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DOV LICHTENBERG, Ph.D.
Emeritus Professor of Pharmacology
Previous Dean, Sackler Faculty of Medicine
Department of Physiology and Pharmacology
TEL AVIV UNIVERSITY
Ramat Aviv, Tel Aviv 69978, Israel
Office: 972-3-6407305
Fax: 972-3-640 9113
Residence: 972-3-6044283
E-mail:physidov@post.tau.ac.il
Curriculum Vita
Born in
Jerusalem (1942), graduated from high school (A) in Tel Aviv (1960)
Married, a father
of four children and a grandfather to 12 grandchildren
Military
service: 1963-1966 Staff officer (Israel Defense Forces)
Education: BSc (1963),
MSc (1967) and PhD (1972) Hebrew University
1972-1974
post-Doctoral Studies California Institute of Technology
Experience:
1968-1972 Hebrew University (Pharmacology) Assistant and Instructor.
1974-1981 Hebrew
University (Pharmacology) Lecturer
1979-1981 University of
Virginia (Biochemistry) Visiting Scientist
1981-2011 Tel Aviv
University, Professor of Pharmacology
2011- Present Tel Aviv
University, Emeritus Professor
Academic administration
1985-1990 Founder and Head, Unit of
interdepartmental core facility
1989-1993
Head of department, Department of Physiology and Pharmacology
1995-1998 Founder and Head, Faculty Graduate
School
1998-2002 vice Dean
2002-2006 Dean
Research Interests
The solubility of lipids in aqueous media is extremely low.
Biological fluids, however, contain
high lipid concentrations
due to solubilization by
surfactants (e.g. bile salts in the biliary system) or emulsification by other
surface active compound (e.g. phospholipids and apolipoproteins in the blood).
In general, our research in the
past 20 years involves studies of the physical-chemistry of lipid
solubilization, emulsification and metabolism in health and disease.The two
major issues of our current research are:
1. Oxidative
modification of lipids in membranes and in plasma lipoproteins, dependence of
the oxidation resistance of lipids on various factors, including physiological
and pathological conditions, including lipid dislipodemiaand antioxidants and
basic aspects of the mechanics involved in lipid oxidation, using both
lipoproteins and liposomalmodel systems.
2. Solubilizationof lipids,
phospholipids and membranes by detergents. These processes are of significance
with respect to solubilizationand reconstitution of biological membranceas well
as in the naturally-occurring solubilization of dietary lipids (including
cholesterol). Our studies address mechanistic, thermodynamic and structural
aspects of these processes
Additional projects include studies of :
1. Biliary factors which affect the
precipitation of cholesterol from cholesterol-phospholipid-bile salt mixed
systems (bile models) and their
relevance to the pathogenesis of cholesterol gallstones.
2. Metabolism of lipid emulsions used for
intravenous nutrition and their effect on bilecomposition (in collaboration
with M. Rubin).
3. The use of self-assembled amphiphiles (in
mixed micelles, emulsion particles and liposomes) for application of
lipid-soluble drugs.
Most of our experimental
work is based on the use of spectroscopic techniques (static and dynamic light
scattering, spectrophotometry and spectrofluorimetry and NMR spectroscopy)
electron microscopy, calorimetry, chemical and specoscopic monitoring of lipid
hydrolysis.
Publications (a
partial list of recent critical reviews)
Dov Lichtenberg, Hasna Ahyayauch, Alicia Alonso, and Felix M. Goni,
2013. Detergent solubilization of lipid bilayers: a balance of driving forces.
Trends in Biochemical Sciences, 2013, 38, 85-93.
Dov
Lichtenberg, Hasna Ahyayauch, and Felix M. Goni, 2013.The Mechanism of Detergent Solubilization of Lipid Bilayers. Biophysical Journal 105 289–299.
Pinchuk, I.,
Lichtenberg, D., 2013. Analysis of the kinetics of lipid
peroxidation in terms of characteristic time-points. Chem. Phys. Lipids, In
Press.
Dov
Lichtenberg, Ilya Pinchuk, 2013. Atherogenesis, the oxidative LDL modification
hypothesis revisited, Advances Bioscience & Biotechnology, 4, 48-61.
