity
3.3.1. Cyclooxygenase inhibition
3.3.2. Lipooxygenase inhibition
3.3.3. Inhibition of inducible nitric oxide synthase
3.3.4. Leukotriene receptor antagonism
3.4. Inhibition of proteases
3.5. Inhibition of cell proliferation
3.5.1. Inhibition of ornithine decarboxylase
3.5.2. Promoting proteasomal degradation of cyclins
3.5.3. Interference with multiple signaling pathways
3.6. Induction of cell differentiation
3.7. Modulation of cell apoptosis
3.8. Signal transduction modulation
3.9. Protection of intercellular communications
SECONDARY PREVENTION
2. Inhibition of mutation and cancer initiation in target cells
2.1. Modification of transmembrane transport
2.1.1. Inhibition of cellular uptake
2.1.2. Stimulation of extrusion outside cells
2.2. Modulation of metabolism
2.2.1. Inhibition of activation of promutagens/ procarcinogens by
4. Inhibition of tumor progression
Phase I
enzymes
2.2.2. Induction of Phase I detoxification and Phase II
conjugation pathways, or acceleration of decomposition
of reactive metabolites
2.2.3. Stimulation of activation, coordinated with
detoxification and blocking of reactive metabolites
2.3. Blocking or competition
2.3.1. Trapping of electrophiles by either chemical reaction or
enzyme–
catalyzed conjugation
2.3.2. Antioxidant activity and scavenging of reactive species
2.3.3. Protection of DNA nucleophilic sites
2.4. Inhibition of cell replication
2.5. Maintenance of DNA structure and modulation of DNA metabolism and repair
2.5.1. Increase of fidelity of DNA replication and repair
2.5.2. Stimulation of repair and/or reversion
of DNA damage
2.5.3. Inhibition of error-prone repair pathways
2.5.4. Correction of hypomethylation
2.5.5. Inhibition of histone deacetylation
2.5.6. Blocking of telomerases or inhibition of their activity
2.6. Control of gene expression
2.6.1. Targeted inactivation of oncogenes
2.6.2. Inhibitionofoncogene expression
2.6.3. Inhibition of oncogene sequences or activity
2.6.3.1. Inhibition of translation targeted to oncogene mRNA
2.6.3.2. Inhibition of transcription of specific DNA sequences
2.6.3.3. Blocking of target genes
2.6.2.4. Farnesyltransferase inhibition
2.6.4. Neutralization or post–translational modification of oncogene products
2.6.5. Replacement of deleted tumor suppressor genes
2.6.6. Mimicking the DNA binding of tumor suppressor genes by antiidiotypic antibodies
2.6.7. Killing of cells lacking tumor suppressor genes
4.1. Inhibition of genotoxic effects (see 1 and 2)
4.2. Antioxidant activity and scavenging of free radicals
4.3. Inhibition of proteases
4.4. Signal transduction modulation
4.5. Effects on the hormonal status
4.5.1. Selective estrogen receptor modulation
4.5.2. Aromatase inhibition
4.5.3. Selective blocking of prostaglandin E2 receptors
4.5.4. Decrease in ovarian hormones by dietary isoflavones
4.5.5. Inhibiting the pituitary secretion of luteinizing hormone
4.5.6. Preventing conversion of testosterone into
dehydrotestosterone by 5a–reductase
4.5.7. Selective androgen receptor antagonism
4.6. Effects on the immune system
4.7. Inhibition of angiogenesis
4.8. Antineoplastic activity by either mechanical, physical, chemical, or biological means
