| Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 8, Number 7, October 2008
Contents
Regulation of the Endoplasmic Reticulum Ca2+-Store
in Cancer Pp. 705-709
A. Bergner and R.M. Huber
[Abstract] [Full
Text Article]
Targeting RSK: An Overview of Small Molecule Inhibitors
Pp. 710-716
T.L. Nguyen
[Abstract]
[Full
Text Article]
A Potent Anti-Carcinoma and Anti-Acute Myeloblastic Leukemia
Agent, AG490 Pp. 717-722
J.R. Caceres-Cortes
[Abstract] [Purchase
Article]
Cancer Therapy: Targeting Cell Cycle Regulators Pp.
723-731
M. Johansson and J.L. Persson
[Abstract] [Purchase
Article]
Recent Developments of Steroid Sulfatase Inhibitors as Anti
Cancer Agents Pp. 732-738
P.A. Foster, M. J. Reed and A.
Purohit
[Abstract]
[Purchase Article]
Novel Diaryl or Heterocyclic Sulfonamides as Antimitotic Agents
Pp. 739-745
L. Hu, Z.-r. Li , J.-d. Jiang and
D.W. Boykin
[Abstract] [Purchase
Article]
Recent Advances in Lamellarin Alkaloids: Isolation, Synthesis
and Activity Pp. 746-760
D. Pla, F. Albericio and M. Álvarez
[Abstract] [Purchase
Article]
Recent Advances in Hsp90 Inhibitors as Antitumor Agents
Pp. 761-782
S. Messaoudi, J.F. Peyrat, J.D. Brion and M.
Alami
[Abstract] [Purchase
Article]
2-Chloroadenosine and Human Prostate Cancer Cells
Pp. 783-789
I. Bellezza, A. Tucci and A. Minelli
[Abstract] [Purchase
Article]
Tumour Hypoxia Affects the Responsiveness of Cancer Cells
to Chemotherapy and Promotes Cancer Progression Pp.
790-797
J.-P. Cosse and C. Michiels
[Abstract] [Purchase
Article]
Protein Kinase CK2 Inhibitors: Emerging Anticancer Therapeutic
Agents? Pp. 798-806
A. Bortolato, G. Cozza and S. Moro
[Abstract] [Purchase
Article]
Dimeric Approaches to Anti-Cancer Chemotherapeutics Pp.
807-816
M.K. Hadden and B.S.J. Blagg
[Abstract] [Purchase
Article]
Abstracts
[Back to top]
[Full
Text Article]
Regulation of the Endoplasmic Reticulum Ca2+-Store
in Cancer
A. Bergner and R.M. Huber
Calcium is a ubiquitous second messenger and is involved
in virtually all cellular functions. Cellular events being
regulated by calcium include gene transcription, metabolism,
proliferation and apoptosis. Cancer growth is based on increased
proliferation, decreased differentiation and decreased apoptosis.
Therefore, the intracellular Ca2+-homeostasis
has become one of the focuses in current cancer research.
Elevation of the cytoplasmic Ca2+-concentration
can result from Ca2+-influx
from the extracellular space or from Ca2+-release
from intracellular stores. The main intracellular Ca2+-store
is the endoplasmic reticulum (ER). The Ca2+-content
of the ER is maintained by trans-membrane proteins involving
the sarco/endoplasmic reticulum Ca2+-ATPase
and the inositol-1,4,5-phosphat receptor. In this review,
we summarize the current knowledge of the ER and its trans-membrane
proteins as regulating structures of the intracellular Ca2+-homeostasis,
what changes occur in malignant cells and how this promotes
cancer. We further review possible pharmacological intervention
and show future perspectives of the intracellular Ca2+-homeostasis
as an anti-cancer target.
[Back to top] [Full
Text Article]
Targeting RSK: An Overview of Small Molecule Inhibitors
T.L. Nguyen
Ribosomal S6 kinase (RSK) is a family of serine/threonine
kinases that has been identified as a promising anti-cancer
target. While a number of protein kinase inhibitors that have
potent activity against other serine/threonine kinases were
shown to also inactivate RSK, there is keen interest in the
three different inhibitor chemotypes that were shown to be
RSK specific, since these compounds have tremendous utility
as chemical probes in elucidating the biochemistry of the
RSK signaling cascade and unraveling the molecular basis of
cancer. Because each compound may have therapeutic potential,
the nonspecific kinase inhibitors as well as the RSK specific
inhibitors will be discussed.
