| Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 9, Number 8, October 2009
Contents
Special Board Members Issue
Editorial Pp. 822
Effects of Oxymatrine from Ku Shen on Cancer Cells
Pp. 823-826
J.W. Ho, P.L.N. Hon and W.O. Chim
[Abstract] [Purchase
Article] [PMID:
19538168 PubMed - indexed for MEDLINE]
Titanium and Vanadium Complexes as Anticancer Agents
Pp. 827-842
I. Kostova
[Abstract] [Purchase
Article] [PMID:
19538167 PubMed - indexed for MEDLINE]
Of Humans and Hamsters: The Hamster Buccal Pouch Carcinogenesis
Model as a Paradigm for Oral Oncogenesis and Chemoprevention
Pp. 843-852
S. Nagini
[Abstract] [Purchase
Article] [PMID:
19538166 PubMed - indexed for MEDLINE]
Tyrosine Kinase Inhibitors for the Treatment of Chronic
Myeloid Leukemia Pp. 853-863
M. Tolomeo, F. Dieli, N. Gebbia and D. Simoni
[Abstract] [Purchase
Article] [PMID:
19538165 PubMed - indexed for MEDLINE]
Synthesis, Molecular Targets, and Antitumor Activities
of Substituted Tetrahydro-1-Oxopyrano[4,3-b][1]Benzopyrans
and Nanogels for Drug Delivery Pp. 864-876
E.M. Perchellet, J.-P.H. Perchellet, C.K. Ganta, D.L.
Troyer, A. Shi and D.H. Hua
[Abstract] [Purchase
Article] [PMID:
19538164 PubMed - indexed for MEDLINE]
A Novel Strategy for Advanced Pancreatic Cancer-Progression
of Molecular Targeting Therapy Pp. 877-881
S. Osada and K. Yoshida
[Abstract] [Purchase
Article] [PMID:
19538163 PubMed - indexed for MEDLINE]
Recent Advances in Validating MDM2 as a Cancer Target
Pp. 882-903
E.R. Rayburn, S.J. Ezell and R. Zhang
[Abstract] [Purchase
Article] [PMID:
19538162 PubMed - indexed for MEDLINE]
Novel Anti-Prostate Cancer Curcumin Analogues That
Enhance Androgen Receptor Degradation Activity Pp.
904-912
Q. Shi, C.C.-Y. Shih and K.H. Lee
[Abstract] [Purchase
Article]
Cytotoxic Anticancer Candidates from Terrestrial Plants
Pp. 913-942
Y.-W. Chin, K.D. Yoon and J. Kim
[Abstract] [Purchase
Article]
Abstracts
[Back to top]
Editorial
ACA-MC is now in its ninth volume. Besides regular
general issues reviewing major advances in various areas of
anti-cancer agents, two Hot Topic Issues have been published
in 2009 with exciting recent developments in the field of
enzymes and other proteins inhibitors. For 2010, a large number
of authors have proposed review articles covering
the latest developments in medicinal chemistry and rational
drug design. Several Hot Topic Issues will also be published,
the first one on prostate cancer therapy.
In this special 2009 Editorial Board Members, nine members
of the ACA-MC Editorial Board present various and recent advances
in the continuous efforts to develop efficient anti-cancer
therapies.
The first paper written by Dr. J. Ho reviews the effects of
oxymatrine, an active constituent isolated from roots of Sophora
flavescens, on cell division of cancer cells.
In the second paper, Dr. I. Kostova describes the antitumor
properties of titanium and vanadium complexes. Though the
exact mechanism of action for these compounds has not been
determined, their interaction with DNA seems to be at least
partially responsible for their antitumor effects.
Dr. Kostova says,“It
is a pleasure to thank and express my appreciation to the
editorial staff for the work they have been doing and continue
to do for the recognition and prosperity of ANTI-CANCER AGENTS
IN MEDICINAL CHEMISTRY!”
The third paper from Dr. S. Nagini is devoted to hamster buccal
pouch carcinogenesis model as a useful system for the study
of synthetic and natural chemopreventive agents.
