Current
Pharmaceutical Biotechnology
ISSN: 1389-2010
Current Pharmaceutical Biotechnology
Volume 7, Number 6, December 2006
Contents
Novel Agents for Multiple Myeloma Treatment
Guest Editors: D. Ribatti and A. Vacca
Editorial Pp. 395
Arsenic Trioxide in Hematological Malignancies: The
New Discovery of an Ancient Drug Pp. 397-405
A. Bonati, V. Rizzoli and P. Lunghi
[Abstract]
Targeting Signaling Pathways in Multiple Myeloma
Pp. 407-413
F. Cavallo, A. Palumbo, G. Tricot and M. Boccadoro
[Abstract]
Immunomodulatory Drugs as a Therapy for Multiple Myeloma
Pp. 415-421
H. De Raeve and K. Vanderkerken
[Abstract]
Targeting Pathways Mediating Bone Disease
Pp. 423-429
N. Giuliani, F. Morandi, S. Tagliaferri and V. Rizzoli
[Abstract]
Thalidomide in Multiple Myeloma Pp. 431-440
T.M. Moehler, J. Hillengass, A. Glasmacher and H. Goldschmidt
[Abstract]
Bortezomib as an Antitumor Agent Pp. 441-448
A.M. Roccaro, T. Hideshima, P.G. Richardson, D. Russo,
D. Ribatti, A. Vacca, F. Dammacco and K.C. Anderson
[Abstract]
Farnesyltransferase Inhibitors and Rapamycin in the
Treatment of Multiple Myeloma Pp. 449-453
M. Zangari, F. Cavallo and G. Tricot
[Abstract]
Essential Fatty Acids
Guest Editor: Undurti N. Das
Editorial Pp. 455
Tumoricidal and Anti-Angiogenic Actions of Gamma-Linolenic
Acid and Its Derivatives Pp. 457-466
U.N. Das
[Abstract]
Essential Fatty Acids - A Review Pp. 467-482
U.N. Das
[Abstract]
Pharmacological Inhibitors of Fatty Acid Synthase
(FASN)-Catalyzed Endogenous Fatty Acid Biogenesis: A New Family
of Anti-Cancer Agents? Pp. 483-494
R. Lupu and J.A. Menendez
[Abstract]
Mediterranean Dietary Traditions for the Molecular
Treatment of Human Cancer: Anti-Oncogenic Actions of the Main
Olive Oil’s Monounsaturated Fatty Acid Oleic Acid (18:1n-9)
Pp. 495-502
J.A. Menendez and R. Lupu
[Abstract]
A Meta-Analysis of Randomized, Placebo-Controlled
Clinical Trials of Efamol® Evening Primrose
Oil in Atopic Eczema. Where Do We Go from Here in Light of
More Recent Discoveries? Pp. 503-524
N.L. Morse and P.M. Clough
[Abstract]
High-Throughput Functional Genomic Methods to Analyze
the Effects of Dietary Lipids Pp. 525-529
L.G. Puskás, D. Ménesi, L.Z. Fehér
and K. Kitajka
[Abstract]
Gamma Linolenic Acid: An Antiinflammatory Omega-6
Fatty Acid Pp. 531-534
R. Kapoor and Y-S. Huang
[Abstract]
Abstracts
[Back to top]
Editorial
Multiple myeloma (MM) is a malignant proliferation
of plasma cells and plasmacytoid cells in the bone marrow
which is characterized nearly always by the presence in the
serum and/or urine of a monoclonal immunoglobulin (Ig) or
Ig fragment.
MM is the second most common hematologic malignancy, accounting
for 15,270 new cancer cases in the United States in the year
2004, and approximately 2% of cancer-related deaths. Several
in vitro and animal model studies have demonstrated the importance
of the bone marrow in promoting MM cell growth, survival,
drug resistance, and migration within the bone marrow microenvironment
and in extramedullary sites, and have already derived new
molecules that target both MM cells and the bone marrow microenvironment.