Finkler M, Lichtenberg
D, Pinchuk I, 2013 The relationship between oxidative stress and exercise. J Basic
Clin Physiol. Pharmacol 17:1-11
Pinchuk, I., Shoval, H., Dotan, Y.,
and Lichtenberg, D., 2012. Evaluation of antioxidants: Scope, limitations and
relevance of assays. Chemistry and Physics of lipids
Contributions
CV Hebrew
Academic Administration (Hebrew)
Contributions
to the field of oxidative stress and antioxidants
The
major goal of our research in the last two decades has been to gain
understanding of the mechanisms of lipid peroxidation, the damage attributed to
peroxidation and the role of oxidative stress and antioxidants in health and
disease. My activity in this field began in 1993. At that time, the major
activity in my research group addressed the self- assembly of mixtures of
different amphiphiles, in an attempt to gain understanding of the
solubilization and reconstitution of biomembranes. In the summer of 1993,
during a short sabbatical I spent in Graz, I met the Late Professor Herman
Esterbauer, who was one of the major contributors to our understanding of the
mechanisms of free radical-induced peroxidation of lipids. One of Professor
Esterbauer’s contributions to the field was the spectroscopic monitoring of LDL
peroxidation. The typical time dependence of this reaction is that peroxidation
is preceded by a ‘lag phase’, which can be used to evaluate the resistance of
the lipids to oxidation.
In our meeting,
we considered collaborating on the mutual dependencies of the physical
properties of self-assembled lipids and their peroxidation induced either by
transition metal ions or by free radical generators. What I learned from that
meeting was that there is need for new methods that will enable evaluation of
the susceptibility of lipids to peroxidation, hence the ‘oxidative stress’ and
the antioxidative capacity of the (growing number) of antioxidants. In our discussion
of the available methods of evaluating the 'lag phase', Professor Esterbauer
stressed the problematic need to fractionate lipoproteins (particularly
irreproducibilities caused by the long process of fractionation). Therefore, I
decided to try to develop a method that can be used to evaluate the OS on the
basis of ex-vivo measurements of peroxidation of lipids in unfractionated serum
or plasma.
Given
the likelihood of irreproducibilities of measurements conducted at one
pre-defined time point (Pinchuk et al. 2012), my research group developed
an optimized spectroscopic method capable of monitoring the kinetics of lipid
peroxidation in unfractionated serum, as described below (Schnitzer et al. 1998b; Schnitzer et
al. 1995a) . Armed with this method of
evaluation of the susceptibility of lipids to oxidation, we studied several
mechanistic and clinical aspects of OS and antioxidants in health and disease as
follows.
(i)
We used existing data and meta-analysis to define ‘oxidative
stress’ in terms of criteria that are relevant to lipid peroxidation (Dotan et al. 2004), and to investigate the association
between these criteria and oxidative stress-related diseases (Dotan, et al. 2012). Assuming that patients under high OS
are likely to benefit from antioxidant supplementation, it was reasonable to
expect that establishing a protocol to assay a universal criterion of OS can be
used to decide who is likely to benefit from supplementation of antioxidants (Dotan et al. 2009a; Dotan et al. 2009b; Lichtenberg, 2011). Unfortunately,
we learned that OS cannot be defined by a universal criterion, probably because
there are different ‘types’ (or classes) of OS, each of which can be estimated
on the basis of different methods (see below "Analysis of Clinical
Data").
(ii)
We used our optimized assay to assess the susceptibility
of lipids to oxidation in individuals under different pathophysiological conditions.
(iii)
We studied the effects of membrane composition on the
susceptibility of oxidizable lipids and on the effect of antioxidants on lipid peroxidation
in relatively simple model membranes (liposomes). This
document is a short description of the results of these studies.
Development of novel methods
In Graz,
I collaborated with Hermetter and Hofer in a successful attempt to develop a
kinetic assay of the oxidation of fluorescent probes designed to monitor
glycerol and sphingophospholipds in lipoproteins (Hofer et al, 1996).
My
first activity in Tel Aviv in this field aimed at developing a method capable
of monitoring lipid peroxidation in unfractionated serum. Two factors
interfered with continuous monitoring of peroxidation products during
peroxidation: First, copper binding to albumin inhibits peroxidation of lipids
in unfractionated serum and plasma. To overcome this difficulty, a very high
concentration of copper is required. Our way of overcoming this problem was to
use a high concentration of citrate, which forms redox-inactive copper
chelates, yet does not prevent peroxidation (Schnitzer
et.al, 1998 and 1995).
In
addition, albumin absorbs light with a maximum at a wavelength of 234nm, which
is also the wavelength at which the absorption of hydroperoxides is maximal.
Our solution to this problem is to monitor the production of hydroperoxides at
245nm (Schnitzer et al, 1997). At this wavelength, the
absorption of hydroperoxide is about 70 % of its value at 234nm, whereas
albumin absorbs only 15% of its maximal absorption. Thus, we give up about a
third of the maximal sensitivity of the test but gain very much on the
signal/noise ratio. Based on these solutions, we have developed an optimized
assay of the susceptibility of lipids in diluted serum in citrate-containing
medium (Schnitzer et al, 1998).
