Current Cancer
Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 7, Number 5, August 2007
Contents
Molecular Targets for the Nutritional Preemption of
Cancer
Guest Editors: John A. Milner and Cindy D. Davis
Molecular Targets for Nutritional Preemption of Cancer
Pp. 410-415
Cindy D. Davis and John A. Milner
[Abstract]
Targeting Carcinogen Metabolism by Dietary Cancer
Preventive Compounds Pp. 416-424
Siwang Yu and Ah-Ng Kong
[Abstract]
Nutrition and DNA Repair – Potential Molecular
Mechanisms of Action Pp. 425-431
J.C. Mathers, J.M. Coxhead and J. Tyson
[Abstract]
Nutrient Regulation of Tumor and Vascular Endothelial
Cell Proliferation Pp. 432-437
J.M. Enciso and K.K. Hirschi
[Abstract]
Using Nutrigenomics to Evaluate Apoptosis as a Preemptive
Target in Cancer Prevention Pp. 438-446
Keith R. Martin
[Abstract]
Cancer Preventive Phytochemicals as Speed Breakers
in Inflammatory Signaling Involved in Aberrant COX-2 Expression
Pp. 447-458
Young-Joon Surh and Joydeb Kumar Kundu
[Abstract]
Cancer Prevention by Dietary Bioactive Components
that Target the Immune Response Pp. 459-464
Lynnette R. Ferguson and Martin Philpott
[Abstract]
Nutritional Modulation of Terminal End Buds: Its Relevance
to Breast Cancer Prevention Pp. 465-474
Leena Hilakivi-Clarke
[Abstract]
Inducible Nitric Oxide Synthase-Vascular Endothelial
Growth Factor Axis: A Potential Target to Inhibit Tumor Angiogenesis
by Dietary Agents Pp. 475-483
Rana P. Singh and Rajesh Agarwal
[Abstract]
Energy Balance and Carcinogenesis: Underlying Pathways
and Targets for Intervention Pp. 484-491
Stephen D. Hursting, Laura M. Lashinger, Lisa H. Colbert,
Connie J. Rogers, Karrie W. Wheatley, Nomeli P. Nunez, Somdat
Mahabir, J. Carl Barrett, Michele R. Forman and Susan N. Perkins
[Abstract]
General Articles
Kit: Molecule of Interest for the Diagnosis and Treatment
of Mastocytosis and other Neoplastic Disorders Pp.
492-503
Mrinal M. Patnaik, Ayalew Tefferi and Animesh Pardanani
[Abstract]
Cyclopentenyl Cytosine (CPEC): An Overview of its
in vitro and in vivo Activity Pp. 504-509
K.J.M. Schimmel, H. Gelderblom and H.J. Guchelaar
[Abstract]
Abstracts
[Back to top]
Molecular Targets for Nutritional Preemption
of Cancer
Cindy D. Davis and John A. Milner
Malignant cells are characterized by alterations in multiple
signaling pathways that promote proliferation, inhibit apoptosis,
promote angiogenesis in the case of solid tumors, and enable
cancer cells to invade and migrate through tissues. A variety
of foods and their bioactive dietary constituents appear to
have merit in reducing cancer risk and modifying tumor behavior.
All of the major signaling pathways, which are deregulated
in cancer, and which serve as potential targets for cancer
prevention, have been reported to respond to one or more dietary
components. Herein, we provide a brief overview of the importance
of diet as a modifier of carcinogen metabolism, DNA repair,
cell proliferation, apoptosis, inflammation, immunity, differentiation,
angiogenesis, hormonal regulation and cellular energetics.
This special issue of Current Cancer Drug Targets
provides a collection of articles from researchers who are
actively involved in examining the role of dietary components
in cancer prevention and therapy. The remaining articles in
this series provide more details about the specifics about
the importance of these processes during carcinogenesis and
proof-of-principal about the modifying capabilities of food
patterns, specific foods and individual bioactive food components.
[Back to top]
Targeting Carcinogen Metabolism by Dietary Cancer
Preventive Compounds
Siwang Yu and Ah-Ng Kong
Prevention is one of the most important and promising strategies
to control cancer. Many dietary bioactive compounds, mostly
phytochemicals, have been found to decrease the risk of carcinogenesis.