Thus, thalidomide and derivatives (Revlimid and the Actimid)
and Velcade have transformed considerably the history of MM
treatment. They have not to be considered as competitors but
rather complementary agents whose impact will probably stem
from their combination and their association with the intensive
treatment.
This issue of “Current Pharmaceutical Biotechnology”
is a collection of reviews focused on “Novel agents
for multiple myeloma treatment”. The goal has been to
provide up-to-date reviews of benefit to a broad audience.
We would like to express our appreciations to all colleagues
for their excellent contributions.
It is our hope that this issue serves as a platform to stimulate
new ideas leading to new discoveries and the expansion of
new frontiers in the field of multiple myeloma treatment.
Domenico Ribatti
Department of Human Anatomy and Histology
University of Bari Medical School
Bari, Italy
E-mail: ribatti@anatomia.uniba.it
Angelo Vacca
Department of Internal Medicine and
Clinical Oncology, University of Bari Medical School
Bari, Italy
E-mail: a.vacca@dimo.uniba.it
[Back to top]
Arsenic Trioxide in Hematological Malignancies: The
New Discovery of an Ancient Drug
A. Bonati, V. Rizzoli and P. Lunghi
Currently, Arsenic Trioxide (ATO) is considered the treatment
of choice for patients with relapsed acute promyelocytic leukemia
(APL). Recently, a durable remission with minimal toxicity
by single agent ATO or ATO + ATRA in newly diagnosed APL was
reported by different groups. These regimens have minimal
toxicity and can be administered on an outpatient basis after
remission induction, thus they could become a real, less toxic
and more economic option to ATRA + anthracyclines in particular
in low risk APL, or in patients that cannot undergo chemotherapy
because of age or comorbid conditions and in patients that
refuse chemotherapy. Significantly, these therapies are a
successful attempt to cure a tumoral disease without chemotherapy.
The results of clinical trials of ATO administration as single
agent in multiple myeloma (MM) and myelodisplastic syndromes
(MDS) were encouraging and showed clinical effects but they
were not close to APL success. On the contrary, results of
clinical trials to treat non-APL acute myeloid leukemia (AML)
were disappointing. We suggest that a combination therapy
with drugs targeting specific pro-survival molecules or capable
to enhance pro-apoptotic pathways may lead to an improvement
of ATO efficacy against hematological malignancies, in particular
AML. Our pre-clinical studies showed that ATO is capable to
induce cell death in acute leukemia cells but the apoptotic
function is limited since it can induce also a mechanism of
cell defense by activating pro-survival molecules such as
MEK-ERK, Bcl-xL, Bcl-2. By combining ATO with specific MEK
inhibitors, we demonstrated that the block of MEK-ERK phosphorylation,
the induction of Bad de-phosphorylation, and activation of
p53AIP1 apoptotic pathway interrupt the pro-survival mechanisms
of ATO and kill the leukemic cells by apoptotic synergism.
Our results provide an experimental basis for combined or
sequential treatment with MEK inhibitors and ATO in AML. The
renaissance of ATO as a drug in moderne medicine may be considered,
together with ATRA success, a victory of empirical analysis,
that had (and has) great impact on Chinese culture.
[Back to top]
Targeting Signaling Pathways in Multiple Myeloma
F. Cavallo, A. Palumbo, G. Tricot and M. Boccadoro
Multiple myeloma (MM) is an incurable malignancy of terminally
differentiated B-cells accounting for approximately 1 to 2%
of all human cancers. The development of MM is believed to
be a multistep transformation process that leads to progressive
accumulation of genetic alterations. The interaction between
MM and bone marrow (BM) microenviroment triggers multiple
proliferative and antiapoptotic signaling pathways. Here we
discuss the current understanding of signaling pathways, and
their potential implication in targeted therapies in MM.
