Nelle patologie neoplastiche, il carcinoma della prostata...
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Transcript of Nelle patologie neoplastiche, il carcinoma della prostata...
Nelle patologie neoplastiche, il carcinoma della prostata.
Stefano Lorenzetti
Contenuto relazione
! Dieta, obesità e cancro ! Prostata, cancro e fertilità: lo zinco ! Molecole bioattive vegetali e consumo di frutta, ortaggi e spezie ! Contaminanti ambientali e della dieta: gli obesogeni ! Cancerogenesi e meccanismi di azione di molecole bioattive vegetali ! Attività anti-infiammatoria come prevenzione
Nutrition and Chemo-prevention: WHY DO WE EAT ?
" A BIOLOGICAL POINT OF VIEW: THE OLD “LIFE CYCLE” DOGMAS
Human beings need to:
! SURVIVE
! REPRODUCE ! EATING (and all steps necessary to prepare eatable foods) is
fundamental to reach the fertile age (food/nutrient intake) but also to have a healthy fertile capability (sex mating)
+
" FOOD IS: ! A COMPLEX MIXTURE ! A SOURCE OF (NON) NUTRIENTS… ! … BUT ALSO A SOURCE OF ENVIRONMENTAL
CONTAMINANTS
Nutrition and Chemo-prevention: WHAT DO WE EAT ?
The food pyramid in the Mediterranean diet
Nutrition and Chemo-prevention: HOW MUCH DO WE EAT ?
" OBESITY IS CAUSED BY A: ! HIGHER CALORIC/NUTRIENT INTAKE (or UNBALANCED
DIET) ! HIGHER INTAKE OF OBESOGENS ?
Nutrition and Chemo-prevention: DOES ANY DIET-CANCER ASSOCIATION EXIST ?
" FOOD AS A CANCER-TRIGGERING FACTOR IF: ! EXCESSIVE INTAKE OF NUTRIENTS leading to i) too many proliferative
events and/or ii) expression of mitogenic growth factors or hormones ! EXCESSIVE INTAKE OF VITAMINS or TRACE ELEMENTS mitogens at high levels ! EXCESSIVE EXPOSURE TO ENVIRONMENTAL CONTAMINANTS some are classified by IARC as (potential carcinogens): e.g. DEHP, Arsenic
GLOBOCAN2008
Nutrition and Chemo-prevention: TOTAL NUTRIENT INTAKE
! Chemo-prevention can be obtained reducing the caloric and/or nutrient (dietary or caloric restriction).
! In animal models, dietary restriction is associated to a lower cancer incidence upn chemical induction with mutagenic agents (Pallavi et al., 2012; Umar et al., 2012)
GLOBOCAN2008
Nutrition and Chemo-prevention: FOCUSSING ON MALES (i)
MALES
GLOBOCAN2008
Nutrition and Chemo-prevention: FOCUSSING ON MALES (ii)
Nutrition and Chemo-prevention: FOCUSSING ON MALES (iii)
! Genetics vs environment (lifestyle)
" Cancer = Uncontrolled cell proliferation Genetic mutations in genes controlling cell proliferation, usually defined oncogenes or oncosuppressors, inherited OR ACQUIRED DURING LIFE
! Efficiency of DNA replication = about 99 %
! DNA replication error rate = 1 x 106 - 1 x 108 range ! Proofreading error rate = about 1 x 105
Nutrition and Chemo-prevention: A FIGHT AGAINST THE FATE (?)
