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



McClure RD, 2005

AR

Male accessory glands (prostate & seminal vesicles)

T - AR



McClure RD, 2005

AR


T - AR

5α-reductase

DHT - AR



McClure RD, 2005

AR


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+



Normal Krebs cycle = CANCER

PROSTATE EPITHELIUM: ZINC AT WORK (ii)

Zn2+



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


CONTAMINANTS



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/


CONTAMINANTS



Nutrition and Chemo-prevention: RED MEAT and COOKING

Di Maso et al., Annals Oncology, 2013

"  al forno - alla griglia "  bollitura - al vapore "  frittura


CONTAMINANTS



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


CONTAMINANTS



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)

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

Nelle patologie neoplastiche, il carcinoma della prostata...

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