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Supporto Nutrizionale e
Fitoterapia in Oncologia
Mariano Bizzarri
Dept. of Experimental Medicine
Systems Biology Group
Uni...
THE PROBLEM:
50% of CANCERS CANNOT BE
CURED by CHEMOTHERAPY
YET, RESISTANCE ACCOUNTS
for TREATMENT FAILURE
in ABOUT 70% of...
NUTRACEUTICALS
PHYTOCHEMICALS
TREATMENT of
CHEMOTHERAPY-
RADIOTHERAPY-
related SIDE-
EFFECTS
PROAPOPTOTIC
EFFECTS
CELL-GRO...
TIME LINE of NUTRACEUTICALS in CANCER PREVENTION and GROWING
AWARENESS as DOCUMENTED in LITERATURE (last 20 YEARS).
AMPLIFICARE la RISPOSTA
alle terapie convenzionali
TRATTAMENTO dei PAZIENTI
non suscettibili di TERAPIA
CONVENZIONALE
TRAT...
MECHANISM of ACTION TARGET
THERAPEUTIC EFFECT
EZETIMIBE MEVALONATE PATHWAY LOWERING CHOLESTEROL NO EFFECTS
STATINS ? ANTI-...
COSA POTREBBE OFFRIRCI
la FITOTERAPIA ?
• Nuove Molecole attive
• Possibilità di approcci integrati sui sistemi biologici
...
GASTRODUODENITI
. Glicyrrizha g.
. A. arcangelica
. I. perforatum
. Altea officinalis
. Condurango
. Menta piperita
. Meli...
DISPEPSIA
PIANTA INDICAZIONE
PRINCIPALE
ALTRE
INDICAZIONI
CONTROINDICAZIONI POSOLOGIA
Artemisia
vulgaris
artemisia
antispa...
FITOTERAPIA :
INDICAZIONI CLINICHE
Terapia degli effetti collaterali
- Epato-protezione e drenaggio biliare
- Astenia
- An...
PRODOTTI
Patologie non oncologiche
• Preparato anti-astenia
• Preparato adiuvante per la
menopausa
• Terapia per patologie...
ATP AMP
GMP cGMP
ADENYL
CICLASE
E2
ER
E2-ER DNA binding
ERα –mRNA levels
ERα-CaM binding
aromatase telomerase
activity
and...
MELATONIN IMPACT on SURVIVAL
Relative risk meta-analysis of
10 RCTs in various cancers using the
random effects model
CLIN...
IMPROVEMENT in SURVIVAL and
SIDE EFFECTS MANAGEMENT
SUPPORTIVE CARE
• concomitant administration of
melatonin significantly reduced
the frequency of
thrombocytopenia, neuroto...
MELATONIN and BREAST CANCER
• Metastatic breast
cancer patients who
were unresponsive to
tamoxifen alone were
given 20 mg ...
META-ANALYSIS, 2012
• Melatonin as an adjuvant
therapy led to significantly
higher tumor remission,
better survival at 1 y...
BRAIN METASTASES
• In a trial, 50 patients with brain
metastases whose disease
had progressed under initial
therapy were r...
INOSITOL
BIOCHEMISTRY
and PHYSIOLOGY
• Inositol is a 6-carbon, cyclic
polyalcohol.
• nine different stereoisomers
have bee...
INOSITOL FOOD CONTENT
• Beans: 45-65 mg/100 g
• Whole grain bread: 39 mg/100 g
• Grapejuice: 133 mg/100 g
• Whole wheat br...
INOSITOL DEFICIENCY
Raminia et. al., 2009
SIGNAL TRASDUCTION
IMPAIRMENT
- Psychiatric disorders
- Diabetic Neuropahy
- Mit...
INOSITOL
SUPPLEMENTATION
INFERTILITY
and ENDOCRINE
DYSFUNCTIONS
MENOPAUSE and
sexual hormones
deficit
DIABETES
SUPPORTIVE ...
INOSITOL
DEFICIENCY
FATTY LIVER
- triglycerides
- esterified cholesterol
- lipolysis
- lipoproteins
BRAIN
- sympathetic ac...
INOSITOL
MICROENVIRONMENT
INSULIN and LIPID
METABOLISM
SEX HORMONE
BALANCE
CYTOSKELETON
REMODELLING
SURVIVAL PATHWAYS
INFL...
Diet and cancer
• Studies conducted over the years
have show a strong correlation
between diet and cancer
• Almost all can...
CD95, TRAIL
FADD
DISC
DR4
DR5
caspase-8
Procaspase-8
GSE
CaM
CaMKK
GSE
Cytochrome C
∆Ψm
AKT P
PI3K
NFkB
ERKp
MAPKp
JNKp
Ik...
Supporto Nutrizionale e Fitoterapia in Oncologia
Supporto Nutrizionale e Fitoterapia in Oncologia
Supporto Nutrizionale e Fitoterapia in Oncologia
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Supporto Nutrizionale e Fitoterapia in Oncologia

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Supporto Nutrizionale e Fitoterapia in Oncologia

  1. 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. 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. 3. NUTRACEUTICALS PHYTOCHEMICALS TREATMENT of CHEMOTHERAPY- RADIOTHERAPY- related SIDE- EFFECTS PROAPOPTOTIC EFFECTS CELL-GROWTH INHIBITION IMMUNE FUNCTION IMPROVEMENT INHIBITION of METASTATIC PROCESS
  4. 4. TIME LINE of NUTRACEUTICALS in CANCER PREVENTION and GROWING AWARENESS as DOCUMENTED in LITERATURE (last 20 YEARS).
  5. 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. 6. MECHANISM of ACTION TARGET THERAPEUTIC EFFECT EZETIMIBE MEVALONATE PATHWAY LOWERING CHOLESTEROL NO EFFECTS STATINS ? ANTI-INFLAMMATION LOWERING CHOLESTEROL OTHER EFFECTS CARDIAC RISK
  7. 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. 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. 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. 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
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. IMPROVEMENT in SURVIVAL and SIDE EFFECTS MANAGEMENT
  15. 15. 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.
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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.
  20. 20. 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) !
  21. 21. 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
  22. 22. INOSITOL SUPPLEMENTATION INFERTILITY and ENDOCRINE DYSFUNCTIONS MENOPAUSE and sexual hormones deficit DIABETES SUPPORTIVE CARE in PSYCHIATRIC DISORDERS CANCER
  23. 23. 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
  24. 24. INOSITOL MICROENVIRONMENT INSULIN and LIPID METABOLISM SEX HORMONE BALANCE CYTOSKELETON REMODELLING SURVIVAL PATHWAYS INFLAMMATORY PATHWAYS
  25. 25. 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
  26. 26. 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

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