" DIET or NUTRITION could have a role only on genetic mutations acquired during life
+
COMPONENTS OF THE MALE REPRODUCTIVE TRACT
A simplified brain-testis circuit: the hypothalamic-pituitary-gonadal axis
McClure RD, 2005
AR
COMPONENTS OF THE MALE REPRODUCTIVE TRACT
A simplified brain-testis circuit: the hypothalamic-pituitary-gonadal axis
McClure RD, 2005
AR
Male accessory glands (prostate & seminal vesicles)
T - AR
COMPONENTS OF THE MALE REPRODUCTIVE TRACT
A simplified brain-testis circuit: the hypothalamic-pituitary-gonadal axis
McClure RD, 2005
AR
Male accessory glands (prostate & seminal vesicles)
T - AR
5α-reductase
DHT - AR
COMPONENTS OF THE MALE REPRODUCTIVE TRACT
A simplified brain-testis circuit: the hypothalamic-pituitary-gonadal axis
McClure RD, 2005
AR
Male accessory glands (prostate & seminal vesicles)
T - AR
5α-reductase
DHT - AR
Male accessory glands WHAT FOR ?
SEMEN = SPERMS (Testes) ≈ 2-5 %
+ PROSTATIC FLUID (Prostate) ≈ 25-30 % ! Prostate-specific antigen (PSA or KLK3) ! Other kallikreins (KLKs) ! Prostatic Acid Phosphatase (PAP) ! Citrate ! Zinc ! Other electrolytes (K, Na, etc.) ! Glucose ! Polyamines (spermine) ! …
+ SEMINAL FLUID (Seminal vesicles) ≈ 65-75 % ! Prostaglandins ! Fructose
+ BULBO-URETHRAL FLUID (Cowper’s glands) ≈ 1 % ! Galactose ! Mucus ! Sialic acid ! …
Zn2+
citrate PSA/KLK3 other KLKs
Costello LC, Franklin RB, 2012
PROSTATE EPITHELIUM: ZINC AT WORK (i)
! Zn+2 food sources Mainly meat and fish but also legumes, seeds, dried fruits, dark chocolate
! Zn+2 tissue localization in the body
Mainly muscle and bone (85%), skin and liver (11%) and also prostate epithelium (4%)
Krebs cycle impairment = high citrate
Zn2+
citrate PSA/KLK3 other KLKs
Costello LC, Franklin RB, 2012
Normal Krebs cycle = CANCER
PROSTATE EPITHELIUM: ZINC AT WORK (ii)
Zn2+
citrate PSA/KLK3 other KLKs
Costello LC, Franklin RB, 2012
Normal Krebs cycle = LOW CITRATE = LOW ZINC = INACTIVE KLKs (including PSA)
= MALE INFERTILITY because sperms loose vectoriality !
PROSTATE EPITHELIUM: ZINC AT WORK (iii)
Bauer et al., 2012
" FOOD IS: ! A COMPLEX MIXTURE ! A SOURCE OF (NON) NUTRIENTS… ! … BUT ALSO A SOURCE OF ENVIRONMENTAL
CONTAMINANTS
Nutrition and Chemo-prevention: WHAT DO WE EAT ?
The food pyramid in the Mediterranean diet
BioacMve agent Cancer Stage of agent development Refs Soy isoflavones Breast Clinical trials 20
Lycopene (tomatoes) Prostate and lung Phase II RCT (prostate); cohort studies (lung)
20
Resveratrol (grapes and red wine)
Oesophageal, intes>nal, colon and others
Preclinical and animal studies 20,146
Omega‑3‑faRy acids (fish oil)
Prostate, breast and colon
Animal models (prostate, breast and colon); Phase II studies (all cancer)
20
Pomegranate Breast, lung and prostate
Preclinical and animal studies (breast and lung); Phase II study (prostate)
20
Curcumin Carcinogenesis, prostate and colorectal
Preclinical and animal studies; limited human trial data
20,76, 146
Nutrition and Chemo-prevention: PLANT BIOACTIVES & PROSTATE CANCER (iii)
THERAPIES «under evaluaMon / comparison»
«NATURAL» DRUGS SYNTHETIC DRUGS
Soy isoflavones SERMs: tamoxifen and raloxifene
Lycopene (tomatoes) 5α-‐reductase inhibitors: finasteride and dutasteride
Resveratrol (grapes and red wine & fruits)
Aromatase inhibitors: anastrozole and exemestane
Omega‑3‑faRy acids (fish oil)
Mebormin
Pomegranate Aspirin (off-‐label) Curcumin
A. Boscoli - Convivio degli dei affresco Corliano (PI)
Nutrition and Chemo-prevention: PLANT BIOACTIVES & PROSTATE CANCER (iv)
PRO-HEALTH-ZINC an Italian pilot study investigating zinc blood levels as a potential
clinical biomarker in prostatic diseases
! PSA secretion (free and total PSA) ! Zinc ! Selenium
http://www.fondazioneprosud.it/prevenzione/le-10-regole-doro-della-prostata/
" FOOD IS: ! A COMPLEX MIXTURE ! A SOURCE OF (NON) NUTRIENTS… ! … BUT ALSO A SOURCE OF ENVIRONMENTAL
CONTAMINANTS
Nutrition and Chemo-prevention: WHAT DO WE EAT ?
