Adventurous TRPs: deorphanizing TRPs with small molecules natural productsAdventurous TRPs: deorphanizing TRPs with small molecules natural products

Giovanni AppendinoUniversità del P iemonte Orientale

Dipartimento di S cienze del Farmaco

I nutraceutic i in onc olog ia : S oluzione s emplic e a problemi

c omples s i o natura morta di c onc etti nebulos i, idee c onfus e e teorie

s pec ula tive?

Perchè parlare di supprotive care erbale

NUCLEUS

Gene Promoter

I prodotti erba li hanno il potenzia le di

qDiminuire g li effetti c olla tera li di diag nos tic a e terapia onc olog ic a (c hirurg ia , c hemo- e radioterapia )

qAumentare l’effic ac ia della terapia (c hemos ens ibilizzazione)

qM ig liorare la qua lità di vita del paziente onc olog ic o

L’evidenza è tuttavia prec linic a o a l mas s imo fa riferimento a deg li s tudi c linic i molto lim ita ti

Le persone non sono dei roditori giganti

L’evidenza è aneddotica

Come: Utilizzo di prodotti erbali durante terapia oncologica

NUCLEUS

Gene Promoter

Pazienti oncologici che combinano prodotti erbali con trattamenti oncologici: 80%.*

Caratteristiche dell’utilizzo:

Ø Non dichiarato ai medici curantiØ Utilizzo di prodotti di dubbia qualità tecnicaØ Utilizzo di dosaggi e modelli di

somministrazione non validati

* Xu, W. Eur. J. Cancer Care 2006, 15, 397-403.

Quando sono utilizzati I prodotti erbali

NUCLEUS

Gene Promoter

ØPreventiva (Prima del tra ttamento): P revenzione tos s ic ità C T s c ansØ Adiuvante (Durante il tra ttamento): G enera le: aumento della qua lità di vitaq C ac hes s iaq Fa tic aq N aus eaS pec ific a : m itig azionediq C is tite indotta da radioterapia a lla pelviq M uc os ite indotta da radio- e c hemioterapiaq R adiodermatiteq E dema indotto da radioterapiaqG enotos s ic ità indotta da iodio radioa ttivoqTos s ic ità epatic aq C ardiotos s ic ità da antrac ic lineØPos t tra ttamento:qLinfedemaqAumento di pes oqV ampate di c a lore e frag ilità os s eaq A umento di D is eas e Free S urviva l (S FS ) e prevenzione di ric adute

S upportive care preventivo

CANCER DIAGNOS IS CAN INDUCE CANCER

NUCLEUS

Gene Promoter

N umber of C T s c ans performed every day in U S : c a 200,000Es timated % of c anc ers c aus ed by C T s cans : c a . 0.4 % of a ll diag nos ed c anc ers (1.5-2% bas ed on c urrent us e of C T)

R adia tion expos ure from a full body s c an is the s ame a s s tanding 2.4 km aw ay from the a tomic

bomb bla s ts in Japan during World War I I

In terms of radia tion expos ure, a C T s c an is equiva lent to 30-440 c hes t X -rays

N. Eng. J. Med. 2007, 357, 2277-2284

Ginkgo and radiation

NUCLEUS

Gene Promoter

Ginko is extraordinarily res is tant to radiation:Ginkgo trees are the only form of higher life that survived the atomic bombing at Hiroshima in 1945 within 2 km from the blast. Six of these trees are still preserved

http://kwanten.home.xs4all.nl/hiroshima.htm

Ginkgo and the nuclear meltdown at Chernobyl

NUCLEUS

Gene Promoter

When taken orally three times a day, 40 mg. of Ginkgo biloba provided recovery workers at Chernobyl protection from radiation-induced clastogenicity

Free Rad. Biol. Med. 1995, 18, 985-991

Mechanism of the anti-clastogenic effects of ginkgo

NUCLEUS

Gene Promoter

The blood of people irradiated accidentally or for therapeutic reasons contains chromosome-damaging factors known as clastogenic factors (CF)Clastogenic activity can persist in blood several years after radiation exposure, and are a risk factor for the late effects of ionizing radiation.1CF are formed via the intermediacy of superoxide and generate superoxide. Their formation is inhibited by the enzyme superoxide dismutase (SOD), that quenches the superoxide ion radical.Ginkgo extracts have superoxide scavenging properties, and could be considered as biolog ic a l ana log ues of S OD , an enzyme that is not orally active, and would have to be injected for in vivo clinical activity.