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Article]
A Potent Anti-Carcinoma and Anti-Acute Myeloblastic Leukemia
Agent, AG490
J.R. Caceres-Cortes
Proteins with tyrosine kinase activity are recognized
as key regulators of cellular processes including growth and
differentiation. Tyrosine kinase receptors e.g. EGFR and soluble
tyrosine kinase proteins e.g. JAK-2, have emerged as essentials
in cell survival for cervical carcinoma and acute myeloblastic
leukemia, respectively. These receptors and soluble cytoplasm
networks have been studied in detail and finally pharmacological
agents, targeted at key molecules, could be produced. Tyrphostins
are kinases inhibitors synthesized on the basic structure
of erbstatin a natural kinase inhibitor. The JAK-2 specific
inhibitor, Tyrphostin AG490 is used to inhibit phosphorylation
of EGFR and signal transducer and activator of transcription
3 [STAT-3], and subsequently reduce invasion and adhesion
potential of malignant cells. This review summarizes experiments
providing a detailed picture of how hematopoietic cancer c-Kit+,
Jak-2+ and non hematopoietic tumors c-Kit+, HER-2+, JAK-2+
can be inhibited by the chemosensitizing agent AG490 causing
programmed cell death. Furthermore, studies presented herein
analyzed several cellular targets that can be modified by
the same death effector. The highly conserved JAK-2/STAT-3,
c-Kit, and HER-2 signaling pathways play pleiotropic roles
during embryonic development and are important for the regulation
of self-renewing tissues. The physiological functions of these
signaling cascades range from stem cell maintenance and influencing
cell fate decisions of progenitor cells, to the induction
of terminal differentiation processes, all of which have been
found to be recapitulated in different forms of cancers. Inhibiting
their action by AG490 represents a therapeutic approach for
the treatment of individual types of cancer and several broad-spectrum.
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Article]
Cancer Therapy: Targeting Cell Cycle
Regulators
M. Johansson and J.L. Persson
Cyclins and CDKs play critical roles in DNA synthesis
and cell division. Alterations in their function may lead
to the disruption of normal cell growth and apoptosis, and
subsequently, result in carcinogenesis. Elevated levels of
cyclins and CDKs are frequently observed in a wide range of
different types of human cancers. Understanding of molecular
mechanisms underlying the cell cycle effects in response to
the chemotherapeutic agents is of great importance for improving
the efficacy of targeted therapeutics and overcoming resistance
to chemotherapeutic agents. Despite the clinical applications
of cell cycle specific chemotherapeutic agents, there is still
an urgent need to develop novel drugs that can target multiple
sites and pathways of the cell cycle while avoiding drug induced
cytotoxicity. In this review article, we will summarize the
development of novel agents that specifically target cell
cycle pathways in human cancer. We will discuss drugs that
can directly interfere with the mitotic process of tumor cells.
Moreover, we tend to address the significance of using small
molecule CDK inhibitors that are derived from natural products.
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Article]
Recent Developments of Steroid Sulfatase Inhibitors as Anti
Cancer Agents
P.A. Foster, M. J. Reed and A.
Purohit
The steroid sulfatase (STS) enzyme plays a pivotal role in
the formation of biologically active steroid hormones. Its
involvement in the hydrolysis of estrone sulfate and dehydroepiandrosterone
sulfate to estrone and dehydroepiandrosterone, respectively,
is an important step in the formation of estradiol and androstenediol,
both of which are estrogenic steroids that can stimulate tumor
growth. Consequently, as STS is widely distributed throughout
the entire body, it has a substantial influence on hormone-dependent
cancer mitogenesis. It is a useful prognostic marker of disease
as a significant majority of breast tumors over-express the
enzyme and there are indications of STS having a role in prostate
cancer. This knowledge has led to the development of potent
STS inhibitors for use as anti-cancer agents. There are now
several steroidal and non-steroidal STS inhibitors available.
New in vivo models, using ovariectomized female nude
mice, have been developed to pre-clinically test these inhibitors.
These studies have demonstrated the excellent efficacy and
effect of STS inhibitors on breast carcinoma development.