The food pyramid in the Mediterranean diet
Nutrition and Chemo-prevention: RED MEAT and COOKING
Di Maso et al., Annals Oncology, 2013
" al forno - alla griglia " bollitura - al vapore " frittura
" FOOD IS: ! A COMPLEX MIXTURE ! A SOURCE OF (NON) NUTRIENTS… ! … BUT ALSO A SOURCE OF ENVIRONMENTAL
CONTAMINANTS
Nutrition and Chemo-prevention: WHAT DO WE EAT ?
The food pyramid in the Mediterranean diet
Nutrition and Chemo-prevention: OBESOGENS
Fetal and early-life exposures to certain obesogens may alter some individuals’ metabolism and fat-cell makeup for life. Other obesogenic effects are linked to adulthood exposures.”
Environ Health Perspect. 2012; 120(2): a62
“Obesity is rising steadily around the world. Convincing evidence suggests that diet and activity level are not the only factors in this trend - chemical “obesogens” may alter human metabolism and predispose some people to gain weight.
" Besides Peroxisome Proliferator-Activated Receptor (PPAR)α, the plasticizer DEHP interacts also with other Nuclear Receptors involved in lipid and glucose metabolism: PPARγ, PXR (Pregnane-X-receptor), LXR (Liver-X-receptor) Mulholland et al Endocr Rev 2005; Salvatore et al., Folia Medica. 2008; Grün et al., Endocrinology. 2007.
" Activation of LXR, PXR and PPARγ has been associated to hepatic steatosis (accumulation of fatty acids within hepatocytes) due to their lipogenic role Zhou et al., Gastroenterology. 2008; Maranghi, Lorenzetti et al., Repr.Toxicol. 2010; Lorenzetti et al., manuscript in preparation
Sugawara et al., Endocr J 2010. Baranowski, JPP 2008. Kliewer, PNAS 2005.
Nutrition and Chemo-prevention: OBESOGENS: MOLECULAR EFFECTORS
Nutrition and Chemo-prevention: OBESOGENS (DEHP): THE «PHTHALATE SYNDROME
" In rodents, fetal exposure to phthalates causes what scientists have termed a 'PHTHALATE SYNDROME‘. It includes decreases in anogenital distance (AGD), increased frequency of incomplete testicular descent and a birth defect of the penis called 'hypospadias,' increased risk of testicular cancer in adulthood, impaired sperm quality and other effects. Swan et al. EHP 2005 and refs therein
Nutrition and Chemo-prevention: OBESOGENS (DEHP): THE «PHTHALATE SYNDROME = TDS
" In rodents, fetal exposure to phthalates causes what scientists have termed a 'PHTHALATE SYNDROME‘. It includes decreases in anogenital distance (AGD), increased frequency of incomplete testicular descent and a birth defect of the penis called 'hypospadias,' increased risk of testicular cancer in adulthood, impaired sperm quality and other effects. Swan et al. EHP 2005 and refs therein
" Scientists studying people have noted a pattern of male abnormalities called 'TESTICULAR DYSGENESIS SYNDROME‘. One leading hypothesis for the cause of TDS has been exposure to endocrine disrupting chemicals (EDCs) like phthalates.