In
another study, we monitored the peroxidation of lipoproteins at 4 different
wavelengths and used the results to evaluate the time-dependencies of the
different reaction products (Pinchuk and Lichtenberg, 1996). In a subsequent review,
devoted to the mechanism of antioxidative effects, we have shown that the
effect of antioxidants on the kinetics of peroxidation can be used to determine
the mechanism responsible for the antioxidative effect (Pinchuk and Lichtenberg, 2002).
We also
developed an assay of the capacity of antioxidants under biologically-relevant
conditions (Pinchuk et al, 2011 and 2012, Pinchuk
and Lichtenberg, 2015). Specifically, most tests
used to evaluate antioxidants are conducted in solution, whereas the
peroxidation of PUFA in vivo occurs at interfaces. We conduct a series of
peroxidation experiments in serum without the assayed antioxidants and in the
presence of different concentrations of the assayed antioxidant. Based on each
such series of experiments, we rank antioxidants in terms of their concentration
needed to double the lag preceding peroxidation (Pinchuk et al, 2011).
In a recent review (Pinchuk et al ,2012) we have demonstrated the risk
of producing irreproducible results if OS is evaluated on the basis of a ‘one
time-point measurement’, namely the importance of kinetic studies. Accordingly,
we studied possible ways to characterize the kinetics. The results of this
analysis can be used to characterize the kinetics of peroxidation in terms of
rate constants and concentrations on the basis of experimentally attainable
factors, particularly well-defined time points (Pinchuk and Lichtenberg, 2014a).
Further development of our approach includes analysis of effects of
compartmentalization of “key players”, such as hydroperoxides and tocopherol,
in lipoprotein particles (Pinchuk and Lichtenberg, 2014b). These studies enable
quantitate analysis of issues that we (and others) previously analyzed only
qualitatively (Pinchuk et al, 1998; Pinchuk and Lichtenberg, 1999), including the
conditions under which oxygen availability is the limiting factor in LDL
oxidation (Raveh et al, 2002) and the dose-dependent effect of copper-chelating
agents on the kinetics of LDL peroxidation (Pinchuk et al, 2001). Using our
optimized assay, we also investigated the effect of hyaluronic acid-linked
phosphatidylethanolamine (HyPE) on the susceptibility of LDL lipids to
oxidation. Interestingly, ‘sugar decoration’ of the LDL surface slow down
peroxidation of the LDL (Schnitzer et al, 2000). In another investigation, we
tested the effects of a potent inhibitor of LDL-associated phospholipase A on
both the activity of the enzyme and the kinetics of LDL peroxidation. We found
that under conditions of complete inhibition of the enzyme, the peroxidation of
the LDL lipids is not affected indicating that of LDL-associated phospholipase
A does not protect LDL against lipid peroxidation in vitro (Schnitzer et al, 1998).
Lipid peroxidation in lipoprotein
fractions and in mixtures of lipoproteins
Much
data is available on LDL oxidation, mainly because oxidized LDL is believed to
be responsible for initiation of atherosclerosis. In fact, under most
conditions, HDL is more susceptible to oxidation than LDL and the
hydroperoxides formed in HDL upon peroxidation may migrate to LDL (Schnitzer et
al, 1995) and promote LDL peroxidation (Raveh et al, 2001 and 2000). This accords with the
unexpected result that the lag preceding rapid peroxidation of serum lipids,
i.e. the sensitivity of serum lipids to copper-induced peroxidation ex-vivo increases
with HDL concentration (Shimonov et al, 1999).
Comparison
of the kinetic profiles of copper-induced oxidation of HDL and LDL at different
copper concentrations revealed that under all the studied experimental
conditions HDL is more susceptible to oxidation than LDL (Raveh et al, 2001).
Native HDL particles contain, on an average, 0.3 molecules of tocopherol.
Hence, each particle contains either one tocopherol molecule or none. At
relatively low copper concentrations, the tocopherol-containing HDL particles
become oxidized prior to the Tocopherol-deficient HDL particles (Raveh et al, 2001).
At high copper, the latter mechanism becomes quenched and HDL oxidation occurs
via a non-inhibited, auto-accelerated mechanism. Under these conditions, the
lag is a decreasing function of the ratio between bound copper and HDL, in
agreement with the proposal that the higher susceptibility of HDL to copper-
induced oxidation under conditions of high copper concentrations is due to the
higher surface density of bound copper to HDL than to LDL (Raveh et al, 2000).