Dardano, A. et al. J. Clin. Endocrinol. Metab. 2007, 92, 4286-4289

Ginkgo and radioiodine-induced genotoxicity- Graves’ disease study

NUCLEUS

Gene Promoter

N ature of the s tudy: Placebo-controlled

Loc ation: Dipartimento di Medicina Interna, Pisa University (Italy)

Popula tion: 25 patients (19 women, mean age 47.9 ± 15.3 yr), all nonsmokers, affected by relapsing Graves’ disease and undergoing 131I treatment.

Dos ag e and duration of the intervention: 120 mg/die Tanakan from day -3 to day +30 respect to treatment

End-point: a) clastogenic score b) efficacy of the therapy (reduction of tyroid volume)

R es ults : s ig nific ant reduc tion of the c la s tog enic s c ore no effec t on the effic ac y of the therapy*

*Efficacy: 100% in the treatment branch, 93% in the placebo; Later developemtn of hypothirodidism: 63% of patients in the treatment branch, 73% in the placebo group

Dardano, A. et al. J. C lin. Endocrinol. Metab. 2007, 92, 4286-4289

Ginkgo and radioiodine-induced genotoxicity- Tyroid cancer study

NUCLEUS

Gene Promoter

N ature of the s tudy: Placebo-controlled

Loc ation: Dipartimento di Medicina Interna, Pisa University (Italy)

Popula tion: 23 patients (age 18-73 yr), all nonsmokers, affected by tyroid cancer that had undergone near-total thyroidectomry and 131I treatment.

Dos ag e and dura tion of the intervention: 120 mg/die Tanakan from day -3 to day +30 respect to treatment

E nd-point: a) clastogenic score and lynphocytes MN level in culture assay of plasma and blood b) thyroid hormone profile

R es ults : S ig nific ant reduc tion of the c la s tog enic s c ore and lymphoc ytes N o differenc e in the thyroid hormone profile betw een the tw o g roups .

*Efficacy: 100% in the treatment branch, 93% in the placebo; Later developemtn of hypothirodidism: 63% of patients in the treatment branch, 73% in the placebo group

Dardano, A. et al. Thyroid. 2012, 22, 318-324

S upportive c are adiuvante

Farmaci a base di cannabinoidi

NUCLEUS

Gene Promoter DRONABINOL (Marinol®)capsule da 2.5 - 5 - 10 mg di THC semisintetico. (Unimed Pharmaceuticals, USA)

NABIXOMOLS(Sativex®)Spray oro-mucosale2.7 mg THC , 2.5mg CB /spruzzo (0.1mL)GWPharma (UK).

NABILONE (Cesamet®)capsule da 1 mgProdotto dalla Cambridge Laboratories Ltd (UK).

L’olio di S imson: il caso di S tephanie Larue

NUCLEUS

Gene Promoter

L’olio di S imson: il caso di S tephanie Larue

NUCLEUS

Gene Promoter

Purtroppo la marijuana NON cura il cancro

NUCLEUS

Gene Promoter

Curcumin is very popular within the cancer population

NUCLEUS

Gene Promoter

http://margaret.healthblogs.org/life-with-myeloma/discovery-of-curcumin/my-curcumin-protocol/my-curcumin-cocoa-mass-recipe-in-english-and-italian/

Challenging the use of turmeric during cancer therapy borders on criminal J ames Duke (J. Am. Herbalist Guild

2010, 9, 60-61)

The curcumin-gemcitabine combination

N U C LEU S

Gene Promoter

N ature of the s tudy:Open-label, phase I

Loc ation: Dept. of Oncology, Rambam Health Care Campus (Haifa, Istrael)

Popula tion: 17 patients with advanced pancreatic cancer.

