Dietary Supplements
in Myelodysplastic Syndromes
Larry Bergstrom MD
Program in Complementary and Integrative Medicine
Division of Consultative Medicine
Mayo Clinic in Arizona
bergstrom.larry@mayo.edu
Disclosures
• None
Objectives
• To know the Definition of Integrative
Medicine
• To recognize the Mediterranean/Anti
inflammatory diet
• To be aware of role of dietary
supplement in care of myelodysplastic
syndromes
Alternative Medicine at the Mayo Clinic
Integrative Medicine Consultation
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2 hour appointment, billed by time
Review of medical condition(s)
Review of patient’s CAM therapy use
Review of potential interactions with
conventional therapies
• Review of additional alternative therapies
• Review of basic health care issues
• Nutrition
• Exercise
• Stress reduction
Supplement Information Resource
http://www.stumbleupon.com/su/7VWq5a/www.informationisbeautiful.n
et/play/snake-oil-supplements/
Supplement Information Resource
http://www.stumbleupon.com/su/7VWq5a/www.informationisbeautiful.
net/play/snake-oil-supplements/
Integrative Nutritional Plan
• Utilizing food as a source of health and
energy
• Emphasis is on food first
• Supplements are supplements to food
• Supplements are used to fill in where
diet cannot cover everything.
• Mediterranean/Anti-inflammatory diet
Mediterranean/Anti inflammatory Diet
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Fish (wild, ocean) 3 x weekly,
Fish oil (EPA + DHA = 1000 mg/day) (omega 3)
Fiber, 35 gm/d
Olive or Canola oil (MUFA, PUFA)
Whole grain produ (fiber, vits, antioxidants)
Soy, e.g. Soy milk, tofu, soy nuts, edamame (isoflavones)
Nuts- walnuts, pecan, almonds, etc (sterols)
Fruit- dark skinned, blueberries, apples etc.
Vegetables, legumes (fiber, vits, carotenoids)
Green tea- 3 c/d (EGCG, antioxidants)
Flax seed- one Tbsp/d (lignans)
Lean meats- chicken, turkey (without skin)
Stanols- beta sitolsterol (therapeutic spreads)
Probiotics- yogurt, kefir etc
Minimal- red meat once a month or less
Avoid- partially hydrogenated anything, high fructose corn
syrup
Supplement Effects
• Antioxidant
• Immune boost
• Apoptosis
• Epigenetic
• Anti inflammatory
• Nutrients
• Inhibition of DNA Methylation
Molecular targets of chemopreventive agents in
cancer.
Cancer Letters(2004) 215:129-140
Supplements Effects
Carcinogenesis vol.28 no.2 pp.233–239, 2007
Supplements
Resveratrol- 500- 1000 mg/d
A polyphenol found in grape skins. Grapes and
grape juice, grape seed extract.
Inhibits proliferation of cancer cells via
apoptosis and also by exerting anti- estrogen
effects
Sales have skyrocketed, strong use in cancer
patients and elderly
Strong inhibitor of CYP2D6 and CYP2D9.
Aggarwal, et al. Anticancer Res. 2004;24:2783‐2840
Banerjee, et al. Cancer Res. 2002;62(17):4945‐4954
Risk factors of Myelodysplastic syndromes
Hospital-based, 354 MDS cases, 452 controls
Relative Risk for developing MDS
Family history of hematopoietic cancer
• Yes
1.66 (0.64–4.30)
Fertilizer/herbicide/pesticide exposure
• High
5.68 (1.50–21.6)
Smoking
• Ever
2.23 (1.33–3.72)
Benzene/solvent/gasoline exposure
• High
1.44 (0.63–3.33)
Alcohol
• Wine, 1 glass/day
• Other alcoholLeukemia (2005) 19, 1912–1918
0.52 (0.29–0.95)
0.62 (0.35–1.12)
Supplements, Actions
Curcumin- Turmeric 300-1000 mg/d (with
black pepper to enhance absorption)
• American Ball-park mustard
• Curry
Supplements, Actions
• Isothiocyanates- PEITC, Cruciferous
vegetables.
• Apoptosis
• Inhibition of DNA methylation
(epigenetics)
Epigenetic roles of nutrition
ß-phenylethyl isothiocyanate
PEITC (Watercress)
• Reactive oxygen species (ROS) stimulate cell
proliferation and induce genetic instability
• Cancer cells make lots of ROS
• PEITC disables glutathione antioxidant
system causing severe ROS accumulation in
cancer cells which have high ROS output
• High ROS causes oxidative cell damage and
death of cell.