In the fourth review, Drs. M. Tolomeo, F. Dieli, N. Gebbia
and D. Simoni reported the in vitro and in vivo results
obtained with the novel tyrosine kinase inhibitors developed
to overcome imatinib resistance in Bcr-Abl expressing hematological
disorders.
In the fifth paper, the synthesis, the molecular targets,
and the antitumor activities of substituted tetrahydro 1-oxopyrano[4,3-b][1]benzopyrans
and nanogels for drug delivery are presented by Drs. E. Perchellet,
J.-P. Perchellet, C. Ganta, D. Trover, A. Shi, and D. Hua.
It is well-known that the efficacy of the treatments for pancreas
cancer is not satisfactory. In the sixth review, Drs. S. Osada
and K. Yoshida reported recent studies on the vitamin K3 (menadione,
2-methyl-1,4-naphthoquinone; VK3)-induced growth inhibitory
effect through ERK pathway as a novel approach to advanced
pancreatic cancer therapy.
The MDM2 oncogene is overexpressed in various human cancers.
Recent studies have demonstrated that many proteins regulate
the MDM2-p53 interaction, and that MDM2 may have p53-independent
oncogenic functions. A better understanding of the regulation
of MDM2 and of the MDM2-p53 interaction is necessary for novel
MDM2 inhibitors. Drs. E. Rayburn, S. Ezell, and R. Zhang discussed
recent advances in validating MDM2 as a cancer target in the
seventh paper.
The eighth paper is devoted to curcumin analogues. Many natural
and synthetic curcumin analogues have been previously reported
to possess anticancer activity. However the knowledge of their
mechanism of action and of their biological targets remains
to be improved. In this review, Drs Q. Shi, C. Shih, and K.H.
Lee reported novel anti-prostate cancer curcumin analogues
that enhance androgen receptor degradation activity.
Natural products are a large source of cytotoxic compounds.
In the last review, the structures and cytotoxicities of new
organic small molecules from terrestrial plants are presented
by Drs. Y.-W. Chin, K. Yoon and J. Kim.
Prof. Michelle Prudhomme
Universite Blaise Pascal –
C.N.R.S. U.F.R. de Recherche Scientifique et Technique
UMR 6504 Synthese, Et Etude
De Systemes A Interet Biologique (S.E.E.S.I.B.)
24, Avenue des Landais
63177 Aubiere Cedex
France
Tel: +33 4 73 40 71 24
Fax: +33 4 73 40 77 17
E-mail: Michelle.PRUDHOMME@univ-bpclermont.fr
[Back to top]
[Purchase
Article] [PMID:
19538168 PubMed - indexed for MEDLINE]
Effects of Oxymatrine from Ku Shen on Cancer Cells
J.W. Ho, P.L.N. Hon and W.O. Chim
Oxymatrine is one of active constituents isolated from Ku
Shen, which is the dried root of Sophora flavescens
Ait. The herb used in different herbal formulations is commonly
known with specific pharmacological properties for treatment
of liver disorders and other diseases such as arrhythmia,
eczema and skin disorders, leukopenia and bronchitis. Sophora
flavescens Ait is known to enhance liver functions and
reduce hepatotoxicity due to oxidative stress and liver injury.
The protection of cells from chemical toxicity is important
in reducing liver damage. Reduction of oxidative stress by
active components of herbal medicines is shown to be beneficial
and important in regulating the normal functions of the liver.
In this study, effects of oxymatrine on cancer cells after
treatment of the cell line with DMSO were reported. This review
described for cells without oxymatrine pre-treatment, cell
injury was implicated as indicated by the decrease in cell
viability. Ku Shen showed protective effects on cells
from the DMSO-induced toxicity. The results show that oxymatrine
can inhibit the G2 and M
phase of H4IIE. The findings suggest that anti-inflammatory
constituents such as oxymatrine could mediate cell division
of cancer cells and reduce cell cytotoxicity due probably
to its capacity to inhibit the metabolic activation of hepato-toxin,
a critical factor in the pathogenesis of chemical-induced
liver injury.