[Back to top]
Immunomodulatory Drugs as a Therapy for Multiple Myeloma
H. De Raeve and K. Vanderkerken
Thalidomide and the analogues lenalidomide (CC-5013, Revlimid®)
and CC-4047 (Actimid®) belong to the family
of immunomodulatory drugs (IMiDs). These agents have anti-angiogenic
properties, modulate TNFα
and IL-12 secretion, co-stimulate T cells, increase NK cell
toxicity and have direct anti-tumour effects. These characteristics
have made of them promising drugs for treatment of relapsed,
refractory and newly diagnosed MM. It seems that lenalidomide
and CC-4047 are more powerful in inhibiting TNFα
and have, except for myelosuppression, less side effects than
Thal. Combination of IMiDs with dexamethasone, bortezomib
and with chemotherapeutic agents are tested in numerous trials,
which will help in determining the optimal combination and
administration schedule of different molecules to take advantage
of non-overlapping toxicities and synergisms between those
agents.
[Back to top]
Targeting Pathways Mediating Bone Disease
N. Giuliani, F. Morandi, S. Tagliaferri and V. Rizzoli
Multiple myeloma (MM) is a plasma cell malignancy characterized
by the high capacity to induce osteolytic bone lesions. Bone
destruction in MM mainly depends on the increase of osteoclast
formation and activity that occurs in close contact with myeloma
cells infiltration. The histomorphometric studies, performed
in MM patients, have demonstrated that MM patients with high
plasma cell infiltrate are also characterized by a lower number
of osteoblasts and a decreased bone formation that contributes,
to the development of bone lesion. In the last years the progress
in acknowledge of the pathophysiology of MM-induced osteolysis
leaded to identify new therapeutics targets in MM bone disease
and developed new drugs in the treatment of patients with
skeletal involvement
[Back to top]
Thalidomide in Multiple Myeloma
T.M. Moehler, J. Hillengass, A. Glasmacher and H. Goldschmidt
Thalidomide (Thal) has antiangiogenic and immunomodulatory
activity. Clinical research provided clear evidence that Thal
is one of the most active drugs for the treatment of multiple
myeloma leading to decrease of monoclonal protein of at least
50 % in 30 % of patients with relapsed or refractory multiple
myeloma. Randomized trials based on a large body of evidence
from phase II trials determined that Thal significantly increases
total response rate in combination regimens (dexamethasone
[Dex] and or chemotherapy) for relapsed as well as newly diagnosed
patients. Thal also decreases time to response in combination
therapy approaches. Thal has therefore been recognized by
leading organizations as part of the treatment concept for
patients with relapsed or refractory disease. Strict guidelines
apply for the treatment and monitoring of Thal therapy to
prevent the teratogenic effects of Thal and to monitor and
prevent other potential adverse events as neuropathy and thrombosis.
Additional randomized studies will now define the status of
Thal for newly diagnosed patients and will be the basis for
the approval in Europe and other countries world wide.
[Back to top]
Bortezomib as an Antitumor Agent
A.M. Roccaro, T. Hideshima, P.G. Richardson, D. Russo,
D. Ribatti, A. Vacca, F. Dammacco and K.C. Anderson
The ubiquitin-proteasome pathway (UPP) is the major non-lysosomal
proteolytic system in the cytosol and nucleus of all eukaryotic
cells. Bortezomib (also known as PS-341 and VelcadeTM)
is a proteasome inhibitor, a novel class of cancer therapies.
Bortezomib blocks multi-ubiquitinated protein degradation
by inhibiting 26S proteasome activity, including regulating
cell cycle, anti-apoptosis, and inflammation, as well as immune
surveillance. In multiple myeloma (MM) cells, bortezomib directly
induces cell stress response followed by activation of c-Jun
NH2 terminal kinase (JNK)/stress-activated protein
kinase (SAPK), and triggers caspase-dependent apoptosis of
tumor cells. Recent clinical studies demonstrated that bortezomib
had remarkable anti-tumor activity in refractory and relapsed
MM, providing the basis to approval by FDA. Its anti-tumor
activities earlier in the course, in combination therapies,
and in other malignancies is ongoing.