Dos ag e and dura tion of the intervention: Gemcitabine (1000 mg/m2) IV.weekly for 3-4 weeks + oral curcumin (8 g/day).for all the duration of the treatment

E nd-point: Determination of MTD

R es ults : Low c omplianc e to c urc umin a t 8 g /day, and need to reduc e it a t 4 g /day. Within the 11 eva lua ted patients , 4 had s table dis eas e, 6 tumor prog res s ion and 1 partia l res pons e. 5 patients enrolled s uffered intrac table abdomina l fullnes s or pa in, and had to dis c ontinue c urc umin.Formulation of c urc umin different from unformua lted c urc umin s hould be inves tig a ted in future s tudies

Epelbaum, R. et al, Nutr. Cancer.. 2010, 62, 1137-1141

The curcumin-docetaxel combination

N U C LEU S

Gene Promoter

N ature of the s tudy:Open-label, phase I

Loc ation: Centre d’Investigation Clinique (Clermont-Ferrand, France)

Popula tion: 14 patients with advanced or metastatic breast cancer.

Dos ag e and duration of the intervention: Docetaxel (100 mg/m2) IV every 3 weeks. Curcumin orally up to 6 g/day for seven days (from d-4 to d+2).

End-point: Primary: determination of maximal tolerated dose (MTD) Secondary: toxicity, safety, tumor markers measurements (VEGF…) and objective clinical response of the combination

R es ults : M TD = 8 g /die c urc umin, but poor c omplianc e bec aus e of the number of pills to take

S ome improvements in biolog ic a l and c linic a l res pons es in mos t pa tients Bayet-Robert, M. et al, Cancer Biol. Ther.. 2010, 9, 8-14

Effect of Meriva ® on the quality of life of cancer patients

N U C LEU S

Gene Promoter

N ature of the s tudy: Placebo-controlled study

Loc ation: Università di Chieti-Pescara (Italy) and University of Milano Popula tion: 160 cancer patients chemo- and radiotherapy naif treated, after surgery, with chemotherapy (80) or radiotherapy (80), and divided between control and treatment groups. All patients in reasonaly good condition (Karnofsky scale score >70)

Dos ag e and duration of the intervention: 3 x 500 mg Meriva® daily for 8 weeks after the end of the first treatment, started at least one month after surgeryEnd-point: Semi-quantitative evaluation of treatment side-effects

Plasma oxidative status R es ults : S ig nific ant differenc e betw een the tw o g roups in terms of

Treatment s ide-effec ts P la s ma oxida tive s ta tus

Quality of life according to the Karnofky Performance S cale index

N U C LEU S

Gene Promoter

M eriva ®e s upportive c are

Nausea indotta da chemioterapia

N U C LEU S

Gene Promoter

Incidenza della nausea indotta da chemioterapia: >70% (Ryan J . L. ,et al. S upp. Care Cancer. 2011, in press .)

Ginger for the reduction of chemotherapy-induced nausea

N U C LEU S

Gene Promoter

N ature of the s tudy: Randomized, double-blind, placebo-controlled, multicenter

Loc ation: Dept. of Dermatology, University of Rochester Medical Center (Rochester, US) (Coordination)

Popula tion: 744 adult cancer patients divided into four arms: one placebo and three dosages of ginger (0.5 g, 1 g, 1.5 g)

Dos ag e and dura tion of the intervention: 3 caps/day ginger or placebo twice/day for 6 days (from -3 to +3 of the beginning of chemotherapy). 5-HT(3) antagonist administered as antiemetic on day 1. Each cap contains 8.5 mg gingeroids

E nd-point: Determination of optimal dosage and efficacy for the reduction of nausea on day 1 of chemotherapy

R es ults : S ig nific ant reduc tion of naus e a t day 1 of c hemotherapy c ompared to plac ebo for the 0.5 g and 1 g dos ag es (17-34 mg g ing eroids /die)

Ryan, J . L..et al, S upport Care Cancer.. 2010

Tossicità epatica

N U C LEU S

Gene Promoter

Incidenza di toss icità epatica: 33-66% , ( 50% di grado III or IV) (Floyd J . et al. S emin Oncol. 2006; 33, 50-67.).

S iliphos® for the prevention of chemotherapy- induced liver toxicity

N U C LEU S

Gene Promoter

Nature of the study Placebo-controlledNumber of patients 24 (T) , 26 (P); age 2-19

Dosage of Siliphos (as silybin) 5.1 mg/Kg/die

Duration of the study 56 days (28 treatment; 28 discontinuation, then blood analysis)

End Point Liver health as measured by biochemical assays (AST, ALT, TB)

Location of the trial Children Hospital New Presbyterian (Columbia and Cornell University associated)

Major investigator Prof. K. Kelly

Ladas E. J . . et al. Cancer 2010, 320-334

THE STUDY MADE HEADLINE NEWS

WHAT THE STUDY AUTHORS SAID“Milk thistle needs to be studied further, to see how effective

it is for a longer course of treatment, and whether it works well in reducing liver inflammation in other types of cancers and with other types of chemotherapy. However, our results are promising as there are no substitute medications for treating liver toxicity.”