Prostate epithelial cells (prostatic fluid)
Adapted from Skakkebaek NE et al., 2001, Human Reproduction 16: 972–8
In young adulthood
At birth
• The phenomenon that adverse environmental exposures in early life are associated with increased susceptibilities for many adult, in particular metabolic diseases is now referred to "developmental origins of adult health and disease" or "Barker" hypothesis.
• [Environmental contaminants] or Fetal overnutrition and undernutrition have similar long-lasting effects on setting of the neuroendocrine control systems, energy homeostasis and metabolism, leading to life-long increased morbidity.
• There are sensitive time windows during early development where environmental cues can program persistent epigenetic modifications, which are generally assumed to mediate these gene-environment interactions.
Nutrition and Chemo-prevention: DEVELOPMENTAL ORIGINS OF ADULT HEALTH AND DISEASE
(DOHAD)
El Hajj et al., 2014
Nutrition and Chemo-prevention: DEVELOPMENTAL ORIGINS OF ADULT HEALTH AND DISEASE OR IN UTERO EXPOSURE TO DIABETES, OBESITY & FAMINE
" FOOD IS: ! A COMPLEX MIXTURE ! A SOURCE OF (NON) NUTRIENTS… ! … BUT ALSO A SOURCE OF ENVIRONMENTAL
CONTAMINANTS
Nutrition and Chemo-prevention: WHAT DO WE EAT ?
The food pyramid in the Mediterranean diet
Davis CD, Exp. Biol. Med., 2007
Nutrition and Chemo-prevention: PLANT BIOACTIVES AND CANCEROGENESIS
Gioti K & Tenta R. Planta Med. 2015
Nutrition and Chemo-prevention: PLANT BIOACTIVES & PROSTATE CANCER (i)
" APOPTOSIS
! caspase triggering
! mitochondrial-dependent cascade triggering
! oncogene inhibition
! NFκB signaling pathway suppression
Gioti K & Tenta R. Planta Med. 2015
Nutrition and Chemo-prevention: PLANT BIOACTIVES & PROSTATE CANCER (ii)
" AUTOPHAGY
! PI3K signaling pathway inhibition
! mTOR complex suppression
! activation of the phagophore formation-related proteins
http://www.pcf.org/site/c.leJRIROrEpH/b.8723169/k.5845/A_New_Diet_to_Quash_Inflammation_May_Benefit_Men8217s_Prostate_Health.htm
While there is no exact definition of the anti-inflammatory diet, it’s similar to the Mediterranean diet.
… heavy weight to fruits and veggies and also includes “unlimited amounts” of herbs and spices such as ginger, cinnamon and garlic. … strong emphasis on tea—two to four cups a day of white, green or oolong—and eating loads of healthy fats such as those found in walnuts and avocados.
Nutrition and Chemo-prevention: ANTI-INFLAMMATORY FOOD PYRAMID
! 5 (or 6) daily portions of fruit and vegetables from alternate color and thus according to the content of various classes of bioactive compounds
Nutrition and Chemo-prevention: QUALITY of NUTRIENT INTAKE (ii)
! 5 (or 6) daily portions of fruit and vegetables from alternate color and thus according to the content of various classes of bioactive compounds
Nutrition and Chemo-prevention: QUALITY of NUTRIENT INTAKE (ii)
ALIMENTI FUNZIONALI
INTEGRATORI ALIMENTARI
NUTRACEUTICI
RACCOMANDAZIONI NUTRIZIONALI
RACCOMANDAZIONI SALUTISTICHE
Stefano Lorenzetti [email protected] Istituto Superiore di Sanità – ISS Dpt. Food Safety and Veterinary Public Health Unit Food and Veterinary Toxicology Viale Regina Elena 299 – 00161 Roma (I) +39.0649902512
«COME TALK TO ME… All the things that we both might say” (P. Gabriel)
Peter Gabriel concert - Vienna, October 3°, 2013