[Back to top]
Farnesyltransferase Inhibitors and Rapamycin in the
Treatment of Multiple Myeloma
M. Zangari, F. Cavallo and G. Tricot
Multiple myeloma (MM) is a B-cell malignancy characterized
by an accumulation of long-lived neoplastic plasma cells (PC)
within the bone marrow (BM). Novel treatments are not only
targeting myeloma cells but also directly interfere with myeloma-stromal
cell interactions, interrupting signal transduction pathways.
Farnesyltransferase inhibitors (FTIs) and rapamycin represent
novel classes of signal transduction inhibitors targeting
principally Ras/MAPK and PI3K/Akt pathway. Pre-clinical and
early clinical reports are presented in this study.
[Back to top]
Editorial
This special issue of Current Pharmaceutical Biotechnology
deals with an exciting topic: “Essential Fatty Acids”
and their implications for human health.
Essential fatty acids (EFAs) are the main constituent of the
phospholipid component of all cell membranes in the human
body. EFAs, as it name implies, are essential for human survival
but cannot be synthesized by the human body and hence, have
to be obtained in our diet. The two EFAs are linoleic acid
(LA) and α-linolenic
acid (ALA). Both LA and ALA form precursors to several of
their long chain metabolites. Some of the important molecules
that are formed from EFAs and their long-chain metabolites
include: various eicosanoids, lipoxins, resolvins, and protectins.
These molecules have several important actions on vascular
tissue, platelets, leukocytes, macrophages, bronchial smooth
muscle, myocardium, kidney, brain, and other cells and tissues
in the body. Depending on the local tissue concentration and
the type of metabolite formed from EFAs, they can have useful
and harmful actions. For instance, excess formation of leukotrienes
may produce inflammation, bronchospasm and thus may cause
bronchial asthma. On the other hand, formation of appropriate
amounts of lipoxins and resolvins may help in the resolution
of inflammation and healing of wounds. In addition, EFAs may
interact with nitric oxide and form nitrolipids that have
potent biological actions. EFAs and their metabolites seem
to have an important role in brain growth and development
and memory formation and consolidation, participate in a variety
of physiological and pathological processes.
In this issue, the metabolism, actions and uses of EFAs and
their metabolites has been outlined by various authors. I
hope that the topics discussed will be useful to many of the
readers.
Undurti N. Das, MD, FAMS
UND Life Sciences
13800 Fairhill Road, #321
Shaker Heights
OH 44120
USA
[Back to top]
Tumoricidal and Anti-Angiogenic Actions of Gamma-Linolenic
Acid and Its Derivatives
U.N. Das
Studies showed that gamma-linolenic acid (GLA) and its derivatives
have the potential to be anti-cancer molecules. In vitro,
in vivo and limited clinical studies showed that GLA
has selective tumoricidal action with little or no side effects.
The mechanism of its action appears to be by inducing apoptosis
of tumor cells by augmenting free radical generation only
in the tumor cells but not normal cells. Intra-arterial injection
of a lithium salt derivative of GLA demonstrated its ability
to selectively occlude tumor-feeding vessels. Since GLA is
an endogenous naturally occurring molecule and has no significant
side effects, it calls for more studies to exploit its potential
as a novel anti-cancer drug.
[Back to top]
Essential Fatty Acids - A Review
U.N. Das
Essential fatty acids (EFAs): cis-linoleic acid (LA) and α-linolenic
acid (ALA) are essential for humans and their deficiency is
rare in humans due to their easy availability in diet. EFAs
are metabolized to their respective long-chain metabolites:
dihomo-gamma-linolenic acid (DGLA), and arachidonic acid (AA)
from LA; and eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA) from ALA. Some of these long-chain metabolites
form precursors to respective prostaglandins (PGs), thromboxanes
(TXs), and leukotrienes (LTs), lipoxins (LXs) and resolvins.
EFAs and their metabolites may function as endogenous angiotensin
converting enzyme and HMG-CoA reductase inhibitors, nitric
oxide enhancers, anti-hypertensives, and anti-atherosclerotic
molecules. EFAs react with nitric oxide (NO) to yield respective
nitroalkene derivatives that have cell-signaling actions via
ligation and activation of peroxisome proliferator-activated
receptors (PPARs). In several diseases such as obesity, hypertension,
diabetes mellitus, coronary heart disease, alcoholism, schizophrenia,
Alzheimer’s disease, atherosclerosis, and cancer the
metabolism of EFAs is altered. Thus, EFAs and their derivatives
have significant clinical implications.