Modulating the metabolism and disposition pathways of carcinogens
represents one of the major mechanisms by which dietary compounds
prevent carcinogenesis. In the present review, the specific
molecular targets of dietary compounds within carcinogen metabolism,
including various enzymes and transporters and their regulatory
signaling pathways, are briefly reviewed. The expression of
phase I enzymes, which presumably mostly activate carcinogens,
is mainly regulated by xenobiotics sensing nuclear receptors
such as AhR, CAR, PXR, and RXR. On the other hand, phase II
enzymes catalyze the conjugations of carcinogens and generally
are transcriptionally controlled by the Nrf2/ARE signaling
pathways. The Nrf2/ARE signaling pathway, which regulates
the expression of many detoxifying enzymes, is a major target
of dietary compounds. The final excretion of carcinogens and
their metabolites is mediated by phase III transporters, which
share many regulatory mechanisms with phase I/II enzymes.
Indeed, the expression of metabolizing enzymes and transporters
is often coordinately regulated. Besides transcriptional regulation,
the activities of phase I/II enzymes and phase III transporters
could be directly activated or inhibited by dietary compounds.
Furthermore, genetic polymorphisms have profound effects on
the individual response to dietary compounds. Finally, the
effects of cancer prevention and the risk of carcinogenesis
are determined by the network composed of known/unknown molecular
targets and signaling pathways and its interaction with various
xenobiotics, including carcinogens, drugs, and diet. With
the rapid advances in the post genomic sciences, it could
be possible to decipher this network and better predict the
clinical outcomes of cancer prevention by dietary bioactive
compounds.
[Back to top]
Nutrition and DNA Repair – Potential Molecular
Mechanisms of Action
J.C. Mathers, J.M. Coxhead and J. Tyson
At its most fundamental, cancer is a genetic disease in the
sense that the primary events in tumorigenesis involve damage
to the genome. The genome is subject to damage continuously
from both exogenous agents and endogenous processes but this
becomes functionally important only if the damage is not detected
and resolved in a timely and effective manner. In mammals
there are 5 DNA repair pathways, encoded by approximately
150 genes, which appear to have arisen early in evolution
and which are highly conserved. Given the substantial epidemiological
and experimental evidence that variation in dietary intake
accounts for a significant proportion of the variance in cancer
prevalence, an a priori case can be made that dietary
factors may influence the effectiveness of DNA repair. A review
of the literature has identified 4 observational and 8 intervention
studies in human subjects where DNA repair (or a component
thereof) has been measured in relation to nutrition. This
rather limited evidence base precludes drawing definitive
conclusions, but the fact that there were significant effects
of dietary supplements in 5 out of the 8 intervention studies
suggests that food components and/or nutritional status may
influence DNA repair. This review considers possible molecular
mechanisms through which such factors could modulate repair.
[Back to top]
Nutrient Regulation of Tumor and Vascular Endothelial
Cell Proliferation
J.M. Enciso and K.K. Hirschi
Specific bioactive dietary components, such as the steroid
receptor superfamily ligands vitamins A and D, have been studied
extensively as potential cancer preventive and therapeutic
agents due to their ability to regulate key processes in a
variety of cell types which are dysregulated in neoplastic
transformation namely, proliferation and differentiation.
Alteration of one or more factors that regulate cell cycle
control has been described as a predisposing event for early
tumor development. In addition to tumor cell proliferation,
the viability, growth and metastasis of solid tumors are also
dependent on the vascularization of the tumor and establishment
of blood flow. Both vitamins A and D exhibit anti-angiogenic
properties which further strengthen their role as potential
targets for the prevention and treatment of cancer. This review
focuses on the role of vitamins A and D in preventing early
tumor initiation and progression via control of the
cell cycle in both tumor and vascular endothelial cells.
[Back to top]
Using Nutrigenomics to Evaluate Apoptosis as a Preemptive
Target in Cancer Prevention
Keith R. Martin
Apoptosis, a form of programmed cell death, is a pivotal defense
against cancer and is essential in maintaining tissue homeostasis.
