Slide del Prof. Mariano Bizzarri

1. Supporto Nutrizionale e
Fitoterapia in Oncologia
Mariano Bizzarri
Dept. of Experimental Medicine
Systems Biology Group
University La Sapienza, Roma
Roma 3 Luglio 2015

2. THE PROBLEM:
50% of CANCERS CANNOT BE
CURED by CHEMOTHERAPY
YET, RESISTANCE ACCOUNTS
for TREATMENT FAILURE
in ABOUT 70% of PATIENTS
EVEN SUCCESFULL TREATMENT
MUST BE DISCONTINUED in 20-30% of
PATIENTS DUE to the EMERGENCE
of RELEVANT SIDE-EFFECTS

3. NUTRACEUTICALS
PHYTOCHEMICALS
TREATMENT of
CHEMOTHERAPY-
RADIOTHERAPY-
related SIDE-
EFFECTS
PROAPOPTOTIC
EFFECTS
CELL-GROWTH
INHIBITION
IMMUNE
FUNCTION
IMPROVEMENT
INHIBITION
of METASTATIC
PROCESS

4. TIME LINE of NUTRACEUTICALS in CANCER PREVENTION and GROWING
AWARENESS as DOCUMENTED in LITERATURE (last 20 YEARS).

5. AMPLIFICARE la RISPOSTA
alle terapie convenzionali
TRATTAMENTO dei PAZIENTI
non suscettibili di TERAPIA
CONVENZIONALE
TRATTAMENTO delle COMORBIDITA’
associate alla TERAPIA
CONVENZIONALE
PREVENZIONE
OBBIETTIVI

6. MECHANISM of ACTION TARGET
THERAPEUTIC EFFECT
EZETIMIBE MEVALONATE PATHWAY LOWERING CHOLESTEROL NO EFFECTS
STATINS ? ANTI-INFLAMMATION
LOWERING CHOLESTEROL
OTHER EFFECTS
CARDIAC RISK

7. COSA POTREBBE OFFRIRCI
la FITOTERAPIA ?
• Nuove Molecole attive
• Possibilità di approcci integrati sui sistemi biologici
• Nuovi targets
• Terapie complementari
• Contenimento della patologia iatrogena
• Terapia per sindromi orfane

8. GASTRODUODENITI
. Glicyrrizha g.
. A. arcangelica
. I. perforatum
. Altea officinalis
. Condurango
. Menta piperita
. Melissa
. Anice
DISPEPSIA
. Assenzio r.
. Verbena
. Anice stellato
. Genziana
. Salvia o.
. Centaurea
. Curcuma
. Menta p.
. Carvi
IPERSECREZIONE ACIDA
. Altea
. Malva
. Semi di psillio
. Semi di lino
. G. glabra
IPOSECREZIONE ACIDA
. Boldo
. Assenzio r.
. Luppolo
. Centaurea
. Genziana
.
.
INAPPETENZA
Urtica dioica
Angelica
Genziana
Marrubio
Fieno greco
Pappa reale
Glicyrrizha g.
Veronica off.
NAUSEA e VOMITO
Anethum graveolens
Zenzero
santoreggia (satureia montana)
Rubus idaea
Melissa
Menta piperita
Matricaria
Lichen islandicus
Achillea
ALTERAZIONI dell’ALVO
DIARREA colon irritabile
Santoreggia
Bistorta
Alchemilla
Mirtillo
Amamelide
Agrimonia
Tomentilla
STIPSI
Tamarindo
Cascara
Cassia fistula
Polipodio
Vaccinium vitis idaea
Aloe
Psillio
Senna
Manna
Rabarbaro cinese
METEORISMO
Curcuma
Finocchio
Carvi
Anice verde
Anice stellato
Ginepro
Menta piperita
Veronica off.
DISTONIA NEUROVEGETATIVA
. Ficus carica
. Tilia tomentosa
. Quercus p
INDICAZIONI CLINICHE
della FITOTERAPIA

