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Silvio De Flora
E’ POSSIBILE PREVENIRE I TUMORI?
Dipartimento di Scienze della Salute
Università degli Studi di Genova
GE
NUEN
SE
ATHE
NAE
UM
Coordinatore GdL SItI Prevenzione Tumori / Screening
Genova, Seminario UNiTE, 01/03/2017
IL GIURAMENTO DI IPPOCRATE
Giuro su Apollo il medico e Asclepio e Igea e Panacea e tutti i dei e le dee, facendoli miei testimoni, che terrò fede a questo giuramento secondo la mia capacità e il mio giudizio….
Asclepio Panacea Igea
Ippocrate
0
100
200
300
400
500
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000
ACCRESP
1407
DIG
INF
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
De
ath
s p
er
10
0,0
00
ITALY, 1901–2000 (RAW MORTALITY DATA)
0
100
200
300
400
500
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000
ACCRESP
1407
DIG
INF
CER
CARD
CAN
De
ath
s p
er
10
0,0
00
ITALY, 1901–2000 (RAW MORTALITY DATA)
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
0
100
200
300
400
500
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000
CAN
DIG
ACCRESP
INF
1436
CER
CARD
De
ath
s p
er
10
0,0
00
ITALY, 1901–2000 (AGE-STANDARDIZED MORTALITY DATA)
–72.4%–74.4%
–51.9%–67.9%
M
M
F
F
CEREBROVASCULARDISEASES
CARDIOVASCULARDISEASES
–18.3%
–12.9%
MF
CANCER
1 2 3
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
0
100
200
300
400
500
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000
ACCRESP
1407
DIG
INF
CER
CARD
CAN
De
ath
s p
er
10
0,0
00
ITALY, 1901–2000 (RAW MORTALITY DATA)
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
METABOLIC DEACTIVATION OF MUTAGENSS. De Flora, Nature 271, 455-456, 1978
METABOLIC DEACTIVATION OF MUTAGENSS. De Flora, Nature 271, 455-456, 1978
CHROMIUM(VI) REDUCING CAPACITY OF ORGANS, CELL
POPULATIONS AND FLUIDS IN THE HUMAN DIGESTIVE SYSTEM
De Flora et al., Carcinogenesis 18, 531–537, 1997
PORTAL SYSTEM BLOOD
[187 - 234 mg Cr(VI)]
INTESTINAL BACTERIA
[11 – 24 mg Cr(VI) eliminated
daily with bacteria in feces]
GASTRIC JUICE
[> 84 – 88 mg Cr(VI)/day]
SALIVA [0.7 – 2.1 mg Cr(VI)/day]
LIVER CELLS
[3,300 mg Cr(VI)]
BRONCHIAL
TREE CELLS
PERIPHERAL
LUNG PARENCHYMA
CELLS [260 mg Cr(VI)]
ELF [0.9 – 1.8 mg Cr(VI)]
PAM [136 mg Cr(VI)]
BLOOD
[187 – 234 mg Cr(VI)]
CHROMIUM(VI) REDUCING CAPACITY OF ORGANS, CELL
POPULATIONS AND FLUIDS IN THE HUMAN RESPIRATORY TRACTDe Flora et al., Carcinogenesis 18, 531–537, 1997
0
100
200
300
400
500
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000
ACCRESP
1407
DIG
INF
CER
CARD
CAN
De
ath
s p
er
10
0,0
00
ITALY, 1901–2000 (RAW MORTALITY DATA)
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
IL CANCRO IN ITALIA
Sede del cancro
Tutte le sedi
Colon-retto
Mammella
Polmone
Prostata
Vescica
Pancreas
Stomaco
N. di casi
(AIRTUM, 2016)
365.000
(190.000 M,
176.000 F)
52.000
50.000
41.000
35.000
27.000
13.500
13.000
N. di morti
(ISTAT, 2013)
176.000
(99.000 M,
77.000 F)
19.000
12.000
33.000
7.000
5.600
11.000
10.000
Prevalenza
(2015)
2.200.000 (2006)
3.000.000 (2015)
(4,7% M, 5,3% F)
427.000
693.000
88.000
399.000
254.000