Many diseases including cancer have been associated with aberrantly
regulated apoptotic cell death, thus elucidation of events
associated with both apoptosis and carcinogenesis provides
the opportunity for dietary intervention with the plethora
of bioactive components in the diet. Apoptosis occurs primarily
through two well-recognized pathways in cells including the
intrinsic, mitochondrial-mediated pathway and the extrinsic,
death receptor-mediated pathway. Dietary components can modulate
apoptosis through effects on protein expression and function,
mRNA expression, and on the human genome, either directly
or indirectly, to modulate gene expression. Thus, apoptosis
is an emerging target of dietary bioactive agents. However,
apoptosis is a complex process, with numerous specific targets
within each pathway that may or may not overlap. Furthermore,
biological systems are also extremely complex and exhibit
properties that extend far beyond observations associated
with each independent cellular process. This is further complicated
by the temporal nature of many of these effects. As a result,
it is critical to evaluate the entire biological system from
the nutrigenomics perspective to include critical evaluation
of DNA polymorphisms or SNPs of a gene, expression of that
specific gene, expression of specific processed mRNA (alternative
splicing), protein production from that mRNA, post-translational
modification of the resultant protein, and formation of respective
metabolites. Evolution of the fields of nutrigenetics, epigenomics,
transcriptomics, proteomics, and metabolomics has begun to
permit this approach so that a comprehensive picture emerges
from not only a single cell but tissues and whole organisms.
Studies such as these can ultimately be used to study tumors
to understand the molecular events that accompany carcinogenesis
and perturbations that occur during cell death processes and
how an individual’s response to diet can impact these
processes.
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Cancer Preventive Phytochemicals as Speed Breakers
in Inflammatory Signaling Involved in Aberrant COX-2 Expression
Young-Joon Surh and Joydeb Kumar Kundu
A causal association between inflammation and cancer has long
been suspected. Multiple lines of compelling evidence from
clinical, epidemiologic and laboratory studies support that
inflammation plays a critical role in the promotion and progression
stages of carcinogenesis. Recent progress in our understanding
of the molecular biology of cancer highlights the intracellular
signal transduction network, including that involved in mediating
the inflammatory response, which often functions abnormally
during carcinogenesis. One of the key players in inflammatory
signaling is cyclooxygenase-2 (COX-2). Aberrant upregulation
of COX-2 is frequently observed in various precancerous and
malignant tissues. Pro-inflammatory stimuli trigger the activation
of an intracellular signal transduction network comprising
proline-directed serine/threonine kinases, and their downstream
transcription factors, resulting in an inappropriate induction
of COX-2. Therefore, the normalization of inappropriately
overamplified signaling cascades implicated in chronic inflammation-associated
carcinogenesis by use of COX-2 specific inhibitors has been
recognized as a rational and pragmatic strategy in molecular
target-based cancer prevention. This review highlights the
cancer preventive effects of some anti-inflammatory phytochemicals
derived from edible plants, and their underlying molecular
mechanisms with a focus on representative transcription factors
and upstream kinases responsible for COX-2 induction.
[Back to top]
Cancer Prevention by Dietary Bioactive Components
that Target the Immune Response
Lynnette R. Ferguson and Martin Philpott
Dietary bioactive food components that interact with the immune
response have considerable potential to reduce the risk of
cancer. Reduction of chronic inflammation or its downstream
consequences may represent a key mechanism that can be reduced
through targeting signal transduction or through antioxidant
effects. Major classes of macronutrients provide numerous
examples, including amino acids such as glutamine or arginine,
lipids such as the omega-3 polyunsaturated fatty acids, DHA
or EPA, or novel carbohydrates such as various sources of
beta-glucans. Vitamins such as C and E are commonly used as
antioxidants, while zinc and selenium are minerals with a
wide spectrum of impacts on the immune system. Some of the
most potent immunomodulators are phytochemicals such as the
polyphenols, EGCG or curcumin, or isothiocyanates such as
PEITC. There is accumulating evidence for cancer prevention
by probiotics and prebiotics, and these may also affect the
immune response. Genomic approaches are becoming increasingly
important in characterising potential mechanisms of cancer
prevention, optimising the rational selection of dietary bioactive
food components, or identifying humans with differing nutrient
requirements for cancer protection.