9. DISPEPSIA
PIANTA INDICAZIONE
PRINCIPALE
ALTRE
INDICAZIONI
CONTROINDICAZIONI POSOLOGIA
Artemisia
vulgaris
artemisia
antispasmodico ipoglicemizzante - TM 35 gtt x
3/die
Erythraea
centaurium
Centaurea
minore
Dispepsia atonica
Achilia
iposecrezione
gastrica
Eupeptica
Antifebbrile
Antinfiammatoria
Diarrea e vomito da
iperdosaggio
TM 30 gtt ½
prima dei 3 pasti
Boldo
fragrans
Dispepsia di
origine
epatobiliare
Coleretica-
colagoga
Inibitore
perossidazione
lipidica
Epatopatia grave
Occlusione vie biliari
Emesi per sovradosaggio
ES 100 mg x1-
3/die
TM 30 gtt x
3/die
Acorus
calamus
calamo
Ipoacidità
gastrica
Inappetenza
citoprotettore
Diaforetico
Drenante
Diuretico
(antigottoso)
Sedativo
Cancerogenicità della
variante asiatica
(βasarone)
ES 100 mg 3/die
10’ prima dei
pasti
TM 30 gtt x 3
10’ prima dei
pasti
Carica
papaya
Eupeptizzante
proteolitica
Inibitore
steroidogenesi
maschile (?)
K prostata
- TM 30 gtt x
3/die prima dei
pasti
Condurango
marsdenia
Dispepsia
Dolore gastrico
Citostatico (k
gastrico)
Cicatrizzante
Vomito gravidico
Disturbi SNC ad alte dosi TM 25 gtt x
3/die

10. FITOTERAPIA :
INDICAZIONI CLINICHE
Terapia degli effetti collaterali
- Epato-protezione e drenaggio biliare
- Astenia
- Anemia
- Patologia gastrointestinale
- Disturbi dell’alvo
- Cachessia neoplastica
- Nausea/vomito
- Affezioni stomatologiche
- Patologia dermatologica
- Neuropatie
- Danni da radioterapia
- Sindromi psichiatriche minori
- Immuno-modulazione
- Profilassi anti-infettiva
Terapia anti-tumorale
- Sinergia con chemio e radio-terapia
- Azione anti-estrogenica
- Trattamento alternativo nei non-responsivi

13. PRODOTTI
Patologie non oncologiche
• Preparato anti-astenia
• Preparato adiuvante per la
menopausa
• Terapia per patologie benigne del
seno
• Trattamento dell’infertilità: inositolo e
acido-α-lipoico
Patologie tumorali
• Estratto di semi di uva (K colon, seno)
• Inositolo
• melatonina

14. ATP AMP
GMP cGMP
ADENYL
CICLASE
E2
ER
E2-ER DNA binding
ERα –mRNA levels
ERα-CaM binding
aromatase telomerase
activity
androgens estrogens
Gβ
GγGα
Gγ
PKCαPKCα AKT
SIRT1
MAPK
JNK
NFkB
MEL
clock
genes
ROS
GSK3β
Bad, Bax, Bak
PI3K
MDM2
p53
X
X
X
X
X
X
X
cytochrome c
DAG +
Ins-3p
Ca2+
Ca2++CaM
PKCα
RZR/
RORα
X
Caspase-8
p27
p21
Caspase-3,
caspase-9,
PARP
AIF
p73
PKA
CREB
Late, caspase-dependent
APOPTOSIS
Early, caspase-
independent APOPTOSIS
TGFβ-1
cell cycle
inhibition
cyclin D1
CdK2
X
CSK remodelling
ROCK
P
Ph-ases
LA uptake
13-HODE
TRAIL
ψSMADs
PLCPIP2
Cox2
tBID
Ca2+
Bcl2, Bcl-xl
FoxO3a
β-catenin
translocation
PP
p300
CHOP
MDM2
MT2
APOPTOSIS
CELL CYCLE
INHIBITION
ENDOCRINE
EFFECTS
CALCIUM and
ROS EFFECTS
CYTOSKELETON

15. MELATONIN IMPACT on SURVIVAL
Relative risk meta-analysis of
10 RCTs in various cancers using the
random effects model
CLINICAL OUTCOMES
• Melatonin reduced the risk of
death at 1 yr (relative risk: 0.66,
95% confidence interval: 0.59–0.73,
I2 ¼ 0%, heterogeneity P £ 0.56).
• Effects were consistent across
melatonin dose, and type of cancer.
• No severe adverse events were
reported.
• The substantial reduction in risk of
death, low adverse events reported
and low costs related to this
intervention suggest great potential
for melatonin in treating cancer

16. IMPROVEMENT in SURVIVAL and
SIDE EFFECTS MANAGEMENT

17. SUPPORTIVE CARE
• concomitant administration of
melatonin significantly reduced
the frequency of
thrombocytopenia, neurotoxicity,
cardiotoxicity, stomatitis and
asthenia.
• This study indicates that the
pineal hormone melatonin may
enhance the efficacy of
chemotherapy and reduce its
toxicity, in advanced cancer
patients of poor clinical status
• Melatonin may be effective in the
treatment of the neoplastic
cachexia by decreasing TNF
blood concentrations.

