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University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Should the diet of colon cancer patients be personalized
based on gene mutation profiles of tumor cells?
Cristina Pereira-Wilson
Cristina Xavier
Dept. of Bioloy, University of Minho,
Braga, Portugal
5th European Nutrition and Dietetics Conference
June 17, 2016
Rome
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Colorectal cancer (CRC) is the third most common cause of cancer related death in western countries.
Hereditary and environmental factors are involved.
Hereditary predisposition corresponds to only about 20% of total cases of CRC, the remainder are sporadic.
Diet may constitute a risk factor but may also have cancer preventive effects.
Mutations accumulate in
Oncogenes and
Tumor suppressor genes
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Colorectal cancer
Sporadic CRC refers to those cases that occur in
individuals over age 50 years without any identifiable
predisposing factors.
Familial cases are those with a family history of CRC
but exclusive of FAP, HNPCC, and the hamartomatous
polyposis syndromes.
The approximate percentage of distribution for each
condition is as follows: sporadic, 75%; familial, 15%;
HNPCC, 5%; FAP, 1%; IBD, 1%; MAP, 1%;
hamartomas, < 1%.
IBD = inflammatory bowel disease; MAP = MYHassociated polyposis
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Genetic prognostic and predictive markers in colorectal cancer
Axel Walther, Elaine Johnstone, Charles Swanton, Rachel Midgley, Ian Tomlinson & David Kerr
Nature Reviews Cancer 9, 489-499 (July 2009)
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Barbaro et al, INTERNATIONAL JOURNAL OF ONCOLOGY, 2014
5th European Nutrition and
Dietetics Conference
Rome, 2016
University of Minho, Braga,
Portugal
Personalized Medicine…
the discovery that KRAS mutation is a marker
of probable failure of epidermal growth factor
receptor (EGFR)-targeted therapy was the
first step in the tailoring of treatment to the
individual.
Prholifer
ation
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Personalized Medicine…
Alterations in the tumor suppressor p53
are known to cause apoptosis evasion
and treatment resistance
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Treatment efficacy depends on
patient’s genetic information
A person’s genetic information will also
affect the response to dietary constituents
5th European Nutrition and
Dietetics Conference
Rome, 2016
University of Minho, Braga,
Portugal
Cell lines dereived from tumors with well characterized genetic backgounds
are useful in the study of effects of dietary constituents
Mutations
Kras
Braf
p53
HCT15
CO115
+
wt
wt
+
+
wt
HCT116 p53 wt
HCT116 p53 null
+
+
wt
wt
wt
null
5th European Nutrition and
Dietetics Conference
Rome, 2016
University of Minho, Braga,
Portugal
Xavier C and Pereira-Wilson C (2016)
PharmaNutrition 4: 112-122
Rosmarinic acid
Luteolin
Ursolic acid
Quercetin
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Compounds dose dependently
decrease cell proliferation
in cells with KRas (HCT15)
or BRaf (CO115) mutations
quercetin (Q),
luteolin (L),
ursolic acid (UA)
and reference compounds, wortmannin (W)
and PD-98059 (PD)
Xavier,C et al., (2009)
Cancer Letters 281, 162-170
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Compounds dose dependently
increase cell death by apoptosis
in cells with KRas (HCT15)
or Braf (CO115) mutations
Quercetin (Q), luteolin (L) and ursolic acid (UA)
and reference compounds, wortmannin (W) and
PD-98059 (PD)
Xavier,C et al., (2009)
Cancer Letters 281, 162-170
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
5-FU is a chemotherapeutic drug
widely used in the treatment of CRC
Tumor cells with p53 mutation
are resistant to 5-FU
Q + 5-FU increases cell death
particularly in CO115
Xavier,C et al. (2011)
Cancer Chemother Pharmacol 68: 1449-1457
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Apoptosis induced by 5-FU and by Q
is linked to an increase p53 and
caspase activation
Is this a p53 dependent effect?...
Xavier,C et al. (2011)
Cancer Chemother Pharmacol 68: 1449-1457
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Apoptosis induction by Q, 5-FU and Q + 5-FU
is p53 dependent
Therefore, quercetin
may increase 5-FU treatment efficacy
in tumors expressing wild type (wt) p53
but will most likely not benefit patients
whose tumors do not express wt p53 or express
a mutated p53
Xavier,C et al. (2011)
Cancer Chemother Pharmacol 68: 1449-1457
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Concluding Remarks
In order to use dietary compounds to enhance the efficacy cancer chemotherapy,
a detailed characterization of their molecular targets and interactions with the pharmaceutical
drugs is needed so as to sellect the patients that will benefit from the combination!
5th European Nutrition and
Dietetics Conference
Rome, 2016
University of Minho, Braga,
Portugal
Poster NUTC 15

Our data shows that the studied legumes have the capacity to
reduce proliferation by keeping the cells differentiated in cell
cycle phase G0-G1.

The cell cycle arrest activity is enhanced by boiling and
pressure cooking.

Importantly, back bean and cowpea demonstrated to be
effective independently of tumor p53 status, contrarily to
soybean.

Taken together, the data suggests that cowpea and black bean
have great potential in the nutritional management of
colorectal cancer patients.
5th European Nutrition and
Dietetics Conference
Rome, 2016
University of Minho, Braga,
Portugal
Thank you for
your
attention!
Cristina Pereira-Wilson
Molecular Nutrition Group
Department of Biology,
University of Minho,
Braga Portugal
Contact:
[email protected]
[email protected]
Collaborations
- M. Rohde
Apoptosis Department,
Institute of Cancer Biology,
Danish Cancer Society,
Copenhagen, Denmark
- R. Seruca
Institute of Molecular Pathology
and Immunology (IPATIMUP)
University of Porto,
Porto, Portugal
Aknowledgments
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Compounds dose dependently
decrease cell proliferation
in cells with KRas or BRaf mutations
Effect on BrdU incorporation of different
concentrations of quercetin (Q), luteolin (L),
ursolic acid (UA) and reference compounds,
wortmannin (W) and PD-98059 (PD), in HCT15
(a) and CO115 (b) cells.
Xavier,C et al., (2009)
Cancer Letters 281, 162-170
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
The ratio total ERK/p-ERK reflects
MAPKinase pathway activity
In KRas mutated cells HCT15 Luteolin (L)
and quercetin (Q) decrease
MAPKinase pathway activity
In Braf mutated cells the compounds
do not change MAPKinase pathway activity
Xavier,C et al., (2009)
Cancer Letters 281, 162-170
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
The ratio p-AKT/Total AKT reflect
the level of activation of the PI3K/AKT pathway
In CO115 cells the compounds decrease
PI3K/AKT activity
In HCT15 cells p-AKT was not detected
Xavier,C et al., (2009)
Cancer Letters 281, 162-170
University of Minho, Braga,
Portugal
5th European Nutrition and
Dietetics Conference
Rome, 2016
Quercetin
decreased activity in MAPKinase pathway
in HCT15 cells that express a mutated Kras
but not in CO115 that has a Braf mutation
in CO115 Q acts on PI3K/AKT
Q acts on several molecular targets
and as a result it inhibits proliferation in both
genetic backgrounds
Xavier,C et al., (2009)
Cancer Letters 281, 162-170