Systematic kinetic
studies on the oxidation in mixtures of HDL and LDL induced by different
concentrations of copper, 2_-azo bis (2-amidinopropane) hydrochloride (AAPH)
and Myeloperoxidase (MPO) revealed that the apparent contradiction regarding
the effects of HDL on LDL peroxidation is a result of the use of different
inducers of peroxidation and of their concentrations. Specifically, oxidation
of LDL induced either by AAPH or MPO is inhibited by HDL under all the studied
conditions, whereas copper-induced oxidation of LDL is inhibited by HDL at low
copper/lipoprotein ratio but accelerated by HDL at high copper/lipoprotein
ratios (Raveh et al, 2001).
The antioxidative
effects of HDL are only partially due to HDL-associated enzymes, as indicated
by the finding that reconstituted HDL, containing no such enzymes, inhibits
peroxidation induced by low copper concentration (Raveh et al, 2000). The
effects of copper concentration can be understood in terms of the ratio of
bound copper to lipoprotein. Specifically, at ‘sub-saturating’ concentrations
of copper, LDL oxidation is inhibited by HDL because the added HDL binds
copper, thus reducing the ratio of bound copper to lipid, consequently reducing
the rate of LDL peroxidation (Raveh et al, 2001). By contrast, at high ‘supra-saturating’
copper concentrations, when the addition of HDL does not reduce the
copper/lipid ratio below ‘saturation’, HDL does not protect LDL against
oxidation. Furthermore, under these conditions HDL accelerates LDL oxidation,
probably because part of the hydroperoxides formed in the ‘more oxidizable’ HDL
migrate to the ‘less oxidizable’ LDL and enhance the oxidation of the LDL
lipids by bound copper (Schnitzer et al, 1995). In addition, the peroxidation
induced by transition metal ions is complex due to acceleration by its products
(Pinchuk, et al. 1998).
In short, the observed
interrelationship between the oxidation of HDL and LDL depends on the oxidative
stress, which should be (and can be) considered in future investigations
regarding the oxidation of lipoprotein mixtures.
Oxidative
stress, as evaluated by different methods
The
term ‘oxidative stress’ (OS) appears in thousands of publications. Yet, it is
an ill-defined term due to the lack of a universal criterion (Dotan et al, 2004). In many publications, a
single method (one of several hundreds existing methods) was used as a
criterion of ‘oxidative stress’. In attempt to define a universal criterion, we
identified publications that contained in their title or abstract the term OS
and at least two methods used to evaluate it. We then looked for correlations
between the OS, as evaluated by different methods. The results were
unambiguous: reasonable correlations were observed between the OS determined on
the basis of different tests only when the tests were of chemically similar
factors (Dotan et al, 2004). Specifically, we observed reasonable correlations
between results of different factors that reflect lipid peroxidation, as
detected by various methods. We observed reasonable correlations between
factors that reflect OS determined on the basis of the levels of DNA
fragmentation products but no correlation between OS, as evaluated by a methods
based on lipid peroxidation and OS, as evaluated on the basis of the level of
DNA fragmentation.
In
practical terms, it implies that the term OS should be used carefully, namely
the method used to evaluate it should be specified (e.g. OS, as determined by
TBARS), to avoid apparent irreproducibilities, as described in our recent
critical review (Pinchuk et al, 2012). In more basic terms, we
concluded that OS cannot be defined by a universal criterion. Our hypothesis
was (and still is) that these results indicate that there are different types
of OS. This does not mean that the term OS is meaningless, being dependent on
method used to evaluate it but that there are different ‘types’ (or Classes) of
oxidative stress, each of which can be estimated on the basis of different
methods (Dotan et al, 2004).
Analysis
of clinical data and of experimentally observed susceptibility of serum lipids
to ex-vivo peroxidation under different conditions
In view
of the apparent existence of different ‘types of OS’, we analyzed the data
available on the OS, as evaluated on different in the four diseases that were
most often associated with oxidative stress and found that the only pathology
that is associated with oxidative stress according to all the criteria is HIV (Dotan
et.al. unpublished results). Unexpectedly, CVD patients are under oxidative
stress only according to measurements of lipid peroxidation (Dotan et al, 2012)
and the same is true for Alzheimer's disease (AD) and diabetes mellitus (DM) (Samocha-Bonet
et al, 2010).
We have
also used our optimized assay for evaluation of the ‘oxidative status’ under
different pathophysiological conditions. We found association between different
pathophysiological states and the lag preceding rapid peroxidation. A few
examples are given below:
(i)
Exhaustive short physical exercise had only a slight effect
on the resistance of serum lipids to oxidation, demonstrating the effectiveness
of the homeostatic mechanisms (Dayan et al, 2005 ; Finkler et al, 2013 and in
preparation).
