Contents
Hypoxia Inducible Factor as a Cancer Drug
Target Pp.391-405
Sarah
J. Welsh and Garth Powis
Nitric Oxide-Releasing Non Steroidal
Anti-Inflammatory Drugs: A New Generation of Anti-Tumoral Molecules Pp.407-426
Christian
Lavagna, Piero Del Soldato, Jean-Luc Burgaud
and Patrick Rampal
Emerging Role of Endoglin (CD105) as a Marker
of Angiogenesis with Clinical Potential in Human Malignancies Pp.427-432
E.
Fonsatti, L. Sigalotti, P. Arslan, M. Altomonte and M. Maio
Thomsen-Friedenreich Disaccharide Immunogenicity Pp.433-443
Fernando
J. Irazoqui and Gustavo A. Nores
Metabolic Biomarker and Kinase Drug Target
Discovery in Cancer Using Stable Isotope-Based Dynamic Metabolic Profiling
(SIDMAP) Pp.445-453
Laszlo G. Boros, Daniel J. Brackett and George G. Harrigan
Cyclooxygenase Inhibition and Mechanisms of
Colorectal Cancer Prevention
Pp.455-463
Timothy A. Chan
[Back to top] Hypoxia Inducible Factor as a Cancer Drug Target
Sarah J. Welsh and Garth Powis
Solid tumors with
areas of hypoxia are the most aggressive and difficult tumors to treat and are
a major reason for treatment failure. Previous attempts to treat hypoxic tumors
have been largely unsuccessful and new agents are needed. The cellular response
to hypoxia is controlled by the hypoxia inducible factor-1 (HIF-1)
transcription factor. HIF-1 consists of an oxygen regulated alpha subunit and a
constitutively expressed beta subunit, which bind and translocate to the
nucleus to activate transcription of a range of genes involved in increasing
glycolysis, inhibition of apoptosis and promotion of angiogenesis and
metastasis. The activity of the HIF-1 complex is primarily controlled by levels
of the alpha subunit and a series of mechanisms exist to control activation of
the HIF-1 pathway. HIF-1α is over-expressed in a large number of human
tumors and its over-expression correlates with poor prognosis and treatment
failure. HIF-1 is therefore an important target for cancer chemotherapy. This
review summarizes the literature surrounding the control of HIF-1, its role in
cancer and potential drugs to target the pathway for cancer therapy.
[Back to top] Nitric Oxide-Releasing Non Steroidal
Anti-Inflammatory Drugs: A New Generation of Anti-Tumoral Molecules
Christian
Lavagna, Piero Del Soldato, Jean-Luc Burgaud
and Patrick Rampal
Colorectal cancer
is the second most common cause of cancer-related mortality in the west. The
high incidence and mortality make effective prevention an important
public-health and economic issue. The regular intake of aspirin and other
non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with
decreased incidence of certain types of cancer particularly those with an
inflammatory component, and then are among the few agents known to be
chemopreventive. Nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs)
are new chemical entities obtained by adding a nitric oxide-releasing moiety to
classical molecules. This new class of molecules has been demonstrated to be
much more safe than NSAIDs due to their ability to reduce gastric toxicity.
They could therefore represent an alternative to classical NSAIDs treatment. In
this review, we sumarise the recent findings in the mechanisms and pathways
involved in the antitumoral effects of both NSAIDs and NO-NSAIDs as well as the
clinical trials performed with these compounds.
[Back to top] Emerging Role of Endoglin (CD105) as a Marker
of Angiogenesis with Clinical Potential in Human Malignancies
Angiogenesis is
crucial for tumor development and progression, and antiangiogenetic therapy
represents a promising approach for cancer treatment. Thus, the in-depth
understanding of the molecular mechanism(s) regulating angiogenesis, together
with the characterization of molecules expressed by endothelial cells and
involved in distinct steps of the angiogenetic process, will greatly improve
the design of new and more effective therapeutic strategies in human
malignancies. Endoglin (CD105), a cell membrane glycoprotein predominantly
expressed on cellular lineages within the vascular system, and over-expressed
on proliferating endothelial cells, is involved in blood vessels development
and represents a powerful marker of neovascularization.
