|
Current Enzyme Inhibition
ISSN: 1573-4080
Current Enzyme Inhibition
Volume 2, Number 2, May 2006
Contents
Defense Against Oxidative Tissue Injury:
The Essential Role Played by Heme Oxygenase-1 Pp.
105-124
Toru Takahashi, Kiyoshi Morita, Reiko Akagi and
Shigeru Sassa
[Abstract]
Sphingomyelinases and the Regulation of Cell Death and Survival
Pp. 125-134
Antonio Gómez-Muñoz
[Abstract]
Inhibition of Abl Kinases by Intramolecular and
Intermolecular Interactions: A Lesson from Structure Studies
and CML Therapy Pp. 135-146
Baojie Li
[Abstract]
Therapeutic Potential of Phosphoinositide 3-Kinase
δ-Selective
Small Molecule Inhibitors Pp. 147-161
Kamal D. Puri
[Abstract]
JAK Family of Tyrosine Kinases: Its Functions and
Alterations in Human Cancer Pp. 163-171
Shahab Uddin, Azhar R. Hussain and Khawla S.
Al-Kuraya
[Abstract]
Caenorhabditis elegans: Study
Model for Animal and Human Cathepsins and Inhibitors Pp.
173-188
Sarwar Hashmi, Khursheed Anwer and Anwar L. Bilgrami
[Abstract]
Development of Steroidal Aromatase Inhibitors
Pp. 189-198
Sonal Dubey
[Abstract]
Abstracts
[Back to top]
Defense Against Oxidative Tissue Injury: The Essential
Role Played by Heme Oxygenase-1
Toru Takahashi, Kiyoshi Morita, Reiko Akagi and
Shigeru Sassa
Oxidative stresses provoke a set of special cellular
responses, particularly those which participate in the defense
against tissue injuries. Free heme, which can be rapidly released
from hemeproteins, may constitute a major threat in the oxidant
stress because it catalyzes the formation of reactive oxygen
species (ROS). To counteract such insults, cells respond by
inducing the 33-kDA heat shock protein, heme oxygenase (HO)
-1, the rate-limiting enzyme in heme degradation. Induced
HO-1 as such removes free heme by an enzymatic process. In
addition, HO-1 induction itself confers protection to tissues
from further oxidative injuries. Consistent with this concept,
the abrogation of HO-1 induction, or chemical ablation of
HO activity abolishes the beneficial effect of HO-1, and results
in the aggravation of tissue injuries. In this article, we
review recent advances on the essential role of HO-1 in tissue
protection in various models of experimental oxidative tissue
injuries and in human disorders, with special emphasis on
the role of its induction in tissue defense and the consequences
of its inhibition on tissue injuries.
[Back to top]
Sphingomyelinases and the Regula-tion of
Cell Death and Survival
Antonio Gómez-Muñoz
The breakdown of sphingomyelin by sphingomyelinases (SMases)
is a crucial event in the regulation of cell survival. This
action produces ceramide, which acts as a second messenger
to stimulate or inhibit downstream effectors leading to cell
growth arrest, or apoptosis. Mammalian cells utilize three
distinct forms of SMases, which can be distinguished by their
optimum pH: acidic, neutral, or alkaline SMases. Acidic and
neutral SMases are particularly important because they are
involved in signal transduction processes. However, stimulation
of SMase activity is not necessarily a pro-apoptotic event,
as ceramides are subject to rapid metabolism by intracellular
ceramidases and kinases to form sphingosine, sphingosine-1-phosphate,
or ceramide-1-phosphate, all of which have mitogenic, or cytoprotective
properties. Therefore, the balance of the intracellular levels
of pro-apoptotic ceramides and anti-apoptotic (or mitogenic)
sphingosine-1-phosphate and ceramide-1-phosphate is crucial
for determining the overall signal that is finally transmitted
in cells. A better understanding of the interactions between
the different metabolites that can be generated from the SMase
pathway would be relevant for elucidation of the mechanisms
that regulate cellular functions, in particular cell death
and proliferation. Most importantly, the development of inhibitors
of SMases may be crucial for establishing therapeutic strategies
for treatment of disease.
