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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 7, Number 3, March 2006
Contents
SMALL MOLECULES OF NATURAL ORIGIN FOR CANCER
THERAPY AND CHEMOPREVENTION
Part I: Pharmacognosy and Molecular Pharmacology of
Small Molecules of Natural Origin for Cancer Therapy and Chemoprevention
Guest Editor: Thomas Efferth
Editorial Pp. 237
Ethnobotany and Ethnopharmacy – Their Role for
Anti-Cancer Drug Development Pp. 239-245
M. Heinrich and P. Bremner
[Abstract]
The Role of Pharmacognosy in Modern Medicine and Pharmacy
Pp. 247-264
W.P. Jones, Y.W. Chin and A.D. Kinghorn
[Abstract]
Biodiversity as a Source of Anticancer Drugs Pp.
265-277
G. Tan, C. Gyllenhaal and D.D. Soejarto
[Abstract]
Natural Products from Marine Invertebrates and Microbes
as Modulators of Antitumor Targets Pp. 279-304
D.J. Newman and G.M. Cragg
[Abstract]
Antimitotic Agents of Natural Origin
Pp. 305-326
A. Nagle, W. Hur and N.S. Gray
[Abstract]
Targeting JAK3 and BTK Tyrosine Kinases With Rationally
Designed-Inhibitors Pp. 327-343
A.O. Vassilev, H.E. Tibbles, D. DuMez, T.K. Venkatachalam
and F.M. Uckun
[Abstract]
Natural Flavonoids Targeting Deregulated Cell Cycle Progression
in Cancer Cells Pp. 345-354
R.P. Singh and R. Agarwal
[Abstract]
Natural Product-Based Inhibitors of Hypoxia-Inducible
Factor-1 (HIF-1) Pp. 355-369
D.G. Nagle and Y-D. Zhou
[Abstract]
Clinical Aspects of Natural Anti-Angiogenic Drugs
Pp. 371-383
C.P. Neal, D.P. Berry, H. Doucas, M.M. Manson, W. Steward
and G. Garcea
[Abstract]
Abstracts
[Back
to top]
Editorial
[Back to top]
Ethnobotany and Ethnopharmacy – Their Role for
Anti-Cancer Drug Development
M. Heinrich and P. Bremner
Local and traditional knowledge has been the starting point
for many successful drug development projects over the last
decades. Here we discuss some examples of anti-cancer drugs
which have had enormous impact as anti-cancer agents (camptothecan,
taxol and derivatives) and a few examples of drugs currently
under various stages of preclinical development. Ethnobotanists
investigate the relationship between humans and plants in
all its complexity, and such research is generally based on
a detailed observation and study of the use a society makes
of plants. The requirements of modern research on natural
products as, for example, outlined in the Convention on Biological
Diversity (Rio Convention) and the overall approach in ethnobotanical
research are also discussed. Selected phytochemical-pharmacological
studies based on traditional plant use are used to highlight
the potential of ethnobotany driven anti-cancer research.
The link between traditionally used plants and targets of
the NF-κB
pathway is discussed using on an EU-funded, multidisciplinary
project as an example. Lastly the potential of chemopreventive
agents derived from traditional food plants is briefly addressed.
[Back to top]
The Role of Pharmacognosy in Modern Medicine
and Pharmacy
W.P. Jones, Y.W. Chin and A.D. Kinghorn
This review details the contribution to modern medicine
and pharmacy made by natural products and drugs derived from
natural products, with an emphasis on essential medicines
and new introductions to the market. Areas covered include
recent advances in the development of drugs derived from marine
organisms, microbes, terrestrial animals, and vascular plants,
and current issues regarding botanical medicines. The role
of natural products in drug discovery and development is evaluated,
particularly with regard to their value as sources of drug
leads with “drug-like” properties. A rationale
for the success of natural products research in providing
new drugs and drug prototypes is presented, drawing on lines
of evidence from chemical informatics and chemical ecology.