[Back to top]
Nutritional Modulation of Terminal End Buds: Its Relevance
to Breast Cancer Prevention
Leena Hilakivi-Clarke
Findings with experimental rodent models reveal that exposures
to dietary factors during the in utero and pubertal
periods when the mammary gland is undergoing extensive modeling
and re-modeling, alter susceptibility to develop mammary tumors.
Similar observations have been made in humans: childhood exposure
to genistein in soy or to some other bioactive food components
reduces later breast cancer risk, although they may have no
effect if consumed during adulthood. Thus, food components
may be more effective in affecting cancer risk in some periods
of life than others. Many of these dietary exposures modify
fetal and postnatal hormonal environment, including changing
the concentrations of estrogens and leptin. The hormonal alterations
then may induce persistent epigenetic changes by affecting
gene promoter regions or by inducing histone modifications
that affect chromatin transcription. The targets of epigenetic
changes are likely to be the terminal end buds (TEBs), the
structures where carcinogen-induced mammary tumors in rats
and mice are initiated. More specifically, the site of these
changes in TEBs may be the stem cells and their niche; this
might explain how an exposure early in life affects the risk
of breast cancer decades later. Similar structures in women,
called terminal ductal lobular units, are the sites where
most human breast cancers rise. According to this hypothetical
model, cancer is initiated only when the epigenetically altered
cells are exposed to carcinogens/radiation, etc. during adult
life. In a “normal” stem cell or its niche, cancer
initiating exposures do not necessarily cause cancer, because
the cells can either repair the damage or undergo apoptosis.
Thus, the most likely molecular targets of early life dietary
exposures are genes that regulate DNA adduct formation, repair
DNA damage or induce apoptosis, such as genes affecting cellular
metabolism, tumor suppressor genes or genes promoting cell
survival. It is possible that some of these epigenetic changes
also explain why the number of TEBs generally, but not always,
correlates with breast cancer risk. This hypothesis may imply
that adult intake of some bioactive dietary components reduces
cancer risk increased by early life dietary exposures or inhibits
tumor growth by reversing epigenetic changes in various molecular
targets.
[Back to top]
Inducible Nitric Oxide Synthase-Vascular Endothelial
Growth Factor Axis: A Potential Target to Inhibit Tumor Angiogenesis
by Dietary Agents
Rana P. Singh and Rajesh Agarwal
Human solid tumors remain latent in the absence of angiogenesis
since it is a critical process for their further growth and
progression. Experimental evidence suggests that targeting
tumor angiogenesis may be a novel strategy to check tumor
growth and metastases. Recent studies suggest that several
bioactive food components can suppress tumor growth by inhibiting
angiogenesis. This suppression occurs because of a direct
effect on the tumor, as well as a direct effect on vascular
endothelial cells. These food components can target epigenetic
processes and thereby suppress the pro-angiogenic tumor microenvironment.
One likely epigenetic target is inducible nitric oxide synthase
(iNOS). iNOS is known to regulate vascular endothelial growth
factor (VEGF) expression, and thereby tumor angiogenesis.
The ability of food components to influence the inducible
form of cyclooxygenase, COX-2 may also contribute to their
impact on tumor growth and angiogenesis. This review focuses
on recent developments related to the angiogenic role of the
iNOS-VEGF axis and how dietary components may target this
axis. Overall, studies suggest that the anti-angiogenic potential
of physiologically concentrations of relevant food components
could be used as a practical approach for cancer prevention
and intervention.
[Back to top]
Energy Balance and Carcinogenesis: Underlying Pathways
and Targets for Intervention
Stephen D. Hursting, Laura M. Lashinger, Lisa H. Colbert,
Connie J. Rogers, Karrie W. Wheatley, Nomeli P. Nunez, Somdat
Mahabir, J. Carl Barrett, Michele R. Forman and Susan N. Perkins
The prevalence of obesity, an established epidemiologic risk
factor for many cancers, has risen steadily for the past several
decades in the U.S. Particularly alarming are the increasing
rates of obesity among children, portending continuing increases
in the rates of obesity and obesity-related cancers for many
years to come. Unfortunately, the mechanisms underlying the
association between obesity and cancer are not well understood.