Dal 2008 al 2016 diminuzione annuale del 2,5% nei maschi, piccolo aumento
nelle femmine (da 169.000 nuovi casi nel 2015 a 176.000 nel 2016)
Dal 2008 al 2013 diminuzione nei maschi (-1,5% annuo) e nelle femmine
(-0,7% annuo)
Rossi et al., 2013
MASCHI FEMMINE
INCIDENZA E MORTALITA’ DEI TUMORI IN ITALIA (1970-2015, DATI STANDARDIZZATI PER ETA’)
IL CANCRO NEL MONDO
Ogni anno il cancro è diagnosticato in più di 14 milioni di individui
Nel 2015, 8,8 milioni di individui sono morti di cancro, 2/3
in paesi a basso-medio reddito
Il cancro rappresenta globalmente 1/6 delle cause di morte
Oltre ad un immenso carico di sofferenze umane, questo
comporta un costo enorme, valutato in 1.160 miliardi di $
all’anno
Le previsioni sono che in pochi anni (da ora al 2030) il numero
di nuovi casi di cancro nel mondo aumenterà del 50%, e cioè
da 14 a 21 milioni, e il numero di morti sarà di 13 milioni
MAINSTREAM
SMOKE
SIDESTREAM
SMOKE
ENVIRONMENTAL
CIGARETTE
SMOKE (ECS)
Year
MALES FEMALES
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
De
ath
sp
er
10
0,0
00CRUDE DATA
AGE-STANDARDIZED DATA
Lung and stomach cancers in Italy
DIETA, ALIMENTAZIONE E CANCRO
FATTORI DI RISCHIO FATTORI PROTETTIVI
Dieta ipercalorica
Dieta iperproteica ?
Dieta iperglucidica (carboidrati semplici)?
Dieta iperlipidica (< 30% Cal; < 10% a. grassi saturi)
Contaminanti naturali (micotossine)
Componenti naturali (idrazine, pesticidi naturali)
Contaminanti artificiali (pesticidi)
Conservanti/additivi/coloranti
Precursori di cancerogeni endogeni
Eccesso di NaCl
Salatura alimenti
Affumicatura alimenti
Abbrustolimento e frittura alimenti
Eccessiva temperatura
Esercizio fisico
Inibitori nitrosazione (Vit. C)
Conservazione alimenti
a bassa temperatura
Forni a microonde
Vitamine antiossidanti (A, ac. folico, C, E)
Elementi chimici (Se, Ca)
Clorofillina
Vari composti protettivi (crucifere)
Fibre indigeribili
Prodotti lattiero-caseari fermentati
Frutta e verdura, bevande (vino, thé)
HPV
HPV
HPV
HPV
HPV
HPV
HBV HCV
HBV HCVHBV HCV
HBV HCV
H.P.
H.P.
EBV
HHV-8HIV
Infectious agents cause 17% of allcancers worldwide,
26% in developing world, 8% in developed world
Labbra e
cavità orale
Melanoma
ESPOSURE OF HAIRLESS MICE TO
HALOGEN LAMPS
S. De Flora & F. D’Agostini, Nature, 1992
CARCINOGENICITY OF THE LIGHT EMITTED BY
HALOGEN LAMPS
WITH COVERWITHOUT COVER
DISEASES
EXPOSURE MARKERS
EFFECTIVE DOSE
EARLY BIOLOGICAL DAMAGE
BIOLOGICALLY
DECODING THE BLACK BOX
Mutagenicity of escreta
Protein adducts
DNA adducts
8-oxo-dG
Metabolic alterations
DNA damage and repair
Cytogenetic effects
Activation of oncogenes
Deletion/mutation of oncosuppressor genes
Proliferation, differentiation, apoptosis, etc.
Analysis of metabolites
RISK
FACTORS
RISK
FACTORS
EXPOSURE MARKERS
EFFECTIVE DOSE
EARLY BIOLOGICAL DAMAGE
BIOLOGICALLY
Mutagenicity of escreta
Protein adducts
DNA adducts
8-oxo-dG
Metabolic alterations
DNA damage and repair
Cytogenetic effects
Activation of oncogenes
Deletion/mutation of oncosuppressor genes
Proliferation, differentiation, apoptosis, etc.
