| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 20, 2008
Contents
Laminin-332-Integrin Interaction: A Target For Cancer
Therapy? Pp. 1968-1975
Daisuke Tsuruta, Hiromi Kobayashi, Hisayoshi Imanishi, Koji
Sugawara, Masamitsu Ishii and Jonathan C.R. Jones
[Abstract]
Platelet-Monocyte Interactions - A Dangerous Liaison
Linking Thrombosis, Inflammation and Atherosclerosis
Pp. 1976-1980
Peter Seizer, Meinrad Gawaz and Andreas E. May
[Abstract]
Substrates and Inhibitors of Human Multidrug Resistance
Associated Proteins and the Implications in Drug Development
Pp. 1981-2039
Shu-Feng Zhou, Lin-Lin Wang, Charlie Changli Xue, Wei
Duan,Chun Guang Li and Yong Li
[Abstract]
Enhancing Drug Discovery Through In Silico
Screening: Strategies to Increase True Positives Retrieval
Rates Pp. 2040-2053
J. Kirchmair, S. Distinto, D. Schuster, G. Spitzer, T.
Langer and G. Wolber
[Abstract]
Therapeutical Relevance of MAP-Kinase Inhibitors
in Renal Pp. 2054-2070
Diseases: Current Knowledge and Future Clinical Perspectives
M. Teresa Grande and José M. López-Novoa
[Abstract]
Identification of Apoptotic Drugs: Multiparametric
Evaluation in Cultured Hepatocytes Pp. 2071-2085
María José Gómez-Lechón, José
Enrique O´Connor, Agustín Lahoz, José
V. Castell and María Teresa Donato
[Abstract]
Abstracts
[Back to top]
Laminin-332-Integrin Interaction: A Target For Cancer Therapy?
Daisuke Tsuruta, Hiromi Kobayashi, Hisayoshi Imanishi, Koji
Sugawara, Masamitsu Ishii and Jonathan C.R. Jones
For many years, extracellular matrix (ECM) was considered
to function as a tissue support and filler. However, we now
know that ECM proteins control many cellular events through
their interaction with cell-surface receptors and cytoplasmic
signaling pathways. For example, they regulate cell proliferation,
cell division, cell adhesion, cell migration, and apoptosis.
We focus in this review on a laminin isoform, laminin-332
(formerly termed laminin-5), a major component of the basement
membrane (BM) of skin and other epithelial tissues. It is
composed of 3 subunits (α3,
β3
and γ3
and interacts with at least two integrin receptors expressed
by epithelial cells (α3β1
and α6β4
integrin). Mutations in either laminin-332 or integrin α6β4
result in junctional epidermolysis bullosa, a blistering skin
disease, while targeting of laminin-332 by autoantibodies
in cicatricial pemphigoid leads to dysadhesion of epithelial
cells from their underlying connective tissue. Abnormal expression
of laminin-332 and its integrin receptors is also a hallmark
of certain tumor types and is believed to promote invasion
of colon, breast and skin cancer cells. Moreover, there is
emerging evidence that laminin-332 and its protease degradation
products are not only found at the leading front of several
tumors but also likely induce and/or promote tumor cell migration.
Thus, in this review, we focus specifically on the role of
laminin-332 and its integrin receptors in adhesion, proliferation,
and migration/invasion of cancer cells. Finally, we discuss
strategies for the development of laminin-332-based antagonists
for the treatment of malignant tumors.
[Back to top]
Platelet-Monocyte Interactions - A Dangerous Liaison
Linking Thrombosis, Inflammation and Atherosclerosis
Peter Seizer, Meinrad Gawaz and Andreas E. May
Atherosclerosis is an inflammatory disease. Monocyte-platelet
interactions may play a key role in this process by various
pathways. They „inflame“ each other as well as
adjacent cell types at the vascular wall by direct physical
interactions, autocrine and paracrine activation processes.
These processes promote monocyte recruitment (in)to the vascular
wall – a key mechanism in atherogenesis. This article
highlights the molecular basis and the inflammatory pathways
initiated by platelet–monocyte interactions.
[Back to top]
Substrates and Inhibitors of Human Multidrug Resistance
Associated Proteins and the Implications in Drug Development
Shu-Feng Zhou, Lin-Lin Wang, Charlie Changli Xue, Wei
Duan,Chun Guang Li and Yong Li
Human contains 49 ATP-binding cassette (ABC) transporter
genes and the multidrug resistance associated proteins (MRP1/ABCC1,
MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6,
MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC
family which contains 13 members. ABCC7 is cystic fibrosis
transmembrane conductance regulator; ABCC8 and ABCC9 are the
sulfonylurea receptors which constitute the ATPsensing subunits
of a complex potassium channel. MRP10/ABCC13 is clearly
a pseudo gene which encodes a truncated protein that is highly
expressed in fetal human liver with the highest similarity
to MRP2/ABCC2 but without transporting activity. These transporters
are localized to the apical and/or basolateral membrane of
the hepatocytes, enterocytes, renal proximal tubule cells
and endothelial cells of the blood-brain barrier. MRP/ABCC
members transport a structurally diverse array of important
endogenous substances and xenobiotics and their metabolites
(in particular conjugates) with different substrate specificity
and transport kinetics. The human MRP/ABCC transporters except
MRP9/ABCC12 are all able to transport organic anions, such
as drugs conjugated to glutathione, sulphate or glucuronate.
In addition, selected MRP/ABCC members may transport a variety
of endogenous compounds, such as leukotriene C4
(LTC4 by MRP1/ABCC1), bilirubin
glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins
E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and
MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids.
