| Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 6, Number 5, September 2006
Contents
Mechanisms of Cancer Prevention by Green and Black
Tea Polyphenols Pp. 389-406
L.A. Beltz, D.K. Bayer, A.L. Moss and I.M. Simet
[Abstract]
Anti-Angiogenic Cancer Therapy Based on Integrin αvβ3
Antagonism Pp. 407-428
W. Cai and X. Chen
[Abstract]
Medicinal Plants from Peru: A Review of Plants as
Potential Agents Against Cancer Pp. 429-444
G.F. Gonzales and L.G. Valerio, Jr.
[Abstract]
Targeting the Hedgehog Signaling Pathway with Small
Molecules Pp. 445-449
A.S. Kiselyov
[Abstract]
Potential Deployment of Angiotensin I Converting Enzyme
Inhibitors and of Angiotensin II Type 1 and Type 2 Receptor
Blockers in Cancer Chemotherapy Pp. 451-460
A. Molteni, S. Heffelfinger, J.E. Moulder, B.D. Uhal and
W. J. Castellani
[Abstract]
Selected Players in the Inflammation Cascade and Drugs
That Target These Inflammation Genes Against Metastasis Pp.
461-468
S. Alikunju and S. Pillarisetti
[Abstract]
Recent Improvements in the Use of Synthetic Peptides
for a Selective Photodynamic Therapy Pp. 469-488
R. Schneider, L. Tirand, C. Frochot, R. Vanderesse, N.
Thomas, J. Gravier, F. Guillemin and M. Barberi-Heyob
[Abstract]
Anti-Cancer Activities of 1,4-Naphthoquinones: A QSAR
Study Pp. 489-499
R.P. Verma
[Abstract]
Abstracts
[Back to top]
Mechanisms of Cancer Prevention by Green and Black
Tea Polyphenols
L.A. Beltz, D.K. Bayer, A.L. Moss and I.M. Simet
Drinking green tea is associated with decreased frequency
of cancer development. This review outlines the wide range
of mechanisms by which epigallocatechin gallate (ECGC) and
other green and black tea polyphenols inhibit cancer cell
survival. EGCG suppressed androgen receptor expression and
signalling via several growth factor receptors. Cell cycle
arrest or apoptosis involved caspase activation and altered
Bcl-2 family member expression. EGCG inhibited telomerase
activity and led to telomere fragmentation. While at high
concentrations polyphenols had pro-oxidative activities, at
much lower levels, anti-oxidative effects occurred. Nitric
oxide production was reduced by EGCG and black tea theaflavins
by suppressing inducible nitric oxide synthase via
blocking nuclear translocation of the transcription factor
nuclear factor-κB
as a result of decreased IκB
kinase activity. Polyphenols up- or down-regulated activity
of a number of key enzymes, including mitogen-activated protein
kinases and protein kinase C, and increased or decreased protein/mRNA
levels, including that of cyclins, oncogenes, and tumor suppressor
genes. Metastasis was inhibited via effects on urokinase
and matrix metalloproteinases. Polyphenols reduced angiogenesis,
in part by decreasing vascular endothelial growth factor production
and receptor phosphorylation. Recent work demonstrated that
EGCG reduced dihydrofolate reductase activity, which would
affect nucleic acid and protein synthesis. It also acted as
an aryl hydrocarbon receptor antagonist by directly binding
the receptor’s molecular chaperone, heat shock protein
90. In conclusion, green and black tea polyphenols act at
numerous points regulating cancer cell growth, survival, and
metastasis, including effects at the DNA, RNA, and protein
levels.
[Back to top]
Anti-Angiogenic Cancer Therapy Based on Integrin
αvβ3
Antagonism
W. Cai and X. Chen
Angiogenesis, the formation of new blood vessels from
pre-existing vasculature, is a fundamental process during
cancer progression. Anti-angiogenic strategies have been pursued
for cancer treatment and prevention of cancer recurrence and
metastasis. Integrins are a family of cell adhesion molecules
consisting of two non-covalently bound transmembrane subunits
(α
and β).