Analysis of metabolites
STOP
PROTECTIVE FACTORS DISEASESMOLECULAR EPIDEMIOLOGY OF
ATHEROSCLEROSIS
S. De Flora et al., FASEB J. 11: 1021-1031, 1997
The levels of 32P postlabeled DNA adducts in the aorta from
85 atherosclerotic patients were significantly correlated with:
-Age of patients
-Number of cigarettes
-High blood pressure
-Blood triglycerides
-Blood cholesterol (total/HDL)
-SFS-positive DNA adducts
-8-Oxo-dGuo S. De Flora & A. Izzotti,
Mutat. Res. 667, 15–26, 2009
DNA DAMAGE, DNA REPAIR, AND TAU ALTERATIONS IN MOUSE BRAIN
S. La Maestra et al., Toxicol. Sci., 2011
Wildtype
FHIT +/–
Time (days)
Mic
e w
ith
alo
pe
cia
(%
)
INHIBITION OF ALOPECIA BY NAC AND BUDESONIDE
R. Balansky et al., Proc. Natl Acad. Sci. USA 103, 7823–8, 2006
8-oxo-dG LEVELS IN THE EYE TRABECULAR MESHWORK
(A. Izzotti et al., Am. J. Med. 114, 638-646, 2003)
25
20
15
10
5
0
GSTM1 - null GSTM1 +
Glaucoma patients (n = 39)
GSTM1 - null GSTM1 +
Controls (n = 47)
8–
ox
o–
dG
/10
5 n
ucle
oti
de
s
PROLIFERATION AND CHRONIC DEGENERATIVE DISEASES
Genetic predisposition
DNA damage and repair
Oxidative stress
Chronic inflammation
Epigenetic mechanisms
CancerAtherosclerotic
plaque
Degenerative
diseases of
the myocardium
Neuro-
degenerative
diseases
CARDIOVASCULAR
DISEASES
CANCER
DIAGNOSIS
THERAPY
EPIDEMIOLOGY
PREVENTION
RISK FACTORS AND PROTECTIVE FACTORS
THE ICEBERG OF CHRONIC DEGENERATIVE DISEASES
COPD
THE 'OMICS TECHNOLOGIES
PROTEOME
Proteins
GENOME
DNA
Color ed by: SHAM vs CS, Default I nt er pret at ion ( sham. t xt )
Gene List : mm u ( 484)
MIRNOME
microRNAmRNA
TRANSCRIPTOME
Chronic
degenerative
diseases and
critical
periods of
life
PROTECTIVE FACTORS
S. De Flora & A. Izzotti, Mutat. Res., 667, 15–26, 2009
126 / 484 miRNAs
(26.0%)
downregulated by ECS
107 / 4858 genes
(2.9%)
upregulated by ECS
50 / 518 proteins
(9.7%)
upregulated by ECS
A. Izzotti et al., FASEB J. 23, 806–812, 2009
mRNA
SHAM
Proteins
SHAM
1000 10000
1000
10000
DNA
ENVIRONMENTAL CIGARETTE SMOKE IN RAT LUNG
MicroRNA
SHAM
0,01 0,1 1 10 100
0,01
0,1
1
10
100
CIG
AR
ETTE
SM
OK
E
BENIGN TUMOR
INITIATION(days - weeks)
PROMOTION(years - decades)
CANCER
PROGRESSION(~ 1 year)
INVASION
Exposure dose
Pharmacologic dose
Cellular dose
Target dose
Molecular dose
TOXICOKINETIKS
AND METABOLISM
DNA DAMAGE
AND REPAIR
CARCINOGENESIS
PROCESS
NEOPLASTIC MASS
S. De Flora et al., Mutat. Res. 480-481, 9-22, 2001
5
0
10
15
20
25
30
35
10
10
10
10
10
10
10
10
10
10
10
10
0
1
2
3
4
5
6
7
8
9
10
11
10
10
10
10
10
10
10
10
10
10
10
10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
Cell
divisions
No. of
cells
Weight
(g)
GROWTH OF THE
NEOPLASTIC MASS
1240 10
310
METASTASIS
PRIMARYPREVENTION
SECONDARY
THERAPY -REHABILITATION
INTERVENTION
STRATEGIES
C
H
E
M
O
P
R
E
V
E
N
T
I
O
N
TERTIARYPREVENTION
PREVENTION
CRESCITA DI SARCOMA DI KAPOSI UMANO IN TOPI NUDI
A. Albini et al., Cancer Res. 61, 8171-8178, 2001
MASCHI
FEMMINE
3 ) +