[Back to top]
Pharmacological Inhibitors of Fatty Acid Synthase
(FASN)-Catalyzed Endogenous Fatty Acid Biogenesis: A New Family
of Anti-Cancer Agents?
R. Lupu and J.A. Menendez
The expression and activity of Fatty Acid Synthase (FASN;
the sole enzyme capable of the reductive de novo
synthesis of long-chain fatty acids from acetyl-CoA, malonyl-CoA,
and nicotinamide adenine dinucleotide phosphate –NADPH-)
is extremely low in nearly all nonmalignant adult tissues,
whereas it is significantly up-regulated or activated in many
cancer types, thus creating the potential for a large therapeutic
index. Since the pioneering observation that inhibition of
FASN activity by the mycotoxin cerulenin preferentially kills
cancer cells and retards the growth of tumors in xenografts
models, numerous in vitro and in vivo studies
have confirmed the potential of FASN as a target for antineoplastic
intervention. Other FASN inhibitors such as the cerulenin
derivative C75, the β-lactone
orlistat, the green tea polyphenol epigallocatechin-3-gallate
(EGCG) and other naturally occurring flavonoids (i.e.,
luteolin, quercetin, and kaempferol), as well as the antibiotic
triclosan, have been identified and have been shown to limit
cancer cell growth by inducing apoptotic cell death. Though
the exact mode of action of these FASN inhibitors is under
discussion, it has been revealed that depletion of end-product
fatty acids, toxic intracellular accumulation of supra-physiological
concentrations of the FASN substrate malonyl-CoA and/or limited
membrane synthesis and/or functioning by altered production
of phospholipids partitioning into detergent-resistant membrane
microdomains (lipid raft-aggregates), can explain, at least
in part, the cytostatic, cytotoxic as well as the apoptotic
effects occurring upon pharmacological inhibition of FASN
activity in cancer cells. Moreover, several cancer-associated
molecular features including nonfunctioning p53, overexpression
of the Her-2/neu (erbB-2) oncogene, and
hyperactivation of the PI-3’K down-stream effector protein
kinase B (AKT), appear to determine an exacerbated sensitivity
to FASN inhibition-induced cancer cell death. Although few
of these inhibitors are expected to be “exclusively”
selective for FASN, the potential of FASN as a target for
antineoplastic intervention has eventually been confirmed
by RNA interference (RNAi)-knockdown of FASN. Certainly, future
studies should definitely elucidate the ultimate biochemical
link between FASN inhibition and cancer cell death. Although
the combination of FASN structural complexity and until recently
the lack of X-ray crystallography data of mammalian FASN created
a significant challenge in the exploitation of FASN as a valuable
target for drug development, it is hoped that the improvement
in the selectivity and potency of forthcoming novel FASN-targeted
small molecule inhibitors by taking advantage, for instance,
of the recent 4.5 Å resolution X-ray crystallographic
map of mammalian FASN, will direct the foundation of a new
family of chemotherapeutic agents in cancer history.
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Mediterranean Dietary Traditions for the Molecular
Treatment of Human Cancer: Anti-Oncogenic Actions of the Main
Olive Oil’s Monounsaturated Fatty Acid Oleic Acid (18:1n-9)
J.A. Menendez and R. Lupu
The final proof about the specific mechanisms by which the
different components of olive oil, the principal source of
fat in a typical “Mediterranean diet”, exert their
potential protective effects on the promotion and progression
of several human cancers requires further investigations.
A recent discovery that dietary fatty acids can interact with
the human genome by regulating the amount and/or activity
of transcription factors has opened a whole new line of research
aimed to molecularly corroborate the anti-cancer benefits
of the olive oil-based Mediterranean diet and the underlying
mechanisms. Our most recent findings reveal that oleic acid
(OA; 18:1n-9), the main olive oil’s monounsaturated
fatty acid, can suppress the overexpression of HER2 (erbB-2),
a well-characterized oncogene playing a key role in the etiology,
invasive progression and metastasis in several human cancers.