CD105 binds
several factors of the Transforming Growth Factor (TGF)-b superfamily, a pleiotropic cytokine that
regulates different cellular functions including proliferation, differentiation
and migration. In human malignancies of different histotype, CD105 is highly
expressed on endothelial cells of both peri- and intratumoral blood vessels,
while it is weakly expressed or absent on neoplastic cells. This unique tissue
distribution strongly suggests for a prognostic, diagnostic and therapeutic
potential of CD105 in neoplastic diseases. In this review we will summarize the
structural and functional features of CD105, as well as its tissue distribution
in normal and neoplastic tissues. Furthermore, the practical implications of
CD105 in human malignancies will also be discussed.
[Back to top] Thomsen-Friedenreich Disaccharide Immunogenicity
Fernando J. Irazoqui
and Gustavo A. Nores
Mucin-type
O-glycans are upregulated and aberrantly glycosylated in many carcinomas. O-glycan
Core 1 (Galb1-3GalNAca-O-),
also called Thomsen-Friedenreich disaccharide, is a cryptic structure
overexpressed in cancer cells through modification of its glycosyltransferase
profile. This molecule is a useful model for study of carbohydrate immunogenicity
as well as a candidate for active specific immunotherapy of cancer patients.
Several strategies are discussed for enhancing immune response to a particular
region of carbohydrate: carbohydrate-protein conjugation, linkers, synthetic
clustered sugars, chemical modifications, peptide/protein mimetics, and
molecular rotation.
[Back to top] Metabolic Biomarker and Kinase Drug Target
Discovery in Cancer Using Stable Isotope-Based Dynamic Metabolic Profiling
(SIDMAP)
Laszlo
G. Boros, Daniel J. Brackett and George
G. Harrigan
Tumor cells
respond to growth signals by the activation of protein kinases, altered gene
expression and significant modifications in substrate flow and re-distribution
among biosynthetic pathways. This results in a proliferating phenotype with
altered cellular function. These transformed cells exhibit unique anabolic
characteristics, which includes increased and preferential utilization of
glucose through the non-oxidative steps of the pentose cycle for nucleic acid
synthesis but limited de novo fatty acid synthesis and TCA cycle glucose
oxidation. This primarily non-oxidative anabolic profile reflects an
undifferentiated highly proliferative aneuploid cell phenotype and serves as a
reliable metabolic biomarker to determine cell proliferation rate and the level
of cell transformation/differentiation in response to drug treatment. Novel
drugs effective in particular cancers exert their anti-proliferative effects by
inducing significant reversions of a few specific non-oxidative anabolic
pathways. Here we present evidence that cell transformation of various
mechanisms is sustained by a unique disproportional substrate distribution
between the two branches of the pentose cycle for nucleic acid synthesis, glycolysis
and the TCA cycle for fatty acid synthesis and glucose oxidation. This can be
demonstrated by the broad labeling and unique specificity of [1,2-13C2]glucose
to trace a large number of metabolites in the metabolome. Stable isotope-based
dynamic metabolic profiles (SIDMAP) serve the drug discovery process by
providing a powerful new tool that integrates the metabolome into a functional
genomics approach to developing new drugs. It can be used in screening kinases
and their metabolic targets, which can therefore be more efficiently
characterized, speeding up and improving drug testing, approval and labeling
processes by saving trial and error type study costs in drug testing.
[Back to top] Cyclooxygenase Inhibition and Mechanisms of
Colorectal Cancer Prevention
Timothy
A. Chan
Colorectal cancer
is a leading cause of cancer death throughout the world. The high prevalence
and mortality associated with colon cancer make effective prevention and
treatment an important public health and economic concern. Among the few agents
known to inhibit colorectal tumorigenesis are the nonsteroidal
anti-inflammatory drugs or NSAIDs, as well as newer agents such as celecoxib
and rofecoxib. Both epidemiologic studies and investigations with animals show
that these compounds possess marked anti-colorectal cancer properties. NSAIDS
are widely known to be inhibitors of the cyclooxygenase (COX) enzymes, and it
is thought that the chemopreventive effects of NSAIDs are at least in part due
to this ability to inhibit COX. More recent studies, however, have suggested
that NSAIDs may also exert anti-cancer effects through mechanisms independent
of COX inhibition. COX-dependent and COX-independent mechanisms are not
mutually exclusive and it is likely that both are involved in the biological
activity of NSAIDs.