[Back to top] [Purchase
Article] [PMID:
19538167 PubMed - indexed for MEDLINE]
Titanium and Vanadium Complexes as Anticancer Agents
I. Kostova
A series of complexes containing titanium and vanadium as
a metal centers have shown to possess a wide spectrum of antitumor
properties. These series belong to the non-platinum metal
antitumor agents that appear to offer a different alternative
for cancer chemotherapy which do not follow mechanism of action
of the platinum complexes. The antitumor activity of both
titanocene and vanadocene complexes has been established against
various animal and xenografted human tumors. The exact mechanism
of action for these compounds has not been determined, the
target is unknown and even the exact chemical nature of the
formulated solutions is still unknown. It has been proposed
that these species interact with DNA, inhibiting the cell
cycle. However, the antitumor mechanism of the titanocenes
is most likely a complex pathway, probably involving a number
of different biological molecules related to the transport
and delivery of Ti species into cancer cells, and, after hydrolysis,
subsequent interaction with nucleic acids and/or proteins
and/or other potential coordinating constituents present in
the intracellular environment. The tendency to hydrolyze seems
to be one of the hypotheses for the tumor-inhibiting potency
of the titanocene dihalides. Vanadium compounds exert preventive
effects against chemical carcinogenesis on animals, by modifying,
mainly, various xenobiotic enzymes, inhibiting, thus, carcinogen-derived
active metabolites. The anticarcinogenic effects of vanadium,
in combination to its low toxicity, established also, by its
administration in humans, suggest vanadium as a candidate
antineoplastic agent against human cancer. New complexes being
more potent and less toxic favor this perspective. The use
of these species as chemotherapeutic agents remains relatively
unexplored and waits for future investigation. Research proceeded
during the recent decades, enriched our knowledge on the chemical
and biochemical properties, as well as the mechanisms of systemic,
cellular and molecular antitumor effects of titanium and vanadium
compounds.
[Back to top] [Purchase
Article] [PMID:
19538166 PubMed - indexed for MEDLINE]
Of Humans and Hamsters: The Hamster Buccal Pouch Carcinogenesis
Model as a Paradigm for Oral Oncogenesis and Chemoprevention
S. Nagini
Oral squamous cell carcinoma (OSCC), a common malignancy worldwide,
is an important contributor to the overall international cancer
burden. Squamous cell carcinomas (SCCs) induced by 7,12-dimethylbenz[a]-
anthracene (DMBA) in the HBP reiterate many of the features
observed in human OSCCs. The major risk factors associated
with human oral cancer such as tobacco, betel quid and alcohol
promote HBP carcinogenesis. SCCs induced by DMBA in the cheek
pouch of Syrian hamsters are morphologically and histologically
similar to human OSCC. Like human oral carcinogenesis, HBP
carcinogenesis is a multistep process that involves sequential
progression from hyperplasia to invasive carcinoma through
varying degrees of dysplasia. In addition, HBP tumours express
several biochemical and molecular markers that are also expressed
in human OSCC. Multiple signaling pathways are dysfunctional
in both human and hamster OSCCs. In particular, cell
proliferation, apoptosis and angiogenesis are intricately
interlinked in malignant transformation of the HBP mucosa
by DMBA. The HBP carcinogenesis model is the best-known animal
system for intervention by chemopreventive agents because
of easy accessibility for examination, and follow-up of lesions.
A number of synthetic and natural products have been documented
to exhibit chemopreventive efficacy in the HBP model. Chemoprevention
studies in the HBP model can serve as a crucial link in the
potential efficacy assessment of candidate agents for oral
cancer prevention and therapy.
[Back to top] [Purchase
Article] [PMID:
19538165 PubMed - indexed for MEDLINE]
Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid
Leukemia
M. Tolomeo, F. Dieli, N. Gebbia and D. Simoni
Imatinib mesylate (Gleevec) is a drug unique for the treatment
of certain forms of cancer. It works by targeting, and turning
off, specific tyrosine kinase proteins that cause the uncontrolled
cell growth and the inhibition of apoptosis in cancer cells.