First, exogenous supplementation with physiological concentrations
of OA significantly down-regulates HER2-coded p185Her-2/nue
oncoprotein in human cancer cells naturally harboring amplification
of the HER gene. Second, OA exposure specifically represses
the transcriptional activity of the human HER2 gene promoter
in tumor-derived cell lines naturally exhibiting HER2 gene
amplification and p185Her-2/nue protein
overexpression but not in cancer cells expressing physiological
levels of HER2. Third, OA treatment induces the up-regulation
of the Ets protein PEA3 (a transcriptional repressor
of the HER2 gene promoter) solely in cancer cells naturally
displaying HER2 gene amplification. Fourth, HER2 gene promoter
bearing a PEA3 site-mutated sequence cannot be negatively
regulated by OA, while treatment with OA fails to repress
the expression of a human full-length HER2 cDNA controlled
by a SV40 viral promoter. Fifth, OA-induced inhibition of
HER2 promoter activity does not occur if HER2 gene-amplified
cancer cells do no concomitantly exhibit high levels of Fatty
Acid Synthase (FASN; Oncogenic antigen-519) as specific depletion
of FASN, which itself similarly suppresses HER2 overexpression
by inducing PEA3-dependent repression of HER2 gene promoter,
strongly antagonizes the inhibitory effects of OA on HER2
gene promoter activity. Considering that OA treatment efficiently
blocks FASN activity and down-regulates FASN protein expression,
it is reasonable to suggest that an accumulation of supra-physiological
concentrations of the FASN substrate malonyl-CoA, due to its
reduced utilization by FASN in the presence of exogenous OA,
appears to act as an indicator of “cell fuel”
availability capable to suppress HER2 expression via
formation of inhibitory “PEA3 protein-PEA3 DNA binding
site” complexes on the endogenous HER2 promoter. Indeed,
malonyl-CoA on its own dramatically decreases HER2 promoter
activity, while OA or malonyl-CoA similarly up-regulates PEA3
gene promoter activity. This previously unrecognized ability
of OA to directly affect the expression of a cluster of interrelated
human cancer genes (i.e., HER2, FASN and PEA3) should
open a new line of research aimed to explore the anti-cancer
effects of OA. Certainly, an appropriate dietary intervention
reproducing this prominent anti-oncogenic feature of the “Mediterranean
diet” must be carried out in animal models and human
pilot studies in the future. Only then we will know whether
the old “Mediterranean dietary traditions” will
become a new molecular approach in the management of cancer
disease.
[Back to top]
A Meta-Analysis of Randomized, Placebo-Controlled
Clinical Trials of Efamol®
Evening Primrose Oil in Atopic Eczema. Where Do We Go from
Here in Light of More Recent Discoveries?
N.L. Morse and P.M. Clough
The global incidence of atopic eczema is escalating. While
new treatment options are becoming available, previous treatments
with certain confirmed benefits are still worth investigating
as safe and effective therapies. One such treatment, Efamol®
evening primrose oil (EPO), was proven efficacious in a 1989
meta-analysis of randomized, double-blind, placebo-controlled
clinical trials. A decade of further testing and subsequent
independent reanalysis of 26 clinical studies including 1207
patients presented here, establishes that Efamol®
EPO has a simultaneous, beneficial effect on itch/pruritis,
crusting, oedema and redness (erythema) that becomes apparent
between 4 and 8 weeks after treatment is initiated. However,
the magnitude of this effect is reduced in association with
increasing frequency of potent steroid use. This and other
confounding variables that are now being reported in the literature
may account for historically reported inconsistent patient
response. Recent research has uncovered unique complexities
in fatty acid metabolism and immune response in the atopic
condition beyond those previously reported and may well have
identified a subcategory of non-responders and has helped
established those that can consistently derive significant
benefit. Further research is needed to provide a better understanding
of the physiology behind this complex disorder and the beneficial
role that fatty acids can play in its development and management.