Much research has demonstrated that integrin signaling plays
a key role in tumor angiogenesis and metastasis. Integrin
αvβ3
is highly expressed on activated endothelial cells and tumor
cells but is not present in resting endothelial cells and
most normal organ systems, which makes it a suitable target
for anti-angiogenic cancer therapy. In this review we will
focus on cancer therapy targeting integrin αvβ3
while other integrins (such as α5β1,
αllbβ3,
αvβ5,
α6β4)
will only be briefly mentioned when relevant. MEDI-522 (a
humanized anti-human integrin αvβ3
monoclonal antibody) and Cilengitide (cyclic peptidic integrin
αvβ3/αvβ5
antagonist) are currently in clinical trials for anti-angiogenic
cancer therapy. Small interfering RNA (siRNA) that specifically
silences integrin αv
and/or β3
was reported to cause tumor shrinkage in preclinical xenograft
models. Combination of anti-integrin αvβ3
therapy and other therapeutic approaches (such as chemotherapy,
radiotherapy and gene therapy) has also been applied for cancer
treatment. Mounting evidence suggests that there is potentially
synergistic effect of combined therapeutic approaches over
single modality alone. Lastly, integrin targeted delivery
(drugs, genes, and radioisotopes) and imaging (optical, MRI,
ultrasound, SPECT, and PET) is discussed in detail.
[Back to top]
Medicinal Plants from Peru: A Review of Plants
as Potential Agents Against Cancer
G.F. Gonzales and L.G. Valerio, Jr.
Natural products have played a significant role in drug
discovery and development especially for agents against cancer
and infectious disease. An analysis of new and approved drugs
for cancer by the United States Food and Drug Administration
over the period of 1981-2002 showed that 62% of these cancer
drugs were of natural origin. Natural compounds possess highly
diverse and complex molecular structures compared to small
molecule synthetic drugs and often provide highly specific
biological activities likely derived from the rigidity and
high number of chiral centers. Ethnotraditional use of plant-derived
natural products has been a major source for discovery of
potential medicinal agents. A number of native Andean and
Amazonian medicines of plant origin are used as traditional
medicine in Peru to treat different dis-eases. Of particular
interest in this mini-review are three plant materials endemic
to Peru with the common names of Cat’s claw (Uncaria
tomentosa), Maca (Lepidium meyenii), and Dragon’s
blood (Croton lechleri) each having been scientifically
investigated for a wide range of therapeutic uses including
as specific anti-cancer agents as originally discovered from
the long history of traditional usage and anecdotal information
by local population groups in South America. Against this
background, we present an evidence-based analysis of the chemistry,
biological properties, and anti-tumor activities for these
three plant materials. In addition, this review will discuss
areas requiring future study and the inherent limitations
in their experimental use as anti-cancer agents.
[Back to top]
Targeting the Hedgehog Signaling Pathway with
Small Molecules
A.S. Kiselyov
In addition to the potential stem cells offer for regenerative
medicine, they also rapidly are becoming a center of focus
in oncology. There are several developmental pathways that
are involved in the deregulated signaling in stem cells resulting
in tumorigenesis. For example, aberrant activation of the
Hedgehog (Hh) pathway has been associated
with numerous malignancies including basal cell carcinoma,
medulloblastoma, prostate, pancreatic and breast cancers.
In vivo evidence suggests the antagonism of excessive
Hh signaling may provide a route to unique mechanism-based
anti-cancer therapies. This review summarizes recent developments
in targeting cell-surface proteins and intracellular targets
from the Hh pathway with small molecules. Hh
signaling is triggered by lipid-modified Hh proteins
that exert their activity via a series of transmembrane
receptors (Patched, Ptc and Smoothened, Smo).
Smoothened (Smo) is a 7-TM protein reported to be
the most druggable target in the Hh signaling cascade.
We further review several published programs geared towards
identification and profiling of synthetic antagonists of Smo.
Challenges and perspectives of this approach are also discussed.
[Back to top]
Potential Deployment of Angiotensin I Converting
Enzyme Inhibitors and of Angiotensin II Type 1 and Type 2
Receptor Blockers in Cancer Chemotherapy
A. Molteni, S. Heffelfinger, J.E. Moulder, B.D. Uhal
and W. J. Castellani
There is significant evidence that both angiotensin I
converting enzyme inhibitors (ACEI) and type 1 and type 2
angiotensin 2 (A2) receptor blockers may inhibit tumor growth.
The finding is supported by many reports where these two classes
of drugs showed cytostatic effects on the cultures of several
lines of both normal and neoplastic cells. These drugs often
transformed the cellular biochemical structures, especially
in neoplastic cell lines. The same drugs also delayed the
growth of different types of tumors in a variety of experimental
animals (breast and lung carcinoma in mice; sarcomas, squamous
cell carcinomas and hepatocellular carcinomas in rats), and
there are a few reports of successful treatment of a limited
number of cases of Kaposi sarcoma and gliomas with these drugs.