Imatinib was designed on the basis of the structure of the
ATP binding site of the Abl protein kinase with the aim to
stabilize the inactive form of Bcr-Abl, an oncoprotein involved
in malignant transformation in chronic myelogenous leukemia
(CML). However, imatinib can also target other tyrosine kinase
proteins different from Bcr-Abl such as Kit, that is the suspected
cause of gastrointestinal stromal tumor (GIST). Despite successful
clinical results observed in the last years, the long-term
effects of imatinib and its ability to completely eradicate
CML are still unknown. Moreover, similar to many other anti-cancer
drugs, clinical resistance to imatinib has emerged. In this
review we will discuss the in vitro and in vivo results
obtained with the novel tyrosine kinase inhibitors developed
to overcome imatinib resistance in Bcr-Abl expressing hematologiocal
disorders.
[Back to top] [Purchase
Article] [PMID:
19538164 PubMed - indexed for MEDLINE]
Synthesis, Molecular Targets, and Antitumor Activities of
Substituted Tetrahydro-1-Oxopyrano[4,3-b][1]Benzopyrans and
Nanogels for Drug Delivery
E.M. Perchellet, J.-P.H. Perchellet, C.K. Ganta, D.L.
Troyer, A. Shi and D.H. Hua
A class of substituted 1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyrans
(tricyclic pyrones; TPs) was synthesized from a one-pot condensation
reaction of 6-substituted 4-hydroxy-2-pyrones and cyclohexenecarboxaldehydes.
The reaction involves a 6π-electrocyclic
ring closing process, and stereo- and regioselectivities were
examined. C3-Pyridyl-containing TPs may represent a novel
synthetic class of microtubule de-stabilizing anti-cancer
drugs that inhibit macromolecule synthesis, tubulin polymerization,
and the proliferation of a spectrum of wild-type and multi-drug
resistant tumor cell lines in vitro. A linear skeleton
with a N-containing aromatic ring attached at C3
of the top A-ring, a central pyran B-ring and a six-membered
bottom C-ring with no alkylation at C7 are required for the
antitumor activities of the lead compounds, a 3-pyridyl benzopyran
(code name H10) and its 2-pyridyl regioisomer
(code name H19). In addition to interacting
with the colchicine-binding site to inhibit tubulin polymerization
and increase the mitotic index, these TP analogs also block
the cellular transport of nucleosides to inhibit DNA synthesis
more effectively than other antimitotic agents. The anticancer
potential of TPs in vivo is suggested by the fact
that i.p. injections of H10 decrease the
growth of solid tumors in mice inoculated with lung or ovarian
carcinomas. A drug-delivery system involving nanogels was
studied. We incorporated the anticancer compound, 6-hydroxymethyl-1,4-anthracenedione
(code name AQ10) into PEG-PEI
nanogel, and found that AQ10-encapsulated
nanogel PEG-PEI is significantly more effective in altering
the growth of Pan 02 (pancreatic cancer) cells compared to
AQ10 or nanogel PEG-PEI alone. Since AQ10
is insoluble in water, PEG-PEI encapsulation represents a
way to solubilize and deliver this as well as other poorly
soluble compounds.
[Back to top] [Purchase
Article] [PMID:
19538163 PubMed - indexed for MEDLINE]
A Novel Strategy for Advanced Pancreatic Cancer-Progression
of Molecular Targeting Therapy
S. Osada and K. Yoshida
Despite recent progress in surgical procedures and therapeutic
modalities, the outcomes of treatment for pancreas cancer
are still not satisfactory. Chemotherapy can provide symptom
relief in some patients, but its impact on survival has been
modest and it can lead to unacceptable levels of toxicity.