In particular, the effects and mechanistic targets of interventions
that modulate energy balance, such as reduced calorie diets
and physical activity, on the carcinogenesis process have
not been well characterized. The purpose of this review is
to provide a strong foundation for future mechanistic-based
research in this area by describing key animal and human studies
of energy balance modulations involving diet, exercise, or
pharmaceutical agents and by focusing on the interrelated
pathways affected by alterations in energy balance. Particular
attention in this review is placed on the components of the
insulin/IGF-1/Akt pathway, which has emerged as a predominant
target for disrupting the obesity-cancer link. Also discussed
is the promise of global approaches, including genomics, proteomics,
and metabolomics, for the elucidation of energy balance-responsive
pathways. The ultimate goal of this work is to provide the
missing mechanistic information necessary to identify targets
for the prevention and control of cancers related to or caused
by excess body weight.
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Kit: Molecule of Interest for the Diagnosis and Treatment
of Mastocytosis and other Neoplastic Disorders
Mrinal M. Patnaik, Ayalew Tefferi and Animesh Pardanani
Kit a type III receptor tyrosine kinase, along with its ligand
the stem cell factor, play a critical role in normal cell
growth, differentiation, development and survival. Ligand
independent activation of kit (dysregulated kit function)
has been found to be an important component of oncogenesis
in a large number of neoplastic disorders such as systemic
mastocytosis, gastro intestinal stromal tumors, germ cell
tumors, acute myelogenous leukemia with the disruption of
the core binding factor, amongst others. The identification
of small molecule inhibitors with activity against Kit, has
offered a wider and more effective range of therapeutic options
in the treatment of these neoplastic processes. Novel tyrosine
kinase inhibitors such as imatinib, nilotinib and dasatinib,
have been found to be effective in the management of various
subtypes of systemic mastocytosis and gastrointestinal stromal
tumors. Non-tyrosine kinase inhibitors like rapamycin, 17-AAG
and IMD- 0354 have been added to the therapeutic armamentarium,
with the hope that combination therapy might have a synergistic
effect, or prevent/delay the development of drug resistance.
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Cyclopentenyl Cytosine (CPEC): An Overview of its
in vitro and in vivo Activity
K.J.M. Schimmel, H. Gelderblom and H.J. Guchelaar
The experimental cytotoxic drug cyclopentenyl cytosine (CPEC)
is an analogue of cytidine. Besides its antiviral effect,
its potential use in the treatment of cancer has become an
important area of research. CPEC is activated by intracellular
phosphorylation ultimately forming its metabolite CPEC-TP.
CPEC-TP is a non competitive inhibitor of cytidine-5’-triphosphate
synthetase (CTP-synthetase), an important enzyme in the formation
of CTP. Studies have shown that cancer cells have a high CTP
synthetase activity, thus making them interesting targets
for chemotherapy. CPEC has been preclinically studied in different
malignancy models. In vitro results on leukemia show
activity in the nanomolar range on several cell lines. However
in vivo results are conflicting and the findings
vary from increase in life span over 100% to only limited
effectiveness. Interesting results have been obtained in colorectal
and neuroblastoma cells. In several neuroblastoma cell lines
incubation with CPEC in combination with cytarabine or gemcitabine
has resulted in increased cell death compared to incubation
with with only one of the agents.
CPEC has been studied in a phase I trial in patients with
solid tumors. In five of 26 patients unexplained cardiotoxicity
(extreme hypotension) occurred. The cardiotoxic effects could
not be reproduced in animal models. However, precautions should
be taken when using this drug in future clinical trials. Low
dosage of CPEC seems necessary and intensive cardiac monitoring
is advisable.
In this manuscript, it is demonstrated that CPEC has an anti-cancer
effect in several tumor models: CPEC might be a potentially
useful drug in anticancer treatment.
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