Vo
lum
e d
el
tum
ore
(c
m
)
0
0.5
1.0
1.5
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
CONTROLLI
Tempo (giorni)5 10 15 20 25 30
3
+
NAC
5 10 15 20 25 30
FEMMINE
MASCHI
1. Inhibition of mutation and cancer initiation in the extracellular environment or in nontarget cells1.1. 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
2. Inhibition of mutation and cancer initiation in target cells2.1. 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
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
3. Inhibition of tumor promotion3.1. 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
4. Inhibition of tumor progression4.1. 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
5. Inhibition of invasion and metastasis5.1. 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
MECHANISMS OF CANCER CHEMOPREVENTIVE AGENTS
S. De Flora and L.R. Ferguson, Mutat. Res., 591, 8–15, 2005
PRIMARY PREVENTION
SECONDARY PREVENTION
TERTIARY PREVENTION
S. De Flora and C. Ramel, Mutat. Res., 202, 285–306, 1988
PREVENTION OF LUNG TUMORS IN MICE
NUMBER OF TUMORS/MOUSE
0.35
CONTROLS
(STANDARD DIET)
11.06
URETHANE
(STANDARD DIET)
1.95
URETHANE
(DIET WITH NAC 0.2%)
S. De Flora et al., Cancer Lett. 32, 235-241,1986
PASSIVE SMOKING IN MUTANT MICE
S. De Flora et al. Molecular alterations and lung tumors in P53mutant mice exposed to cigarette smoke. Cancer Res. 63, 793–800, 2003
A. Izzotti et al. Gene expression in the lung of P53 mutant mice exposed to cigarette smoke. Cancer Res. 64, 8566–72, 2004
P53
F. D’Agostini et al. Early loss of Fhit in the respiratory tract of rodents exposed to environmental smoke. Cancer Res. 66, 3936–41, 2006
S. De Flora et al. Molecular alterations induced by cigarette smoke in mice heterozygous for Fhit. Cancer Res. 67, 1001–6, 2007
R. Balansky et al. Influence of Fhit on benzo(a)pyrene induced tumors and alopecia in mice. PNAS 103, 7823–8, 2006
Fhit
Phenethyl
Isothiocyanate Blackberry Myo-inositol N-Acetylcysteine Strawberry Ascorbic acid
Natural
agents
DIETARY AND PHARMACOLOGICAL AGENTS THAT HAVE BEEN TESTED FOR
THE ABILITY TO INTERFERE IN CIGARETTE SMOKE CARCINOGENESIS(S. De Flora et al., Trends Pharmacol. Sci. 37, 120-142, 2016)
Budesonide Aspirin Naproxen Licofelone Celecoxib
Anti-
inflammatory
drugs
Antidiabetic
drugsMetformin Pioglitazone
Bexarotene
Anticancer
drugs
Vorinostat Lapatinib
Gender
LIGANDS OF THE NUCLEAR
HORMONE SUPERFAMILYReference
Pioglitazone
(PPAR-γ-ligand)M
F
M+F
8.7
0
0
0
0
0
0
0
0
Izzotti et al.,
Carcinogenesis, 2013
La Maestra et al.,
Carcinogenesis, 2013
IbidemBexarotene or Targretin ® (RXR-
specific retinoid)
M
F
M+F
0
0
0
12.2
0
0
0
0
0
PIOGLITAZONE
BEXAROTENE
Microadenomas Adenomas Malignant tumors
Pioglitazone +
BexaroteneM
F
M+ F
2.6
0
0
0
0
0
78.2
100
89.2
Ibidem
SHAM NAC OPZ OPZ+ NAC
5,6-BF PEITC I3C PEITC+ I3C
A. Izzotti et al., Mutat. Res. 591, 212–223, 2005
SMOKE-FREE RATS