Recently, 667 COUMATE, an irreversible type of inhibitor which
utilizes a phenol sulfamate ester as its active pharmacophore,
has completed a Phase I clinical trial in postmenopausal women
with breast cancer. These studies have indicated the potential
clinical benefit for the use of STS inhibitors. Most pre-clinical
and clinical studies have focused on breast cancer as the
target for STS inhibition. However, there are other hormone-dependent
malignancies, such as endometrial and prostate cancer, that
could in the future be treated with these new potent STS inhibitors.
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Article]
Novel Diaryl or Heterocyclic Sulfonamides as Antimitotic
Agents
L. Hu, Z.-r. Li , J.-d. Jiang and
D.W. Boykin
The sulfonamides constitute an important class of drugs,
which display a variety of activities including antibacterial,
anti-carbonic anhydrase, diuretic, hypoglycemic and antithyroid
effectiveness. A number of sulfonamides have been reported
to be potent anticancer agents, which interact with a wide
range of different cellular targets. Among these interesting
sulfonamides, the diaryl or heterocyclic sulfonamides have
recently emerged as an important class of antimitotic agents
against different types of cancer, including multidrug resistant
tumors. This review summarizes the recent advances of the
diaryl or heterocyclic sulfonamides as novel antimitotic agents.
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Article]
Recent Advances in Lamellarin Alkaloids: Isolation, Synthesis
and Activity
D. Pla, F. Albericio and M. Álvarez
Lamellarins are a large family of marine alkaloids with
potential anticancer activity that have been isolated from
diverse marine organisms, mainly ascidians and sponges. All
lamellarins feature a 3,4-diarylpyrrole system. Pentacyclic
lamellarins, whose polyheterocyclic system has a pyrrole core,
are the most active compounds. Some of these alkaloids are
potently cytotoxic to various tumor cell lines. To date, Lam-D
and Lam-H have been identified as lead compounds for the inhibition
of topoisomerase I and HIV-1 integrase, respectively—nuclear
enzymes which are over-expressed in deregulation disorders.
Moreover, these compounds have been reported for their efficacy
in treatment of multi-drug resistant (MDR) tumors cells without
mediated drug efflux, as well as their immunomodulatory activity
and selectivity towards melanoma cell lines. This article
is an overview of recent literature on lamellarins, encompassing
their isolation, recent synthetic strategies for their total
synthesis, the preparation of their analogs, studies on their
mechanisms of action, and their structure-activity relationships
(SAR).
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Article]
Recent Advances in Hsp90 Inhibitors as Antitumor Agents
S. Messaoudi, J.F. Peyrat, J.D. Brion and
M. Alami
One promising therapeutic strategy for treating cancer
is to specifically target signal transduction pathways that
have a key role in oncogenic transformation and malignant
progression. Hsp90 is an emerging therapeutic target of interest
for the treatment of cancer. It is responsible for modulating
cellular response to stress by maintaining the function of
numerous signalling proteins – known as ‘client
proteins’ – that are associated with cancer cell
survival and proliferation. Many cancers result from specific
mutations in, or aberrant expression of, these client proteins.
Small molecule Hsp90 inhibitors bind to the ATP binding pocket,
inhibit chaperone function and could potentially result in
cytostasis or cell death. Consequently, many client proteins
are targeted for degradation via the ubiquitin-proteasome
pathway including receptor and non receptor kinases (Erb-B2,
epidermal growth factor receptor, and Src family kinases),
serine/threonine kinases (c-Raf-1 and Cdk4), steroid hormone
receptors (androgen and estrogen), and apoptosis regulators
such as mutant p53. Inhibition of Hsp90 function has also
proven effective in killing cancer cells that have developed
resistance to targeted therapies such as kinase inhibitors.
This review is intended to update recent developments in new
Hsp90 inhibitors as antitumors agents, the design, biological
evaluation and their clinical trials studies.
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Article]
2-Chloroadenosine and Human Prostate Cancer Cells
I. Bellezza, A. Tucci and A. Minelli
Cladribine, i.e.2-deoxy-Chloroadenosine is currently
in use as chemotherapeutic agent in chronic lymphoid malignancies
and pediatric acute myelogenous leukemia whereas the structurally
related counterpart, 2-Chloroadenosine, has been less studied.