[Back to top]
Inhibition of Abl Kinases by Intramolecular
and Intermolecular Interactions: A Lesson from Structure Studies
and CML Therapy
Baojie Li
BCR-ABL is a product of Philadelphia chromosome and is present
in 95% of all cases of chronic myelogenous leukemia (CML)
and 5-10% of acute lymphoblastic leukemia (ALL). The proto-oncogene,
c-Abl, is essential for mouse development and postnatal
survival. CML is believed to be caused by the abnormality
of a single gene (BCR-ABL) and requires BCR-ABL expression
for maintenance of the disease. Imatinib (Gleevec, STI571,
or CP57148B), a synthetic inhibitor for Abl kinases, PDGF
receptor and c-Kit, has been proven effective in the treatment
of CML, especially in chronic phase patients. Yet imatinib
is less efficacious in the treatment of blast crisis CML patients
and some patients develop drug resistance. This has led to
the search for additional inhibitors for combination therapy.
The elucidation of the co-crystal structures of Abl with inhibitors
and the identification of mutations in BCR-ABL that render
imatinib resistance have shed light on the molecular mechanisms
for Abl activation and inhibition. This knowledge will facilitate
the design of alternative inhibitors for BCR-ABL. This review
updates our understanding of the molecular mechanisms of Abl
inhibition by intramolecular interactions between different
domains, and by intermolecular interactions with proteins
and small molecules. Structure-based drug design will expedite
the development of new inhibitors that are effective on imatinib-resistant
BCR-ABL and that can distinguish endogenous Abl from BCR-ABL.
[Back to top]
Therapeutic Potential of Phosph-oinositide
3-Kinase δ-Selective
Small Molecule Inhibitors
Kamal D. Puri
The Class I phosphoinositide 3-kinase (PI3K) family of enzymes
consists of four closely related isoforms (p110α,
p110β,
p110γ,
and p110δ)
that generate phospholipid second messengers and control pathways
governing important cellular events such as migration, proliferation,
apoptosis, neovascularization and metastasis. Recent findings
suggesting involvement of these enzymes in the pathogenesis
of numerous diseases have triggered considerable interest
in the development of antagonists to class I PI3Ks as therapeutic
agents. The two most widely used PI3K inhibitors, wortmannin
and LY294002, do not distinguish adequately the activities
of different PI3K isoforms and lack acceptable pharmacological
and toxicological profiles. The fact that p110δ
and p110γ
expression is more restricted to cells of hematopoietic origin,
in combination with recent genetic evidence, supports the
hypothesis that selective inhibitors of these isoforms might
exhibit more acceptable pharmacological and toxicological
profiles. More recently several small molecule inhibitors,
selective for the p110δ
isoform, have been identified and evaluated in animal models
of human disease. This review has summarized the current knowledge
of the emerging therapeutic value of class I PI3Ks in general,
and p110δ
in particular, for the intervention in several pathological
disorders. Herein, the phenotypic consequences of genetically
targeting PI3K signaling in mice, identification and characterization
of PI3K isoform selective inhibitors and their efficacy in
animal models of human disease such as cancer, autoimmune/inflammatory
disorders and allergic diseases have beeen discussed. Lastly,
the challenges of considering PI3Ks as targets for therapeutic
intervention has also been summarized.
[Back to top]
JAK Family of Tyrosine Kinases: Its Functions
and Alterations in Human Cancer
Shahab Uddin, Azhar R. Hussain and Khawla S.