Conclusion: Efamol® EPO has a simultaneous,
beneficial effect on itch/pruritis, crusting, oedema and redness
(erythema) that becomes apparent between 4 and 8 weeks after
treatment is initiated. However, the magnitude of this effect
is reduced in association with increasing frequency of potent
steroid use.
[Back to top]
High-Throughput Functional Genomic Methods to Analyze
the Effects of Dietary Lipids
L.G. Puskás, D. Ménesi, L.Z. Fehér
and K. Kitajka
The applications of ’omics’ (genomics, transcriptomics,
proteomics and metabolomics) technologies in nutritional studies
have opened new possibilities to understand the effects and
the action of different diets both in healthy and diseased
states and help to define personalized diets and to develop
new drugs that revert or prevent the negative dietary effects.
Several single nucleotide polymorphisms have already been
investigated for potential gene-diet interactions in the response
to different lipid diets. It is also well-known that besides
the known cellular effects of lipid nutrition, dietary lipids
influence gene expression in a tissue, concentration and age-dependent
manner. Protein expression and post-translational changes
due to different diets have been reported as well. To understand
the molecular basis of the effects and roles of dietary lipids
high-throughput functional genomic methods such as DNA- or
protein microarrays, high-throughput NMR and mass spectrometry
are needed to assess the changes in a global way at the genome,
at the transcriptome, at the proteome and at the metabolome
level. The present review will focus on different high-throughput
technologies from the aspects of assessing the effects of
dietary fatty acids including cholesterol and polyunsaturated
fatty acids. Several genes were identified that exhibited
altered expression in response to fish-oil treatment of human
lung cancer cells, including protein kinase C, natriuretic
peptide receptor-A, PKNbeta, interleukin-1 receptor associated
kinase-1 (IRAK-1) and diacylglycerol kinase genes by using
high-throughput quantitative real-time PCR. Other results
will also be mentioned obtained from cholesterol and polyunsaturated
fatty acid fed animals by using DNA- and protein microarrays.
[Back to top]
Gamma Linolenic Acid: An Antiinflammatory Omega-6
Fatty Acid
R. Kapoor and Y-S. Huang
Inflammation plays an important role in health and
disease. Most of the chronic diseases of modern society, including
cancer, diabetes, heart disease, arthritis, Alzheimer’s
disease, etc. have inflammatory component. At the same time,
the link between diet and disease is also being recognized.
Amongst dietary constituents, fat has gained most recognition
in affecting health. Saturated and trans fatty acids have
been implicated in obesity, heart disease, diabetes and cancer
while polyunsaturated fatty acids (PUFAs) generally have a
positive effect on health. The PUFAs of omega-3 and omega-6
series play a significant role in health and disease by generating
potent modulatory molecules for inflammatory responses, including
eicosanoids (prostaglandins, and leukotrienes), and cytokines
(interleukins) and affecting the gene expression of various
bioactive molecules. Gamma linolenic acid (GLA, all cis 6,
9, 12-Octadecatrienoic acid, C18:3, n-6), is produced in the
body from linoleic acid (all cis 6,9-octadecadienoic acid),
an essential fatty acid of omega-6 series by the enzyme delta-6-desaturase.
Preformed GLA is present in trace amounts in green leafy vegetables
and in nuts. The most significant source of GLA for infants
is breast milk. GLA is further metabolized to dihomogamma
linlenic acid (DGLA) which undergoes oxidative metabolism
by cyclooxygenases and lipoxygenases to produce anti-inflammatory
eicosanoids (prostaglandins of series 1 and leukotrienes of
series 3). GLA and its metabolites also affect expression
of various genes where by regulating the levels of gene products
including matrix proteins. These gene products play a significant
role in immune functions and also in cell death (apoptosis).
The present review will emphasize the role of GLA in modulating
inflammatory response, and hence its potential applications
as an anti-inflammatory nutrient or adjuvant.
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