(ii)
Active labor is associated with OS in the mother but the
OS in the fetus remains similar to that of the mother, independent of the mode
of delivery (Fogel et al, 2005),
(iii)
Different abdominal surgery protocols, including
laparoscopic protocols, do not influence the low OS attributed to anesthesia (Rubin
et al, unpublished results),
(iv)
Treatment of
hypercholesterolemia patients with statins increases the resistance of serum
lipids to oxidation (Rubinstein et al, unpublished results).
(v)
Following MI, the serum lipids are very susceptible to
peroxidation and the recovery to normal levels is slow (Fainaru et al, 2002). In hemodialysis patients with
history of MI the lipids are very susceptible to ex vivo peroxidation unless
they are treated with vitamin E (Boaz et al, 2003).
(vi)
The sensitivity of serum lipids of prostate cancer
patients to peroxidation increases upon progression of the disease but this
increased sensitivity lags behind the clinical symptoms, indicating that the
oxidative stress is more likely to be a result rather than the cause of the
cancer (Yossepowitch et al , 2007).
(vii)
The mean OS of obese patients, as evaluated on the basis
of the susceptibility of their serum lipids to ex-vivo peroxidation, is not different
from that observed for healthy people, probably due to the high content of Urate
in their blood (Samocha-Bonet et al, 2003).
(viii)
The OS of women after in-term premature rupture of
membranes do not differ from other women (Fainaru et al, 2007).
Altogether, we found no
evidence for causal relationship between the alteration of oxidative status and
specific pathology. We attribute the complexity of the observed dependence of OS
on pathophysiological factors to the multifactorial network of interrelated
factors responsible for maintaining a homeostatic level of a redox state. More research is required to
evaluate possible causal relationship between the alteration of oxidative status
and specific pathologies.
Lipid
peroxidation and antioxidants in model membranes
Given
the complexity of peroxidation and its dependence on ‘antioxidants’, we studied
these issues in the relatively simple liposomes, commonly used as model
membranes. These studies deepened our understanding of the complex effect of
Albumin (Samocha-Bonet et al, 2004), the (protective) effects of cholesterol (Schnitzer
et al, 2007a and 2007b) and the (pro-oxidative) effect of inclusion of
negatively charged phospholipids (PA and PS) in the lipid bilayers on
copper-induced peroxidation. Since AAPH-induced peroxidation is not affected by
the charge, we attribute the effect of charge to an increased binding of copper
ions to the negatively charged vesicles (Gal et al, 2003 and 2007).
The
effect of low molecular weight antioxidants on lipid peroxidation is complex.
Under weak or moderate oxidative stress, water-soluble antioxidants accelerate
copper-induced peroxidation of liposomal polyunsaturated fatty acid residues of
the phospholipids, whereas under strong oxidative stress the low molecular
weight antioxidant tocopherol (vitamin E) is a potent antioxidant (Bittner et
al, 2002). Interestingly, externally-added Toc promoted peroxidation whereas
co-sonicated Toc inhibited peroxidation (Gal et al, 2003).
Another finding of possible importance
is that peroxidation of PS-containing liposomes (but not of PA-containing
liposomes) is inhibited by nanomolar concentrations of tocopherol as well as by
other 12 out of 37 tested phenols (Gal et al, 2007). These 12 compounds, unlike
the other 25, can form semiquinonic structures. A complex of a compound of this
structure with a copper-PS complex at the liposomal interface is likely to
possess the observed ‘super antioxidative-activity’ but this possibility has
yet to be tested.
In reviewing the existing literature
about antioxidants, we found only sparse information on the combined effect of
antioxidants in their mixtures. In an attempt to clarify this issue, we have
investigated the mutual effects of the two most abundant naturally occurring
water soluble antioxidants urate and ascorbate (vitamin C) on each other's
oxidation and fund that in mixtures of these antioxidants their peroxidation is
mutually inhibited (Samocha-Bonet et al, 2005 ; Samocha-Bonet
et al., 2004). We also found that these two
antioxidants are potent inhibitors of the oxidation of vitamin E in liposomes
made of non-oxidizable lipids and of both vitamin E and oxidizable lipids in
lipids containing PLPC.
Another important finding of our
studies on the oxidation of liposomal lipids is that in mixtures containing
excess citrate, as in our optimized assay of the peroxidation of serum lipids,
albumin promotes lipid peroxidation (Samocha-Bonet et al, 2004). This means that in our
assay, the oxidizing agent is neither copper-citrate nor traces of unbound
copper but a redox active copper-albumin complex of a stoichiometry of 2:1
copper/albumin.