Nevertheless, 2-Chloroadenosine has been shown to be capable
of inducing apoptosis in several cell lines by acting either
via adenosine receptors or via uptake that
is followed by metabolic transformations leading to nucleotide
analogues, i.e. antimetabolites effective in the treatment
of a variety of malignancies. Triphosphate nucleoside analogues
show specificity for cell in S-phase, inhibit DNA synthesis
and kill the cells by mechanisms still largely unknown. 2-Chloroadenosine,
at low micromolar concentration, acts as a metabolic precursor
of an S-phase specific nucleoside analogue in human prostate
cancer PC3 cells and inhibits DNA synthesis thereby leading
to accumulation of cells in the S-phase. However, although
responsible for the acquisition of resistance, the adenosine
derivative is capable of sensitising the cells to the action
of other antineoplastic agents and the ability of nucleoside
analogues to trigger cell cycle arrest can be exploited to
maximize cytotoxicity in combination with cell cycle checkpoint
disregulators. 2-Chloroadenosine, in combination with Docetaxel,
known to improve the survival of hormone-refractory prostate
cancer patients, further decreases in vitro PC3 cell
proliferation and invasiveness. Moreover, 2-Chloroadenosine
is capable of modulating PAR-1 and IL-23 gene expression suggesting
a modulation of cancer metastasis and immune system activity.
The present review summarizes research performed in our laboratory
to propose a novel role for 2-Chloroadenosine as an anticancer
agent.
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Article]
Tumour Hypoxia Affects the Responsiveness of Cancer Cells
to Chemotherapy and Promotes Cancer Progression
J.-P. Cosse and C. Michiels
A solid tumour forms an organ-like structure that is
comprised of cancer cells as well as stroma cells (fibroblasts,
inflammatory cells) that are embedded in an extracellular
matrix and are nourished by vascular network. However, tumoral
microenvironment is heterogeneous due to the abnormal vasculature
network and high proliferation rate of cancer cells. Because
of these features, some regions are starved from oxygen, a
phenomenon called hypoxia. Transient hypoxia is associated
with inadequate blood flow while chronic hypoxia is the consequence
of the increased oxygen diffusion distance due to tumour expansion.
Both types of hypoxia are correlated with poor outcome for
patients. Moreover, hypoxia also enhances chemoresistance
of cancer cells. Firstly, the delivery of drugs in hypoxic
area and cellular uptake of it are affected by hypoxia or
associated acidity. Secondly, some chemotherapeutic drugs
require oxygen to generate free radicals that contribute to
cytotoxicity. Last, hypoxia induces cellular adaptations that
compromise the effectiveness of chemotherapy. In response
to nutrient deprivation due to hypoxia, the rate of proliferation
of cancer cells decreases but chemotherapeutic drugs are more
effective against proliferating cells. On the other hand,
hypoxia induces adaptation by post-translational and transcriptional
changes that promote cell survival and resistance to chemotherapy.
Through these changes, hypoxia promotes angiogenesis, shift
to glycolytic metabolism, expression of ABC transporters,
cell survival by inducing the expression of genes encoding
growth factors and the modulation of apoptotic process. The
aim of this review is to provide a description of known hypoxia-induced
mechanisms of chemoresistance at a cellular level.
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Protein Kinase CK2 Inhibitors: Emerging Anticancer Therapeutic
Agents?
A. Bortolato, G. Cozza and S. Moro
Protein kinase CK2 is a ubiquitous, essential, and highly
pleiotropic protein kinase whose abnormally high constitutive
activity is suspected to underlie its pathogenic potential
in neoplasia and other diseases. A number of structurally
unrelated CK2 inhibitors, tested on a variety of cells derived
from tumours, including lymphomas, leukaemias, multiple myeloma
and prostate carcinoma, display a pro-apoptotic effect which
is roughly proportional to their in vitro inhibitory
potency.
In the present review we summarize the most recent discovery
of potent and selective CK2 inhibitors and their prospective
as future anti-cancer agents.
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Dimeric Approaches to Anti-Cancer Chemotherapeutics
M.K. Hadden and B.S.J. Blagg
Numerous proteins responsible for cell proliferation
and differentiation exist either as hetero or homodimers or
become activated through dimerization as a key step in their
respective signaling cascade. Many of these proteins have
been identified as major components in oncogenic signaling
pathways and have become popular targets for the development
of anti-tumor agents. For this reason, bivalent anti-cancer
drugs that could potentially interact with each monomer of
a dimeric protein target have been developed. This review
provides a brief background on prevalent dimeric drug targets
within the anti-cancer field and focuses mainly on dimeric
natural product and synthetic cancer chemotherapeutics.
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