18. MELATONIN and BREAST CANCER
• Metastatic breast
cancer patients who
were unresponsive to
tamoxifen alone were
given 20 mg melatonin
daily in the evening
along with tamoxifen . A
response was achieved
in 28% of these
patients.
• It has also been shown
that melatonin
increases the cytostatic
antiestrogen sensitivity
of tamoxifen via an
unknown mechanism

19. META-ANALYSIS, 2012
• Melatonin as an adjuvant
therapy led to significantly
higher tumor remission,
better survival at 1 year,
and less
radiochemotherapy-
related side effects
including
thrombocytopenia,
neurotoxicity, and fatigue.
• In many cases, the
cancers that were being
treated were refractory to
standard therapy and as
such more amenable to
the adjunct use of an
untested and unproven
therapy like melatonin

20. BRAIN METASTASES
• In a trial, 50 patients with brain
metastases whose disease
had progressed under initial
therapy were randomized to
receive supportive care alone
or supportive care and
melatonin. Nine of the 24
patients who received
melatonin survived 1 year
compared with 3 of 26 who did
not receive melatonin (23). The
• mean survival time was 9.2
versus 5.5 months and the
time free from brain
progression was 5.9 versus
2.7 months in patients
receiving melatonin

21. INOSITOL
BIOCHEMISTRY
and PHYSIOLOGY
• Inositol is a 6-carbon, cyclic
polyalcohol.
• nine different stereoisomers
have been discovered till
now
• Myo-inositol being the most
abundant stereoisomer in
nature.

22. INOSITOL FOOD CONTENT
• Beans: 45-65 mg/100 g
• Whole grain bread: 39 mg/100 g
• Grapejuice: 133 mg/100 g
• Whole wheat bread: 34 mg/100 g
• Spaghetti 90 mg/100 g
• Chocholate 86 mg/100 g
• Rice 60-110 mg/100 g
• Lentils 270-1500 mg/100 g
• Almond 350-940 mg/100 g
daily requirement: 1-2 g/day ASSUMPTION: 0.3-1 g/day (in Western countries) !

23. INOSITOL DEFICIENCY
Raminia et. al., 2009
SIGNAL TRASDUCTION
IMPAIRMENT
- Psychiatric disorders
- Diabetic Neuropahy
- Mitocondrial metabolism
- Insulin insensitivity
- Developmental disorders
- CANCER
- PCOS
INTEREST FOR INOSITOL
IS TAKING OFF

24. INOSITOL
SUPPLEMENTATION
INFERTILITY
and ENDOCRINE
DYSFUNCTIONS
MENOPAUSE and
sexual hormones
deficit
DIABETES
SUPPORTIVE CARE
in PSYCHIATRIC
DISORDERS
CANCER

25. INOSITOL
DEFICIENCY
FATTY LIVER
- triglycerides
- esterified cholesterol
- lipolysis
- lipoproteins
BRAIN
- sympathetic activity
- neurotransmitters (?)
FATTY metabolism
- fatty acid synthase
- acetyl-CoA
carboxylase
- intestinal lipodistrophy
-
LUNG
- surfactant decrease
- surfactant
phosphatidylcoline
GLUCOSE
- Citric acid cycle
impairment
- hyperglicaemia
- reduced glycogne
incorporation

26. INOSITOL
MICROENVIRONMENT
INSULIN and LIPID
METABOLISM
SEX HORMONE
BALANCE
CYTOSKELETON
REMODELLING
SURVIVAL PATHWAYS
INFLAMMATORY
PATHWAYS

27. Diet and cancer
• Studies conducted over the years
have show a strong correlation
between diet and cancer
• Almost all cancers (80-90%) are
caused due to environmental factors,
and of these, 30-40% of cancers are
directly linked to the diet
• Most epidemiological data suggest a
protective role for fruits and
vegetables in the prevention of
several common epithelial cancers

29. CD95, TRAIL
FADD
DISC
DR4
DR5
caspase-8
Procaspase-8
GSE
CaM
CaMKK
GSE
Cytochrome C
∆Ψm
AKT P
PI3K
NFkB
ERKp
MAPKp
JNKp
IkB-Ub
Ca2+
X
Caspase-3,
caspase-9,
PARP
Bad, Bax, Bak
Bcl2, Bcl-xl
Late, caspase-
dependent APOPTOSIS
Early, caspase-
independent APOPTOSIS
AIF
APAF1
PUMA
apoptosome
p21
C D-E
CdK2,
4,6
RbP
P
E2F
Inhibition of
cell proliferation
X
p19
p53
Mdm2
IP3
proteasome
β-catenin
translocation
down-regulation
MMP2
MMP9
uPA
Fascin
CSK remodelling
ECM interactions
COX2
MDM2
survivin
GSE
PKCα
PKCδ
X
EGFR
PDGF
VEGF
AMPK
G2-M, G1
arrest
HIF-1α
X ARHATs