Indiscriminate
(‘preventive’) supplementation of Vitamin E
Two
independent meta-analyses concluded that vitamin E supplementation increases
mortality. This conclusion raised much justifiable criticism, based on the
limitations of meta-analysis. In an attempt to end this controversy, we have
adopted the Markov-model approach, which is free of most of the limitations
involved in using meta-analyses. Using the latter decision analysis approach,
we discovered that indiscriminate, high dose supplementation of (the best
seller) vitamin E results in a decrease of the number of quality-adjusted life
years (QALY) by 0.30 (95%CI .21 to 0.39) QALY, namely that indiscriminate
supplementation of vitamin E does more harm than good (Dotan et al, 2009b). Yet, we have reasons to
believe that vitamin E is a “double-edge sword” and that supplementation may be
beneficial to some individuals but should not be consumed indiscriminately. The
challenge is to define a criterion (or criteria) capable of predicting who is
likely to benefit from supplementation of vitamin E. Preliminary studies indicate
that some people (unlike others) are ‘vitamin E responders’. We therefore
propose initiating vitamin E supplementation and deciding on whether to
continue supplementation on the basis of the result of a relatively short term
supplementation (Dotan et al, 2009b; Lichtenberg, 2011).
The
role of ROS in the formation and dissociation of Amyloid fibrils
Fibrilization of amyloid polypeptides
is accompanied by formation of reactive free radicals (FR), which, in turn, are
assumed to further promote amyloid-related pathologies. Different polyphenols,
all of which are established antioxidants, cause dissociation of ‘mature’
amyloid fibrils. Using ESR, we found that polyphenol–induced dissociation of
fibrils is also accompanied by formation of free radicals. Kinetic studies show
that the formation of ROS lags behind dissociation of the fibrils, indicating
that if a casual relationship exists between these two processes, then
formation of free radicals may be considered a consequence and not a cause of
dissociation (Shoval et al, 2007 and 2008). In an attempt to gain understanding
of this poorly understood process, we have monitored simultaneously both the
dissociation of Aβ42 fibrils and the formation of free radicals as
observed upon addition of six different polyphenols to ‘mature fibrils’. These
kinetic studies show that the formation of FR lags behind dissociation of the
fibrils, indicating that if a casual relationship exists between these two
processes, then FR formation may be considered a consequence and not a cause of
dissociation. We also found that all the studied amyloid fibrils dissociation processes
were accompanied by production of free radicals.
Curcumin synergistically
promotes inhibition of cancer cell growth by celecoxib
Cyclooxygenase-2 (COX-2) plays a
central role in the development of colorectal cancer via its antiapoptotic
effects, increased invasiveness, and promotion of angiogenesis. Several in
vitro, in vivo, and clinical studies have previously indicated that the
specific COX-2 inhibitor, celecoxib may prevent colorectal cancer. However, the
long-term use of celecoxib is limited due to its cardiovascular toxicity.
Curcumin is one of the most a potent antioxidants. It is also an effective
anti-inflammatory and antitumor drug whose chemo-preventive efficacy has been
attributed, at least in part, to its ability to inhibit COX-2, inhibit the
activation of transcription factors-activator protein and/ or down-regulate
epidermal growth factor receptor. In short, both Curcumin and celecoxib inhibit
COX-2 by different mechanisms.
Dr Lev-Ari and Prof Arber therefore
expected Curcumin to promote celecoxib inhibition of cancer cells. In fact, we
found that Curcumin synergistically potentiates the growth-inhibitory and
pro-apoptotic effects of celecoxib in both colorectal cancer cells and
osteoarthritis synovial adherent cells, shifting the dose-response curve of
celecoxib to the left. Both these effects probably involves inhibition of the
COX-2 more than one pathway and may involve other non COX-2 pathways (Lev Ari
et al, 2005 and 2006). This synergistic effect is clinically important because
it can occur in the Serum of patients receiving standard, non-toxic
anti-inflammatory or antineoplastic dosages of celecoxib (Lev Ari et al, 2008).
References
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Fainaru, O., Fainaru, M., Adler, Y., Pinchuk, I., and Lichtenberg, D., 1999. Acute myocardial, infarction is
associated with increased susceptibility of serum lipids to copper-induced
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Bittner, O., Gal, S., Pinchuk, I., Danino, D., Shinar, H.,
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Boaz, M., Smetana, S., Matas, Z., Bor, A., Pinchuk, I.,
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in hemodialysis patients with and without history of myocardial infarction.
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Dayan, A.,
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I., and Lichtenberg, D., 2003. Peroxidation
of liposomal palmitoyllinoleoylphosphatidylcholine (PLPC), effects of surface
charge on the oxidizability and on the potency of antioxidants. Chemistry and
Physics of Lipids 126, 95-110.