Several innovative strategies for natural products drug discovery
and evaluation of botanical medicines are also reviewed.
[Back to top]
Biodiversity as a Source of Anticancer Drugs
G. Tan, C. Gyllenhaal and D.D. Soejarto
Natural Products have been the most significant source of
drugs and drug leads in history. Their dominant role in cancer
chemotherapeutics is clear with about 74% of anticancer compounds
being either natural products, or natural product-derived.
The biodiversity of the world provides a resource of unlimited
structural diversity for bioprospecting by international drug
discovery programs such as the ICBGs and NCDDGs, the latter
focusing exclusively on anticancer compounds. However, many
sources of natural products remain largely untapped. Technology
is gradually overcoming the traditional difficulties encountered
in natural products research by improving access to biodiverse
resources, and ensuring the compatibility of samples with
high throughput procedures. However, the acquisition of predictive
biodiversity remains challenging. Plant and organism species
may be selected on the basis of potentially useful phytochemical
composition by consulting ethnopharmacological, chemosystematic,
and ecological information. On the con-servation/political
front, the Convention on Biological Diversity (CBD) is allaying
the anxiety surrounding the notion of biopiracy, which has
defeated many attempts to discover and develop new natural
products for human benefit. As it becomes increasingly evident
and important, the CBD fosters cooperation and adaptation
to new regulations and collaborative research agreements with
source countries. Even as the past inadequacies of combinatorial
chemistry are being analyzed, the intrinsic value of natural
products as a source of drug leads is being increasingly appreciated.
Their rich structural and stereochemical characteristics make
them valuable as templates for exploring novel molecular diversity
with the aim of synthesizing lead generation libraries with
greater biological relevance. This will ensure an ample supply
of starting materials for screening against the multitude
of potentially “druggable” targets uncovered by
genomics technologies. Far from being mutually exclusive,
biodiversity and genomics should be the driving force of drug
discovery in the 21st century.
[Back to top]
Natural Products from Marine Invertebrates and Microbes
as Modulators of Antitumor Targets
D.J. Newman and G.M. Cragg
Over the last twenty-five to thirty years, exploration of
the marine fauna and microbial flora has progressed from a
random search by natural product chemists who liked to dive
and wished to combine their hobby with their profession, to
fully integrated programs of systemic investigation of the
chemical agents elaborated by marine organisms of all phyla
(as presumably defensive agents against predators) for their
potential as leads to human-use drug candidates where the
putative mechanisms have been identified as modulation of,
and/or interaction with, potential molecular targets, rather
than just exhibiting general cytotoxicity. This review is
not exhaustive but is meant to cover the highlights of such
agents and is arranged on a (nominal) target basis rather
than by organism or chemical class.
[Back to top]
Antimitotic Agents of Natural Origin
A. Nagle, W. Hur and N.S. Gray
Antimitotic agents have been the most successful pharmacological
agents for the treatment of cancer. The term “antimitotic
agent” has traditionally been synonymous with tubulin-targeting
compounds, but as a consequence of the large number of new
compounds and mechanisms that have been identified recently,
a much broader definition is currently needed. This review
attempts to provide a broad overview of compounds and their
cognate protein targets which result in a block in mitosis.
Focus has been placed on agents that act directly on the mitotic
machinery rather than on targets further upstream such as
growth factor receptors.
[Back to top]
Targeting JAK3 and BTK Tyrosine Kinases With Rationally
Designed-Inhibitors
A.O. Vassilev, H.E. Tibbles, D. DuMez, T.K. Venkatachalam
and F.M. Uckun
Multifunctional rational drug design of protein tyrosine
kinases inhibitors allows a potent drug to be utilized to
treat more than one disease for greater patient benefits.
Many protein tyrosine kinases (PTK), including Janus kinase
3 (JAK3) and Bruton’s tyrosine kinase (BTK), have been
identified as potential drug targets to treat diverse diseases
including cancer and disorders of the immune system. Here
we review advances in JAK3 and BTK inhibitors and describe
the therapeutic potential of these potent agents in the clinical
setting.
