Fall 2011 - Institute of Medical Science - University of Toronto

FEATURE
analysis suggested a small increase in highgrade
cancer in the dutasteride arm. One patient
(0.04%) was found to have Gleason 8-10
cancer in the placebo arm compared to 12
patients (0.5%) in the dutasteride arm. While
there is evidence that this increase in grade
was an artifact, it has led to concern about
the widespread implementation of 5ARIs for
prevention in healthy men. These patients
also more commonly experienced sexual side
effects. These studies provide further impetus
for developing safe preventive agents that
have more acceptable side-effect profiles and
avoid the increased grade phenomenon.
The mechanism by which high-fat diets contribute
to cancer progression is thought likely
to be related to increased insulin and/or related
growth factor levels. Low-carbohydrate
diets are based on maintaining low insulin
levels. Our hypothesis is that a low-insulinemic
diet, by virtue of reducing circulating
insulin and IGF levels, may protect against
the carcinogenic effect associated with highfat
intake.
In our laboratory, we have studied the influence
of vitamin E, selenium, lycopene, flavonoids,
and dietary intervention with a low
carbohydrate diet on the growth, progression,
and gene expression of a transgenic prostate
cancer model (Lady TRAMP). This work was
carried out by Dr. Vasu Venkateswaran and
a number of fellows and graduate students.
Our results are summarized as follows 5-11 :
Experimental Results
We have also evaluated the relationship between
diet, exercise, and prostate cancer
progression in a xenograft model. This study,
carried out by our IMS graduate students,
compared cancer progression in mice exercised
on a treadmill for several hours per
day, maintained on either a standard, or high
fat-high carbohydrate diet. This study found,
perhaps not surprisingly, that regular exercise
in conjunction with a normal diet inhibited
cancer growth. However, the group with
the most rapid cancer progression was the
exercising mice on a high fat-high carbohydrate
diet. These animals had a higher energy
intake than the non-exercising animals. Our
hypothesis is that the exercise stimulated an
increase in dietary intake of a ‘bad’ diet, resulting
in increased cancer cell proliferation.
We believe this process is mediated through
the insulin-IGF1 axis as well as other pathways.
This is something to consider the next
time you eat a Big Mac after a workout!
The relationship between dietary intake
and prostate cancer incidence and mortality
is complex. Extensive epidemiologic data
points to a strong positive relationship between
fat intake and prostate cancer progression;
while a diet rich in fruits and vegetables
(particularly lycopene containing plants like
tomatoes) as well as soy products are suggested
to have protective effects. The Japanese
have shifted to a more Western diet over the
last 20 years, and this has been accompanied
by a rapid increase in prostate cancer incidence
and mortality, which is now approaching
North American rates. Specifically, with
approximately one half the population of the
US, the number of cases has increased over
the last 20 years from 10% to 65% of the US
incidence. Of course, separating the impact
Vitamin E, selenium, and lycopene dramatically inhibit the development of prostate cancer in this model.
Lycopene is a necessary component of this effect.
Several flavonoids dramatically inhibit the growth of prostate cancer in a xenograft model. This is mediated
through a number of cell cycle specific genes and pathways.
A low carbohydrate diet reduces the growth rate of prostate cancer xenografts in mice on a high-fat diet
compared to an isocaloric high-carbohydrate diet. This is mediated through the IGF family of mitogens.
of increased case detection by PSA screening
on these figures is challenging. Nonetheless,
the overwhelming weight of evidence suggests
that a diet more oriented towards plants
and away from animal fat is prostate healthy.
This dietary shift also results in lower cholesterol
and triglycerides, leading to improved
cardiovascular health, which shows that a
prostate-healthy diet is really a diet healthy
for the whole body.
References
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Cassin BJ, Pontes JJ, Haas GP. High grade prostatic intraepithelial
neoplasia (HGPIN) and prostatic adenocarcinoma
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2. Lippman SM, Klein EA, Goodman PJ, Lucia MS,
Thompson IM, Ford LG, Parnes HL, Minasian LM, et
al. Effect of selenium and vitamin E on risk of prostate
cancer and other cancers: the Selenium and Vitamin E
Cancer Prevention Trial (SELECT). JAMA. 2009 Jan
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3. Thompson IM, Goodman PJ, Tangen CM, Lucia MS,
Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins
JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM,
Crowley JJ, Coltman CA Jr. The influence of finasteride
on the development of prostate cancer. N Engl J Med.
2003 Jul 17;349(3):215-24.
4. Andriole GL, Bostwick DG, Brawley OW, Gomella
LG, Marberger M, Montorsi F, Pettaway CA, Tammela
TL, Teloken C, Tindall DJ, Somerville MC, Wilson TH,
Fowler IL, Rittmaster RS; REDUCE Study Group. Effect
of dutasteride on the risk of prostate cancer. Engl J Med.
2010 Apr 1;362(13):1192-202.
5. Haddad AQ, Venkateswaran V, Viswanathan L, Teahan
SJ, Fleshner NE, Klotz LH. Novel antiproliferative flavonoids
induce cell cycle arrest in human prostate cancer
cell lines. Prostate Cancer Prostatic Dis. 2006;9(1):68-76.
6. Venkateswaran V, Fleshner NE, Sugar LM, Klotz LH.
Antioxidants block prostate cancer in lady transgenic
mice. Cancer Res. 2004 Aug 15;64(16):5891-6.
7. Venkateswaran V, Klotz LH. Diet and prostate cancer:
mechanisms of action and implications for chemoprevention.
Nat Rev Urol. 2010 Aug;7(8):442-53. Epub 2010
Jul 20. Review.
8. Haddad AQ, Fleshner N, Nelson C, Saour B, Musquera
M, Venkateswaran V, Klotz L. Antiproliferative
mechanisms of the flavonoids 2,2’-dihydroxychalcone
and fisetin in human prostate cancer cells. Nutr Cancer.
2010;62(5):668-81.
9. Hou M, Venier N, Sugar L, Musquera M, Pollak M,
Kiss A, Fleshner N, Klotz L, Venkateswaran V. Protective
effect of metformin in CD1 mice placed on a high
carbohydrate-high fat diet. Biochem Biophys Res Commun.
2010 Jul 2;397(3):537-42. Epub 2010 Jun 2.
10. Cervi D, Pak B, Venier NA, Sugar LM, Nam RK,
Fleshner NE, Klotz LH, Venkateswaran V. Micronutrients
attenuate progression of prostate cancer by elevating
the endogenous inhibitor of angiogenesis, platelet
factor-4..BMC Cancer. 2010 Jun 4;10:258.
11. Venkateswaran V, Klotz LH, Ramani M, Sugar
LM, Jacob LE, Nam RK, Fleshner NE. A combination
of micronutrients is beneficial in reducing the incidence
of prostate cancer and increasing survival in the
Lady transgenic model. Cancer Prev Res (Phila). 2009
May;2(5):473-83.
IMS MAGAZINE FALL 2011 PROSTATE CANCER | 16