Hofer, G.,
Lichtenberg, D., Kostner, G.M., and Hermetter, A., 1996. Oxidation of fluorescent glycero- and
sphingophospholipids in human plasma lipoproteins: Alkenylacyl subclasses are
preferred targets. Clinical Biochemistry 29, 445-450.
Lev-Ari, S.,
Lichtenberg, D., and Arber, N., 2008. Compositions for treatment of cancer and inflammation.
Recent Patents on Anti-Cancer Drug Discovery 3, 55-62.
Lev-Ari, S.,
Strier, L., Kazanov, D., Elkayam, O., Lichtenberg, D., Caspi, D., and Arber,
N., 2006. Curcumin
synergistically potentiates the growth-inhibitory and pro-apoptotic effects of
celecoxib in osteoarthritis synovial adherent cells. Rheumatology 45, 171-177.
Lev-Ari, S., Strier, L., Kazanov, D., Madar-Shapiro, L.,
Dvory-Sobol, H., Pinchuk, I., Marian, B., Lichtenberg, D., and Arber, N., 2005.
Celecoxib and curcumin synergistically inhibit the growth of colorectal cancer
cells. Clinical Cancer Research 11, 6738-6744.
Lichtenberg D and Pinchuk I,
2013. Atherogenesis, the oxidized LDL modification hypothesis- revisited Advances
in Bioscience and Biotechnology, in press.
Lichtenberg D, 2011. Who is
likely to gain from high dose supplementation of vitamin E? Harefuah, 150, 37-40
(In Hebrew, an English Abstract is available).
Pinchuk, I. and
Lichtenberg, D., 1996. Continuous
monitoring of intermediates and final products of oxidation of low-density
lipoprotein by means of UV-spectroscopy. Free Radical Research 24, 351-360.
Pinchuk, I. and
Lichtenberg, D., 1999. Copper-induced
LDL peroxidation: interrelated dependencies of the kinetics on the
concentrations of copper, hydroperoxides and tocopherol. Febs Letters 450,
186-190.
Pinchuk, I. and
Lichtenberg, D., 2002. The
mechanism of action of antioxidants against lipoprotein peroxidation,
evaluation based on kinetic experiments. Progress in Lipid Research 41,
279-314.
Pinchuk, I. and
Lichtenberg, D., 2014a. Analysis
of the kinetics of lipid peroxidation in terms of characteristic time-points. Chemistry
and Physics of Lipids, 178, 63-76.
Pinchuk, I. and
Lichtenberg, D., 2014b. The
effect of compartmentalization on the kinetics of transition metal ion-induced
LDL peroxidation. Abstract of ISOFRR annual meeting.
Pinchuk, I. and
Lichtenberg, D., 2015. Prolongation
of the Lag Time Preceding Peroxidation of Serum Lipids: A Measure of
Antioxidant Capacity. in Advanced Protocols in Oxidative Stress III, Armstrong,
D. (Ed.), Humana Press.
Pinchuk, I., Gal,
S., and Lichtenberg, D., 2001. The
dose-dependent effect of copper-chelating agents on the kinetics of
peroxidation of low-density lipoprotein (LDL). Free Radical Research 34,
349-362.
Pinchuk, I.,
Schnitzer, E., and Lichtenberg, D., 1998. Kinetic analysis of copper-induced
peroxidation of LDL. Biochimica et Biophysica Acta-Lipids and Lipid Metabolism
1389, 155-172.
Pinchuk, I.,
Shoval, H., Bor, A., Schnitzer, E., Dotan, Y., and Lichtenberg, D., 2011. Ranking antioxidants based on
their effect on human serum lipids peroxidation. Chemistry and Physics of
Lipids 164, 42-48.
Pinchuk, I., Shoval, H., Dotan, Y., and Lichtenberg, D.,
2012. Evaluation of antioxidants: Scope, limitations and relevance of assays.
Chemistry and Physics of Lipids 165, 638-647.
Raveh, O.,
Pinchuk, I., Fainaru, M., and Lichtenberg, D., 2001. Kinetics of lipid peroxidation in
mixtures of HDL and LDL, mutual effects. Free Radical Biology and Medicine 31,
1486-1497.
Raveh, O.,
Pinchuk, I., Fainaru, M., and Lichtenberg, D., 2002. Oxygen availability as a possible
limiting factor in LDL oxidation. Free Radical Research 36, 1109-1114.
Raveh, O.,
Pinchuk, I., Schnitzer, E., Fainaru, M., Schaffer, Z., and Lichtenberg, D.,
2000. Kinetic
analysis of copper-induced peroxidation of HDL, autoaccelerated and
tocopherol-mediated peroxidation. Free Radical Biology and Medicine 29,
131-146.