• Animal studies
Trachootham D. Selective killing of oncogenically transformed cells through a
ROS mediated mechanism by ß-phenylethyl isothiocyanate. CANCER CELL
2006 10;241–252
Indole 3 Carbinol (I3C) 300 mg/d
3,3'-Diindolylmethane (DIM)100-300 mg/d
(Broccoli etc)
Cruciferous vegetables
Cruciferous Vegetables
Supplement Actions
• Luteolin- Celery, green pepper,
peppermint. Sensitizes TRAIL-induced
apoptosis, Induction of TRAIL, along
with Bid cleavage and the activation of
caspases
• Organosulfur compounds- Garlic and
onion. Induction of p53, Bax and
downregulation of Bcl-2, cytochrome c
release,activation of caspases
•Carcinogenesis vol.28 no.2 pp.233–239, 2007
Supplement, Actions
Genistein- Soybean, soy isoflavone
• Degradation of c-FLIP Induced MMP
change, caspase-3, activation and PARP
cleavage, downregulation of Bcl-2, Bcl-XL
expression, activation of caspase-3
•Carcinogenesis vol.28 no.2 pp.233–239, 2007
Vitamin C
Pretreatment with vitamin C caused a dose
dependent attenuation of cytotoxicity with
all antineoplastic agents tested. (Mouse
lymphoma cells)
*No primary articles
using Vit C in MDS
Cancer
A
Res 2008;68:8031-8038.
n
Gingerol and Curcumin in low
risk myelodysplastic syndromes
• 9 patients with low or Int-1 risk MDS
• Curcumin 8 Gm/day and Gingerol 1.4 Gm/day
• 1 lost to follow-up, 2 too early for evaluation. 4/6
remaining improved, 3 showing trilineage
improvement. Two had stable disease
ACR Meeting Abstracts 2008: 5528
Vitamin D treatment in MDS
• 19 pts. Responders- either granulocyte or
platelet count ↑ 50%, Hgb ↑ 1·5 g/dl, Transfusion
needs ↓ 50%.
• Calcifediol- 5 pts, Calcitriol- 14 pts
• Calcifediol- 1/5 rspnd, 3/5 nonrspnd, 1/5 prog.
• Calcitriol- 10/14 rspnd, (2 major) 4/14nonrspnd
• Baseline Vit D levels not related to response.
Conclusion: “Vit D3 could induce a longstanding
response in some low-intermediate risk MDS
patients without inducing hypercalcemia”.
Brit J of Haematology, 1998, 100, 516–520
Green Tea and Bortezomib
BAD!
• Golden EB. Green tea polyphenols block the
anticancer effects of bortezomib and other
boronic acid-based proteasome inhibitors.
Blood, 4 June 2009, Vol. 113, No. 23, pp.
5927-5937
GOOD!
• Wang Q. Potentiation of (−)-epigallocatechin3-gallate-induced apoptosis by bortezomib in
multiple myeloma cells Acta Biochim
Biophys Sin (2009) 41 (12): 1018-1026
Mushrooms, ß-Glucans
• Up-regulate the immune system by
stimulation of macrophage, NK cells, T
cells, immune system cytokines.
• Reishi, Agaricus blazei, Maitake, and
Trametes versicolor.
• Commercial products- lentinan,
polysaccharide K
Are Antioxidants
counterproductive during Cancer
treatment?
• Small studies, variable results.
• Variable doses of antioxidants
• Larger doses supplements not helpful
but may decrease treatment toxicity
• Foods that contain antioxidants may be
helpful
• Combinations of antioxidants may be
more promising
Literature Review of antioxidant supplementation
on chemotherapeutic toxicity
• 33 of 965 articles: RCT, met criteria, N=
2,446
• 24/33 reported ↓ toxicities from concurrent
use of antioxidants with chemotherapy.
• 9 reported no difference in toxicities
• 1 (vitamin A) reported a significant increase
in toxicity in the antioxidant group
• 5 reported antioxidant group had more full
dose or less dose-reduction than control
groups
Into J Cancer. 2008 Sep 15;123(6):1227-39
Supplement Summary
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Resveratrol
500-1000 mg/d
Indole-3-Carbinol
300-400 mg/d
Turmeric (black pepper) 300-1000 mg/d
EGCG
500-750 mg/d
DIM
300 mg/d
Vit D
1000 IU/d
PEITC
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Fish Oil (sum of DHA+EPA) 1000 mg/d
Bibliography
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Khan N, Apoptosis by dietary factors: the suicide solution for
delaying cancer growth Carcinogenesis vol.28 no.2 pp.233–239,
2007
Heaney ML et. al. Vitamin C Antagonizes the Cytotoxic Effects of
Antineoplastic Drugs. Cancer Res. 2008 Oct 1;68(19):8031-8
Raza, Azra, et. al. Multi-lineage response to a combination of
gingerol and curcumin in low risk myelodysplastic syndromes. ACR
Meeting Abstracts 2008 2008: 5528
Strom S, et al. Myelodysplesias Risk factors of myelodysplastic
syndromes: a case–control study Leukemia (2005) 19, 1912–1918.
Schumacker PT. Reactive Oxygen Species in Cancer Cells. Cancer
Cell, 2006 Sept;10(3):175-176
Fang M. Dietary Polyphenols May Affect DNA Methylation. J. Nutr.
137: 223S–228S, 2007.
Bibliography
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Mellibovsky I. et al. Vitamin D treatment in myelodysplastic
syndromes Brit J of Haematology, 1998, 100, 516–520
Choi SW. Epigenetics: A New Bridge between Nutrition and Health.
Adv. Nutr. 2010 1: 8–16
Golden EB. Green tea polyphenols block the anticancer effects of
bortezomib and other boronic acid-based proteasome inhibitors.
Blood, 4 June 2009, Vol. 113, No. 23, pp. 5927-5937
Wang Q. Potentiation of (−)-epigallocatechin-3-gallate-induced
apoptosis by bortezomib in multiple myeloma cells Acta Biochim
Biophys Sin (2009) 41 (12): 1018-1026