TERTIARY PREVENTION
5. Inhibition of invasion and metastasis
5.1. Antioxidant activity and scavenging of free radicals
5.2. Signal transduction modulation
5.3. Inhibition of cell proliferation (see 3.4)
5.4. Modulation of cell apoptosis
5.5. Induction of cell differentiation
5.6. Inhibition of angiogenesis
5.7. Effect on cell-adhesion molecules
5.8. Inhibition of proteases involved in basement membrane degradation and
modulation of the interaction with the extracellular matrix
5.9. Activation of antimetastasis genes
ANGIOGENESI E
ANTIANGIOGENESI
LA NAC INIBISCE L’ESPRESSIONE DEL
VEGF IN CELLULE DI SARCOMA DI KAPOSI
VASCOLARIZZAZIONE DI SPUGNE DI MATRIGEL
NAC –
NAC +
T. Cai et al., Lab. Invest. 79, 1151-1159, 1999
CRESCITA DI SARCOMA DI KAPOSI UMANO IN TOPI NUDI
CONTROLLI
NAC
1.5
1.0
0
F
E
M
M
I
N
E
M
A
S
C
H
I
M
A
S
C
H
I
4.0
3.5
3.0
2.5
2.0
)3
Volume del tumore (cm3)
0.5
F
E
M
M
I
N
E
1.5
+
+
1.0
0.5
0
5
10
15
20
25
30 5
10
Tempo (giorni)
15
20
25
30
A. Albini et al., Cancer Res. 61, 8171-8178, 2001
REQUISITI
EFFICACIA
INTERVENTI (Bersagli)
TERAPIA (malati di cancro)
PREVENZIONE TERZIARIA
(malati di cancro curati)
INTERVENTO PRECOCE
(malati di cancro in fase preclinica o precoce)
PREVENZIONE DELLA PROGRESSIONE
(individui affetti da lesioni precancerose)
BASSO COSTO
PRATICITA’
TOLLERABILITA’
CHEMIOPREVENZIONE MIRATA
(individui ad alto rischio)
INTERVENTO DI SANITA’ PUBBLICA
(soggetti sani nella popolazione)
S. De Flora et al., IARC Sci. Publ. No. 139, 1996, pp. 291-301
Anticancer drugs
Anthracyclines and
anthraquinolones
Capecitabine, Cytarabine,
5–Fluorouracil
Paclitaxel, Vinca alkaloids
Cyclophosphamide
TK Inhibitors (Trastuzumab,
Imatinib, Bevacizumab,
Sorafenib, Sunitinib, etc)
COX–2 inhibitors
Estrogen receptor modulators
Irradiation to the thorax
Mechanisms of cardiotoxicity
Mitochondrial dysfunction
Apoptosis of cardiomyocytes
ROS generation
DNA damage
Endothelial cell damage
Antibody directed cellular cytotoxicity
ATP block
Cell signaling, survival block
Fibrosis
Hypertension
Sinus bradicardia
Atrium-ventricular block
Ventricular tachycardia
Arrhythmias
Thromboembolism
Protective agents
ACE inhibitors
Beta–blockers
Statins
Dexrazoxane
L–Carnitine
Coenzyme Q10
N–Acetyl–L–Cysteine
Glutathione
Erdosteine
Selenium
Zinc
Melatonin
Flavonoids and polyphenols
Platelet antiaggregants
A. Albini, G. Pennesi, R. Cammarota, F. Donatelli, S. De Flora, D.M. Noonan,
Cardiotoxicity of anticancer drugs: The need for cardio-oncology and
cardio-oncological prevention, J. Natl Cancer Inst., 102, 14-25, 2010
PHARMACOGENOMICS / NUTRIGENOMICS
OF CHEMOPREVENTIVE AGENTS
2.4
2.0
before NAC
6 months after NAC
1.6
MN
(‰)
1.2
*
0.8
0.4
0
All
subjects
Fast
NAT2
+
GSTM1
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
ITALY, GENERAL MORTALITY DATA, 1901–2000
35
ITALY, 2000
Population: 58 million
Deaths: 1,276,000
Mortality rate: 22‰
Rates per 100.000
30
25
ITALY, 2000
Population: 58 million
Deaths: 560,000
Mortality rate: 9.7‰
20
15
10
5
ITALY, 1901
Population: 33 million
Deaths: 726,000
Mortality rate: 22‰
0
1900
1910
1920
1930
1940
1950
1960
1970
1980
1990
2000