Samocha-Bonet, D.,
Gal, S., Schnitzer, E., Lichtenberg, D., and Pinchuk, I., 2004. Lipid peroxidation in the
presence of albumin, inhibitory and prooxidative effects. Free Radical Research
38, 1173-1181.
Samocha-Bonet, D., Heilbronn, L.K., Lichtenberg, D., and
Campbell, L.V., 2010. Does skeletal muscle oxidative stress initiate insulin
resistance in genetically predisposed individuals? Trends in Endocrinology and
Metabolism 21, 83-88.
Samocha-Bonet, D., Lichtenberg, D., and Pinchuk, I., 2005.
Kinetic studies of copper-induced oxidation of urate, ascorbate and their
mixtures. Journal of Inorganic Biochemistry 99, 1963-1972.
Samocha-Bonet, D.,
Lichtenberg, D., Tomer, A., Deutsch, V., Mardi, T., Goldin, Y., bu-Abeid, S.,
Shenkerman, G., Patshornik, H., Shapira, I., and Berliner, S., 2003. Enhanced erythrocyte
adhesiveness/aggregation in obesity corresponds to low-grade inflammation.
Obesity Research 11, 403-407.
Schnitzer,
E. and Lichtenberg, D., 1994. Reevaluation
of the Structure of Low-Density Lipoproteins. Chemistry and Physics of Lipids
70, 63-74.
Schnitzer, E.,
Dagan, A., Krimsky, M., Lichtenberg, D., Pinchuk, I., Shinar, H., and Yedgar,
S., 2000. Interaction
of hyaluronic acid-linked phosphatidylethanolamine (HyPE) with LDL and its
effect on the susceptibility of LDL lipids to oxidation. Chemistry and Physics
of Lipids 104, 149-160.
Schnitzer, E.,
Fainaru, M., and Lichtenberg, D., 1995. Oxidation of Low-Density-Lipoprotein Upon Sequential
Exposure to Copper Ions. Free Radical Research 23, 137-149.
Schnitzer, E.,
Pinchuk, I., and Lichtenberg, D., 2007. Peroxidation of liposomal lipids. European Biophysics
Journal with Biophysics Letters 36, 499-515.
Schnitzer, E.,
Pinchuk, I., Bor, A., Fainaru, M., and Lichtenberg, D., 1997. The effect of albumin on
copper-induced LDL oxidation. Biochimica et Biophysica Acta-Lipids and Lipid
Metabolism 1344, 300-311.
Schnitzer, E.,
Pinchuk, I., Bor, A., Fainaru, M., Samuni, A.M., and Lichtenberg, D., 1998. Lipid oxidation in
unfractionated serum and plasma. Chemistry and Physics of Lipids 92, 151-170.
Schnitzer, E.,
Pinchuk, I., Bor, A., Leikin-Frenkel, A., and Lichtenberg, D., 2007. Oxidation of liposomal
cholesterol and its effect on phospholipid peroxidation. Chemistry and Physics
of Lipids 146, 43-53.
Schnitzer, E.,
Pinchuk, I., Fainaru, M., Lichtenberg, D., and Yedgar, S., 1998. LDL-associated phospholipase A
does not protect LDL against lipid peroxidation in vitro. Free Radical Biology
and Medicine 24, 1294-1303.
Schnitzer, E.,
Pinchuk, I., Fainaru, M., Schafer, Z., and Lichtenberg, D., 1995. Copper-Induced Lipid Oxidation
in Unfractionated Plasma - the Lag Preceding Oxidation as a Measured of
Oxidation-Resistance. Biochemical and Biophysical Research Communications 216,
854-861.
Shimonov, M., Pinchuk, I., Bor, A., Beigel, I., Fainaru,
M., Rubin, M., and Lichtenberg, D., 1999. Susceptibility of serum lipids to
copper-induced peroxidation correlates with the level of high-density lipoprotein
cholesterol. Lipids 34, 255-259.
Shoval, H.,
Lichtenberg, D., and Gazit, E., 2007. The molecular mechanisms of the anti-amyloid effects of
phenols. Amyloid-Journal of Protein Folding Disorders 14, 73-87.
Shoval, H., Weiner, L., Gazit, E., Levy, M., Pinchuk, I.,
and Lichtenberg, D., 2008. Polyphenol-induced dissociation of various amyloid
fibrils results in a methionine-independent formation of ROS. Biochimica et
Biophysica Acta-Proteins and Proteomics 1784, 1570-1577.
Yossepowitch, O.,
Pinchuk, I., Gur, U., Neumann, A., Lichtenherg, D., and Baniel, J., 2007. Advanced but not localized
prostate cancer is associated with increased oxidative stress. Journal of
Urology 178, 1238-1243.