ECS NACOPZ OPZ+ NAC
5,6-BF PEITCI3C PEITC+ I3C
SMOKE-EXPOSED RATS
EXPRESSION OF 4858 GENES IN RAT LUNG
SAFETY EFFICACY
-0.4 -0.3 0.20.10-0.1-0.2 0.80.70.60.50.40.3
0.2
0.1
0
-0.1
-0.2
0.6
0.5
0.4
0.3
ECS + BF
ECS + OPZECS + I3C
ECS + NAC
ECS + PEITC
ECS + OPZ + NAC
ECS + PEITC + I3C
SHAM
ECS
NAC
OPZ PEITC + I3C
PEITC
NAC + OPZBFP
CA
co
mp
on
en
t 2
PCA component 1
EFFECT OF ENVIRONMENTAL CIGARETTE SMOKE AND
CHEMOPREVENTIVES ON miRNA EXPRESSION IN RAT LUNG
A. Izzotti et al, Cancer Prev. Res. 3, 62–72, 2010
LUNG miRNAs
Emphysema-free lung
Em
physe
ma-
bea
ring
lung
Mic
road
enom
as-
bea
ring
lung
Microadenoma-free lung
Alveolar hyperplasia-free lung
EMPHYSEMA
ALVEOLAR
HYPERPLASIA
MICROADENOMAS
ADENOMA
Adenoma-free lung
Aden
om
a-bea
ring
lung
Alv
eola
rhyper
pla
sia-
bea
ring
lung
BLOOD miRNAs
Blood and lung microRNAs
as biomarkers of pulmonary
tumorigenesis in cigarette
smoke-exposed mice
Izzotti A., Balansky R., Ganchev G.,
Iltcheva M., Longobardi M., Pulliero A.,
Geretto M., Micale R.T., La Maestra S.,
Miller M.S., Steele V.E., De Flora S.
Oncotarget, 2016
TERTIARY PREVENTION(Treated cancer patients)
EARLY INTERVENTION(Cancer patients in preclinical or early stage)
PREVENTION OF PROGRESSION(Individuals affected by precancerous lesions)
TARGETED CHEMOPREVENTION(High risk individuals)
PUBLIC HEALTH INTERVENTION(Healthy subjects in the population)
EFFICACY
LOW COST
PRACTICALITY
TOLERABILITY
REQUIREMENTS INTERVENTION (Targets)
S. De Flora et al., IARC Sci. Publ. No. 139, 1996, pp. 291-301
THERAPY (Cancer patients)
ACE inhibitors
Beta–blockers
Statins
Dexrazoxane
L–Carnitine
Coenzyme Q10
N–Acetyl–L–Cysteine
Glutathione
Erdosteine
Selenium
Zinc
Melatonin
Flavonoids and polyphenols
Platelet antiaggregants
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
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
Anticancer drugs Mechanisms of cardiotoxicity Protective agents
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
ITALY, GENERAL MORTALITY DATA, 1901–2000
Rate
s p
er
100.0
00
0
5
15
25
30
35
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000
10
20
ITALY, 1901Population: 33 millionDeaths: 726,000Mortality rate: 22‰
ITALY, 2000Population: 58 millionDeaths: 560,000Mortality rate: 9.7‰
ITALY, 2000
Population: 58 million
Mortality rate:
Deaths:
22‰
1,276,000
THE EPIDEMIOLOGICAL REVOLUTION OF THE 20th CENTURY
S. De Flora, A. Quaglia, C. Bennicelli & M. Vercelli, FASEB J. 19, 892–897, 2005
Francesco
D’Agostini
Carlo
Bennicelli
Anna
Camoirano
Silvio
De Flora
Sebastiano
La Maestra
Maria
Bagnasco
Ilaria
RighiRoumen
BalanskyAlberto
Izzotti
Rosanna
T. Micale
Cristina
Cartiglia
Mariagrazia
Longobardi
Tanya M.
Pennisi
UNIVERSITY OF GENOA, ITALY
DEPARTMENT OF HEALTH SCIENCES
Laboratory of Environmental Genomics and Cancer Prevention
Patrizia
Larghero
Alessandra
BattistellaAlessandra
Pulliero
Vinesh Kumar
Thidil
PulyappadambaGiorgia
Travaini