In vitro, the MRP/ABCC transporters can collectively
confer resistance to natural product anticancer drugs and
their conjugated metabolites, platinum compounds, folate antimetabolites,
nucleoside and nucleotide analogs, arsenical and antimonial
oxyanions, peptide-based agents, and in concert with alterations
in phase II conjugating or biosynthetic enzymes, classical
alkylating agents, alkylating agents. Several MRP/ABCC members
(MRPs 1-3) are associated with tumor resistance which is often
caused by an increased efflux and decreased intracellular
accumulation of natural product anticancer drugs and other
anticancer agents. Drug targeting of these transporters to
overcome MRP/ABCC-mediated multidrug resistance may play a
role in cancer chemotherapy. Most MRP/ABCC transporters are
subject to inhibition by a variety of compounds.
Based on currently available preclinical and limited clinical
data, it can be expected that modulation of MRP members may
represent a useful approach in the management of anticancer
and antimicrobial drug resistance and possibly of inflammatory
diseases and other diseases. A better understanding of their
substrates and inhibitors has important implications in development
of drugs for treatment of cancer and inflammation.
[Back to top]
Enhancing Drug Discovery Through In Silico Screening:
Strategies to Increase True Positives Retrieval Rates
J. Kirchmair, S. Distinto, D. Schuster, G. Spitzer, T.
Langer and G. Wolber
Computational chemistry software for lead discovery has
become well established in pharmaceutical industry and has
found its way to the desktop computers of medicinal chemists
for different purposes, providing insight on the mode of action
and binding properties, and creating new ideas for lead structure
refinement. In this review we investigate the performance
and reliability of recent state-of-the-art data modeling techniques,
as well as ligand-based and structure-based modeling approaches
for 3D virtual screening. We discuss and summarize recently
published success stories and lately developed techniques.
Parallel screening is one of these emerging approaches allowing
for efficient activity in silico profiling of several
compounds against different targets or anti-targets simultaneously.
This is of special interest to medicinal chemists, as the
approach allows revealing unknown binding modes (‘target-fishing’)
as well as integrated ADME profiling or – more generally
– the prediction of off-target effects.
[Back to top]
Therapeutical Relevance of MAP-Kinase Inhibitors in
Renal
Diseases: Current Knowledge and Future Clinical Perspectives
M. Teresa Grande and José M. López-Novoa
Renal failure, both acute and chronic, represents an
important health problem by its social, sanitary and economic
aspects. Mitogen-activated protein kinases (MAPK) are a family
of mediators involved in the transduction of extracellular
stimuli to intracellular responses. The best studied members
of this family are extracellular signal-regulated kinases
1 and 2 (ERK1 and ERK2), Jun NH2-terminal
kinase (JNK), p38 kinase and extracellular signal regulated
kinases 5 (ERK5) also known as big MAP Kinase 1 (BMK1). MAPKs
plays a role in regulating renal function and all these pathways
have been demonstrated to be activated in many “in
vivo” and cellular models or renal failure. As
MAP kinases are key regulators in the control of cell proliferation
and cell death, many more or less specific inhibitors of these
pathways are being developed for the treatment of tumors.
The purpose of this review is to examine the data available
on the role of MAPKs activation in “in vivo”
models of renal failure, as well as in different renal cell
types (especially in mesangial cells, podocytes, tubular epithelial
cells and fibroblasts) subjected to stress or damage. We have
also reviewed the effect of MAPKs inhibition on renal damage,
both “in vivo” and “in vitro”.
Data collected allow to suggest that therapy of chronic and
acute renal disease with MAPKs inhibitors is a promising therapeutic
area, although much more basic and clinical studies are necessary
before this kind of therapy can be used in the everyday clinic.
[Back to top]
Identification of Apoptotic Drugs: Multiparametric Evaluation
in Cultured Hepatocytes
María José Gómez-Lechón, José
Enrique O´Connor, Agustín Lahoz,
José V. Castell and María Teresa Donato
It is now recognized that necrosis is not the only mechanism
responsible for chemically-induced cell death. It is believed
that apoptosis could be the major form of cell death induced
by toxicants and that necrosis is associated only with circumstances
of gross cell injury. The liver is a key target organ for
drug toxicity and an important effort in drug-discovery deals
with the identification of molecules with hepatotoxic potential.
The importance of apoptosis in toxicology has been underestimated
given the difficulty of identifying apoptotic cells in in
vitro models when apoptosis normally degenerates to secondary
necrosis. Nowadays, the central role played by apoptosis in
the toxicity of many xenobiotics and P450-generated metabolites
is recognized. The detection of drug-induced apoptosis constitutes
one of the highest priorities of the pharmaceutical industry.
Different markers aimed at identifying apoptotic compounds
irrespectively of the pathway of how cell apoptosis was initiated
have been proposed. The aim of the present paper is to review
the utility of some available in vitro strategies
for studying drug-induced liver apoptosis. The evaluation
of apoptotic or anti-apoptotic effects of chemicals in hepatocytes
is illustrated by several examples including model apoptotic
compounds, pharmaceutical drugs which have been shown to induce
apoptosis as an adverse effect; and drugs preventing apoptosis.
By combining appropriated markers, apoptosis can be detected
in hepatocytes long before cell necrosis, at sub-cytotoxic
concentrations of the drugs. The possibility of using small
amounts of cells cultured in multiwell formats and automation
has notably contributed to develop reproducible, reliable,
sensitive, easy-to-handle and rapid multiparametric assays
that are ideally amenable to high throughput screening (HTS).
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