[Back to top]
Natural Flavonoids Targeting Deregulated Cell Cycle
Progression in Cancer Cells
R.P. Singh and R. Agarwal
The prolonged duration requiring alteration of multigenetic
and epigenetic molecular events for cancer development provides
a strong rationale for cancer prevention, which is developing
as a potential strategy to arrest or reverse carcinogenic
changes before the appearance of the malignant disease. Cell
cycle progression is an important biological event having
controlled regulation in normal cells, which almost universally
becomes aberrant or deregulated in transformed and neoplastic
cells. In this regard, targeting deregulated cell cycle progression
and its modulation by various natural and synthetic agents
are gaining widespread attention in recent years to control
the unchecked growth and proliferation in cancer cells. Infact,
a vast number of experimental studies convincingly show that
many phytochemicals halt uncontrolled cell cycle progression
in cancer cells. Among these phytochemicals, natural flavonoids
have been identified as a one of the major classes of natural
anticancer agents exerting antineoplastic activity via
cell cycle arrest as a major mechanism in various types of
cancer cells. This review is focused at the modulatory effects
of natural flavonoids on cell cycle regulators including cyclin-dependent
kinases and their inhibitors, cyclins, p53, retinoblastoma
family of proteins, E2Fs, check-point kinases, ATM/ATR and
survivin controlling G1/S and G2/M check-point transitions
in cell cycle progression, and discusses how these molecular
changes could contribute to the antineoplastic effects of
natural flavonoids.
[Back to top]
Natural Product-Based Inhibitors of Hypoxia-Inducible
Factor-1 (HIF-1)
D.G. Nagle and Y-D. Zhou
The transcription factor hypoxia-inducible factor-1 (HIF-1)
regulates the expression of more than 70 genes involved in
cellular adaptation and survival under hypoxic stress. Activation
of HIF-1 is associated with numerous physiological and pathological
processes that include tumorigenesis, vascular remodeling,
inflammation, and hypoxia/ischemia-related tissue damage.
Clinical studies suggested that HIF-1 activation correlates
directly with advanced disease stages and treatment resistance
among cancer patients. Preclinical studies support the inhibition
of HIF-1 as a major molecular target for antitumor drug discovery.
Considerable effort is underway, in government laboratories,
industry and academia, to identify therapeutically useful
small molecule HIF-1 inhibitors. Natural products (low molecular
weight organic compounds produced by plants, microbes, and
animals) continue to play a major role in modern antitumor
drug discovery. Most of the compounds discovered to inhibit
HIF-1 are natural products or synthetic compounds with structures
that are based on natural product leads. Natural products
have also served a vital role as molecular probes to elucidate
the pathways that regulate HIF-1 activity. Natural products
and natural product-derived compounds that inhibit HIF-1 are
summarized in light of their biological source, chemical class,
and effect on HIF-1 and HIF-mediated gene regulation. When
known, the mechanism(s) of action of HIF-1 inhibitors are
described. Many of the substances found to inhibit HIF-1 are
non-druggable compounds that are too cytotoxic to serve as
drug leads. The application of high-throughput screening methods,
complementary molecular-targeted assays, and structurally
diverse chemical libraries hold promise for the discovery
of therapeutically useful HIF-1 inhibitors.
[Back to top]
Clinical Aspects of Natural Anti-Angiogenic Drugs
C.P. Neal, D.P. Berry, H. Doucas, M.M. Manson, W. Steward
and G. Garcea
Natural products represent a rich resource for drug discovery
and are currently being exploited to target tumour angiogenesis.
A vast array of products of natural origin have been shown
to have anti-angiogenic potential in preclinical models, including
purified endogenous inhibitors, and exogenous compounds derived
from varied species of plant, animal and micro-organism. Over
a dozen of these agents have now entered clinical trial. This
review discusses evidence for the efficacy of this drug class
and key issues in the translation of preclinical results into
the development
of efficacious drugs for clinical use.
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