Retrospective studies in hypertensive subjects treated with
ACEI or A2 receptor blockers also seem to indicate that the
incidence and growth of different neoplasms was delayed when
these patients were compared to hypertensive patients receiving
alternate medications. There is strong indication that the
pharmacologic effect of these drugs may be exerted by reduction
or inhibition of the synthesis of angiotensin 2. A2 is a powerful
mitogen and its effect on cellular growth is exerted through
stimulation of many factors, including transforming growth
factor β
(TGFβ),
epidermal growth factor (EGF), smooth muscle actin (SMA),
and tyrosine kinase. A2 also regulates apoptotic mechanisms
and angiogenesis. The pharmacologic action of most of these
drugs, however, is not necessarily limited to downregulaton
of A2. Many ACEI, especially those containing the sulfhydryl
(SH group), possess antioxidant or metalloprotease inhibitory
properties per se. These experimental and retrospective
data justify clinical testing of these drugs in appropriate
randomized trials. Several such trials are currently in process.
If these trials confirm the experimental and retrospective
studies, these agents will provide a significant contribution
to the therapeutic treatment of many malignancies in humans.
[Back to top]
Selected Players in the Inflammation Cascade
and Drugs That Target These Inflammation Genes Against Metastasis
S. Alikunju and S. Pillarisetti
Despite many recent advances the prognosis of cancer
patients with metastasis still remains poor. In metastatic
invasion, tumor cells interact with endothelial cells through
several distinct adhesion molecules. Adherent tumor cells
extravasate into tissues by degrading basement membranes with
matrix degrading enzymes such as heparanases and matrix metalloproteinases.
Endothelial expression of matrix degrading enzymes and adhesion
molecules are under the control of inflammatory cytokines.
These inflammatory proteins and the signaling pathways involved
in the expression of these genes are under intense investigation
as therapeutic targets to prevent tumor growth and metastasis.
The current review focuses on selected players of the inflammation
cascade and drugs that target these inflammatory genes.
[Back to top]
Recent Improvements in the Use of Synthetic Peptides
for a Selective Photodynamic Therapy
R. Schneider, L. Tirand, C. Frochot, R. Vanderesse,
N. Thomas, J. Gravier, F. Guillemin and M. Barberi-Heyob
Photodynamic therapy (PDT) is a relatively new cytotoxic
treatment, predominantly used in anti-cancer approaches, that
depends on the retention of photosensitizers in tumor and
their activation after light exposure. Photosensitizers are
photoactive compounds such as porphyrins and chlorins that
upon photoactivation, effect strongly localized oxidative
damage within the target cells. The ability to confine activation
of the photosensitizer by restricting illumination to the
tumor allows for a certain degree of selectivity. Nevertheless,
the targeted delivery of photosensitizers to defined cells
is a major problem in PDT of cancer, and one area of importance
is photosensitizer targeting. Alterations or increased levels
in receptor expression of specific cellular type occur in
the diseased tissues. Therefore, photosensitizers can be covalently
attached to molecules such as peptides, leading to a receptor-mediated
targeting strategy. These active-targeting approaches may
be particularly useful for anti-vascular PDT. Moreover, it
has been shown that the photocytotoxicity of photodynamic
drugs could be enhanced by delivering high amounts of a photosensitizer
into subcellular organelles such as the nucleus where nucleic
acids represent target molecules sensitive to photodamage.
The recent progresses in the use of active-targeting strategy
with synthetic peptides and the interest of using an active-targeting
strategy in PDT, which could allow efficient cellular internalization
of photosensitizers, are described in this review.
[Back to top]
Anti-Cancer Activities of 1,4-Naphthoquinones:
A QSAR Study
R.P. Verma
Quinone moieties are present in many drugs such as anthracyclines,
daunorubicin, doxorubicin, mitomycin, mitoxantrones and saintopin,
which are used clinically in the therapy of solid cancers.
The cytotoxic effects of these quinones are mainly due to
the following two factors: (i) inhibition of DNA topoisomerase-II
and, (ii) formation of semiquinone radical that can transfer
an electron to oxygen to produce super oxide, which is catalyzed
by flavoenzymes such as NADPH-cytochrome-P-450 reductase.
Both semiquinone and super oxide of quinones can generate
the hydroxyl radical, which is the cause of DNA strand breaks.
1,4-naphthoquinone contains two quinone groups that have the
ability to accept one or two electrons to form the corresponding
radical anion or di-anion species. It is probably dependent
on the quinone redox cycling that yields "reactive oxygen
species" (ROS) as well as arylation reactions, which
is common to quinones for biological relevance. In the present
review, an attempt has been made to collect the cytotoxicity
data on different series of 1,4-naphthoquinones against four
different cancer cell lines that are L1210, A549, SNU-1, and
K562, which were acquired by using identical method, and has
been discussed in terms of QSAR (quantitative structure-activity
relationships) to understand the chemical-biological interactions.
QSAR results have shown that the cytotoxic activities of 1,4-naphthoquinones
depend largely on their hydrophobicity.
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