Al-Kuraya
The Janus kinases (JAKs) enzymes are a family of cytosolic
tyrosine kinases that are associated with membrane receptors
and play a critical role in the rapid transduction of signals
from cell surface to the nucleus. There are four different
tyrosine kinases (Tyk2, Jak1, Jak2, Jak3) that share significant
structural homology with each other. Binding of cytokines
or growth factors to their cognate receptor activate JAK kinases,
which in turn mediate the subsequent tyrosine phosphorylation
of STAT proteins. Phosphorylated STAT proteins form dimers,
translocate to the nucleus, and bind to specific DNA elements
to induce or modulate expression of target genes. Aberrant
activation of JAK kinases has been implicated in many hematological
malignancies and carcinomas. There is also accumulating evidence
that constitutive activation of different Jaks and Stats mediate
neoplastic transformation and promote abnormal cell proliferation
in various malignancies. This review will discuss the role
of various Jak-kinase dependent signal transduction pathways
in malignancies as well as therapeutic implications of the
recent advances in the field.
[Back to top]
Caenorhabditis elegans:
Study Model for Animal and Human Cathepsins and Inhibitors
Sarwar Hashmi, Khursheed Anwer and Anwar L. Bilgrami
Cysteine proteases belong to C1 family, which includes plant
and lysosomal cathepsin-like proteases. Cathepsins, detected
and isolated from numerous biological sources, are well adapted
to acidic and reducing conditions of lysosomal system. Cathepsins
perform the activities of a wide variety of enzymes such as
broad- and narrow-range endo-peptidases, aminopeptidases,
dipeptidyl peptidases with exo- and endo-peptidases. They
are involved in many physiological events. The enzymes can
be destructive if their activity is not controlled by their
endogenous inhibitors. Eleven cathepsins, i.e., B, C, F, H,
K, L, O, S, V, W, and X or Z, designated so far in human are
also identified in other organisms. Although there are great
deal of information available on the physiological function
of these cathepsins at cellular level very little is known
about their function at organism level. The genome sequences
from many organisms including human, Drosophila,
and free-living nematode, Caenorhabditis elegans
allow comparative genomics as the first order functional analysis.
The genome sequence of C. elegans allows comparative
sequence analyses to identify parasite or human gene that
share homology with C. elegans. Genome sequences
in combination with an ideal model system such as C. elegans
will facilitate identification of key cellular functions that
could lead to the identification of mechanisms of drug resistance,
as well as discovery of novel drug targets and antigens with
vaccine potential. This review covers recent research on the
role of “papain-like” class of cysteine
proteases in cellular physiology and focuses on most comprehensively
studied cathepsin B and L enzymes in C. elegans.
Besides, it also reviews the function of a recently described
cathepsin Z.
[Back to top]
Development of Steroidal Aromatase Inhibitors
Sonal Dubey
Aromatase inhibition is an effective and rate-limiting step
in estrogen production and in the treatment of advanced postmenopausal
breast cancer. More than 3 decades of active research have
already been put in its design, development and evaluation.
The aromatase inhibitors can be classified either based on
their mechanism of action, i.e. competitive aromatase inhibitors,
which compete with the substrate androstenedione for non-covalent
binding to the active site of the enzyme, irreversible inhibitors
that bind to the active site of the enzyme covalently and
mechanism-based or suicide inhibitors, which mimic the substrate
and require catalytic amounts of the enzyme to be converted
to the reactive intermediate resulting in inactivation of
the enzyme. Aromatase inhibitors can also be classified as
non-steroidal and steroidal types. The prototype non-steroidal
inhibitor aminoglutethimide provided the impetus for the development
of related compounds while the steroidal inhibitors function
as false substrates for aromatase with expected high selectivity.
This review article focuses mainly on the steroidal aromatase
inhibitors that have been developed to date, and which are
classified on the basis of various modifications in the different
rings (A,B,C,D) and position C-19 in the basic androstene
nucleus. The second-generation drug 4-hydroxyandrostenedione
(formestane), which is an excellent example of success achieved
by carrying out modification in ring A, was introduced to
clinical practice in 1990. Among the latest example is the
orally active, third generation drug exemestane which is an
irreversible inhibitor. The full potential of the new steroidal
aromatase inhibitors is currently being investigated by many
workers to evaluate their use in the management of breast
cancer either directly or as an adjuvant to surgery in postmenopausal
patients with early diagnosis.
|