To develop novel and potentially less toxic forms of cancer
therapy, molecular targeting therapy is being based initially
on the knowledge of cellular signal transduction. The new
approaches in treatment have originated from biochemical studies
in combination with recent technology to block the progress
of carcinogenesis or invasion. As one of the most successful
of such agents, an antibody or antagonist against the receptor
of epidermal growth factor or vascular endothelial growth
factor has been proven in carcinoma treatment, and recent
steps have been taken to apply this type of treatment to pancreas
cancer. However, there are still serious problems for these
receptor-associated signaling blockers; namely, the antibody
or antagonist has no efficacy if the target cells grow independently
of the receptor-related signaling. On the other hands, extra-cellular
signal-regulated kinase (ERK) is well known to represent a
convergent point for the intracellular signaling pathways
in whole cancer cells. In the present, by reviewing our recent
studies that evaluate the usefulness of the vitamin K3 (menadione,
2-methyl-1,4-naphthoquinone; VK3)-induced growth inhibitory
effect through ERK pathway, this novel approach to cancer
therapy and its potential in future clinical applications
will be highlighted.
[Back to top] [Purchase
Article] [PMID:
19538162 PubMed - indexed for MEDLINE]
Recent Advances in Validating MDM2 as a Cancer Target
E.R. Rayburn, S.J. Ezell and R. Zhang
The MDM2 oncogene is overexpressed in various human cancers.
Its expression correlates with the phenotypes of high-grade,
late-stage, and more resistant tumors. The auto-regulatory
loop between MDM2 and the tumor suppressor p53 has long been
considered the epitome of a rational target for cancer therapy.
As such, many novel agents have been generated to interfere
with the interaction of the two proteins, which results in
the activation of p53. Among these agents are several small
molecule inhibitors synthesized based upon the crystal structures
of the MDM2-p53 complex. With use of high-throughput screening,
several specific and effective agents for inhibition of the
protein-protein interaction were discovered. Recent investigations,
however, have demonstrated that many proteins regulate the
MDM2-p53 interaction, and that MDM2 may have p53-independent
oncogenic functions. In order for novel MDM2 inhibitors to
be translated to the clinic, it is necessary to obtain a better
understanding of the regulation of MDM2 and of the MDM2-p53
interaction. In particular, the implications of various interactions
between certain regulator(s) and MDM2/p53 under different
circumstances need to be elucidated to determine which pathway(s)
represent the best targets for therapy. Targeting both MDM2
itself and regulators of MDM2 and the MDM2-p53 interaction,
or use of MDM2 inhibitors in combination with conventional
treatments, may improve prospects for tumor eradication.
[Back to top] [Purchase
Article]
Novel Anti-Prostate Cancer Curcumin Analogues
That Enhance Androgen Receptor Degradation Activity
Q. Shi, C.C.-Y. Shih and K.H. Lee
The androgen receptor (AR) plays a crucial role in the physiological
and pathological functions of androgen. As a transcription
factor, the AR modulates androgen activity by regulating the
transcription of target genes that are involved in numerous
physiological functions and pathological disorders, such as
acne vulgaris, androgenetic alopecia, benign prostate hyperplasia
(BPH), and prostate cancers. Although many natural and synthetic
curcumin analogues have been reported to possess anticancer
activity through a common cytotoxic property against proliferating
tumor cells, none has been reported to inhibit cancer cell
growth through a more specific mechanism or target in the
cancer cells. Recently, new curcumin analogues were studied
extensively regarding their synthesis, structure-activity
(i.e., anticancer activity) relationships, and mechanism of
action. These compounds, such as ASC-J9 and
its analogues (3 and 4),
have now been shown to inhibit prostate cancer proliferation
through a novel mechanism of enhancing AR degradation.
[Back to top]
[Purchase
Article]
Cytotoxic Anticancer Candidates from Terrestrial Plants
Y.-W. Chin, K.D. Yoon and J. Kim
Naturally occurring cytotoxic compounds have been considered
to be a valuable pool of lead compounds in the development
of potential anticancer drugs. Currently, some cytotoxic compounds
of terrestrial plants are being used as cancer therapeutic
drugs and more candidates are under clinical trials along
with cytotoxic small molecules of terrestrial microorganisms
and marine organisms. In the present review, the structures
and representative cytotoxicities of new organic small molecules
(over 200 molecules) obtained from terrestrial plants between
2001 and 2004 are presented. |