K. Kelly, from a press release of the American Cancer S ociety

Edema indotto da radioterapia

NUCLEUS

Gene Promoter

Boswellia as a steroid-sparing agent for cerebral edema

NUCLEUS

Gene Promoter

N ature of the s tudy: randomized, placebo-controlled, double blind

Loc ation: Dept. Radiation Oncology, Univeristy Hospital, Freiburg (Germany)

Popula tion: 44 patients with primary or secondary malignant cerebral tumors, receiving radiotherapy.

Dos ag e and dura tion of the intervention: 4.2 g of Boswellia Extract (BSE)/day

E nd-point: Primary: Volume of cerebral edema measured by MRI Secundary: toxicity, cognitive function, quality of life, need for dexamethasone medication R es ults : S ig nific a tive reduc tion (>75% ) in 60% of patients rec eiving B S E vs 26% w ith plac ebo

N o s ig nific ant advers e reac tions N o s ig nific a tn effec t on qua lity of life, cog nitive func tion, and

us e of dexamethas one

Kirste, S.. et al, Cancer. 2011, 117, 3788-3795

Cistite indotta da radioterapia

NUCLEUS

Gene Promoter

Cranberry for prostate cancer related UTI

NUCLEUS

Gene Promoter

Nature of the study ControlledNumber of patients 370 (184 treatment + 186 control)Dosage 200 mg of a standardized cranberry extract

(30% PAC according to EU Pharmacopoeia)

Duration of the study 6-7 weeks, starting the day of bladder catheterization

End Point Objective: Number of UTI as established by urocultureSubjective:urinary symptoms (nycturia, mictional urgency and frequency, dysuria

Location Italy (Cremona hospital, radiology center)Results Statistically significant reduction of UTI (9% in

the treatment branch vs 24% in the control) and of the urinary symptoms

Bonetta, A.; Di Pierro, F. submitted for publication

S upporting care post-trattamento

Coumarins, phenolics and the treatment of cancer lymphedema

NUCLEUS

Gene Promoter

Nature of the study: controlled study

Location: Istituto Nazionale per la Ricerca sul Cancro (Genova, Italy)

Population: 21 breast cancer survivors with chronic upper arm lymphedema secondary to removal of axilary lymphnodes.

Dosage and duration of the intervention: 400 mg of a standardized Melilotus officinale extract standardized in coumarin (8 mg) in a single daily administration for 6 months.

End-point: reduction of lymphedema, as measured by upper arm circumpherence.

Results : Modest, but s tatis tically s ignificant reduction of edema (5% of the initial value) and discomfort.

Pastura, G. et al.. Clin. Ter. 1999, 150, 403-408

The potential of combining phenolics and using new formulations

NUCLEUS

Gene Promoter

Pastura, G. et al.. Clin. Ter. 1999, 150, 403-408

Aumento di peso

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Gene Promoter

Green tea and post-treatment overweight status

NUCLEUS

Gene Promoter

Nature of the s tudy: placebo-controlled

Location: Dept. Nutritional Sciences, University of Ariziona

Population: 54 overweight breast cancer survivors (BMI: 30.1 Kg/m-2).

Dosage and duration of the intervention: 960 mL/day of decaffeinated green tea vs placebo tea (Lipton tea bags, ca 60 mg catechins/bag, 4 bags/day)/ 6 months

End-point: a) weight b) body composition and resting metabolic rate c) energy intake, glucose, HOMA-IR, lipid profile

Results : Modest reduction of weight (-1.2 Kg vs + 0.2 in control) S ignificant reduction in energy intake

Increase of cholesterol HDL Nons ignificant improvement of HDL/LDL ratio and HOMA-IR

Stendell-Hollis, N.R. J.Hum. Nutr. Diet 2010, 23, 590-600

Conclusioni

NUCLEUS

Gene Promoter

E’ più importante conoscere che persona ha una malattia piuttosto che quale malattia ha una persona Ippocrate

Martirio di Sant’Agata

Giovanni Lanfranco, inizio XVII secolo