Current Cancer Drug Targets, Volume 5, No. 5, 2005
Contents
Antiproliferative Efficacy of Angiotensin II
Receptor Blockers in Prostate Cancer Pp.307-323
Hiroji
Uemura, Noboru Nakaigawa, Hitoshi Ishiguro and Yoshinobu Kubota
Inflammation and Cancer: When NF-kB Amalgamates the Perilous Partnership Pp.325-344
Marina
A. Dobrovolskaia and Serguei V. Kozlov
Molecular Targets from VHL Studies into the
Oxygen-Sensing Pathway
Pp.345-356
M.A.
Maynard and M. Ohh
The Therapeutic Potential of 4-1BB (CD137) in
Cancer Pp.357-363
Kyung-Ok
Nam, Woo Jin Kang, Byoung S. Kwon, Sung Jin Kim and Hyeon-Woo Lee
The MCM Complex: Its Role in DNA Replication
and Implications for Cancer Therapy Pp.365-380
Ming
Lei
Abstracts
[Back to top] Antiproliferative Efficacy of Angiotensin II
Receptor Blockers in Prostate Cancer
Hiroji Uemura, Noboru Nakaigawa, Hitoshi Ishiguro and Yoshinobu Kubota
An apparent low
prevalence of cancer in hypertensive patients receiving angiotensin converting
enzyme inhibitors is reported; however, the molecular mechanisms have not been
elucidated. Angiotensin-II (Ang-II) is well known to be associated with
hypertension, as a main peptide of the renin-angiotensin system, and its
detailed molecular mechanisms have recently been elucidated. For instance,
Ang-II directly activates the mitogenic signal transduction pathway through the
angiotensin-II type-1 (AT1) receptor in smooth muscle cells and cardiac
myocytes. Ang-II receptor blockers (ARBs), a class of antihypertensive agent,
suppress signal transduction pathways mediated by growth factors such as
epidermal growth factor (EGF), through the AT1 receptor. Our studies
demonstrated that an ARB had the potential for antiproliferative effects and
inhibition of angiogenesis in prostate cancer cells. The AT1 receptor is
categorized in the guanosine phosphate binding protein-coupled receptors
(GPCRs), which are viewed as critical regulators of the interactions between
epithelial and stromal cells. Hence, we consider that in overcoming prostate
cancer, it is very important to inhibit GPCR signaling in cancer cells by ARBs.
It is unclear how prostate cancer growth changes from being hormone dependent
to independent, and no effective therapy has therefore been developed. Our
clinical data revealed that ARB administration decreased prostate specific
antigen (PSA) and improved performance status in patients with hormone-refractory
prostate cancer. This review provides an insight into the key role of Ang-II
and the possibility of ARBs for molecular targeting of mitogenesis and
angiogenesis in prostate cancer.
[Back to top] Inflammation and Cancer: When NF-kB Amalgamates the Perilous Partnership
Marina
A. Dobrovolskaia and Serguei V. Kozlov
Chronic
inflammation has long been suggested to constitute a risk factor for a variety
of epithelial cancers such as malignancies of prostate, cervix, esophagus,
stomach, liver, colon, pancreas, and bladder. An inflammatory response is
typically accompanied by generation of free radicals, stimulation of cytokines,
chemokines, growth and angiogenic factors. Free radicals, capable of both directly
damaging DNA and affecting the DNA repair machinery, enhance genetic
instability of affected cells, thus contributing to the first stage of
neoplastic transformation also known as “initiation”. Cytokines and growth
factors can further promote tumor growth by stimulating cell proliferation,
adhesion, vascularization, and metastatic potential of later stage tumors.
Nuclear factor
kappa B (NF-kB) is a family of ubiquitously expressed
transcription factors that are widely believed to trigger both the onset and
the resolution of inflammation. NF-kB also
governs the expression of genes encoding proteins essential in control of
stress response, maintenance of intercellular communications, and regulation of
cellular proliferation and apoptosis. Recent data have expanded the concept of
inflammation as a critical component in carcinogenesis suggesting new
anti-inflammatory therapies for a complementary approach in treating a variety
of tumor types. These observations highlighted the NF-kB pathway as an attractive avenue for drug
discovery and development. The present review will outline recent advances in
our understanding of NF-kB function
in the inflammatory processes and its input in tumor initiation/promotion, as
well as summarize the development of animal and cell culture models for
validating drug candidates with NF-kB-modulating
activities, and applications of the latter in cancer therapy.
[Back to top] Molecular Targets from VHL Studies into the
Oxygen-Sensing Pathway
M.A.
Maynard and M. Ohh
Inheritance of a
faulty von Hippel-Lindau (VHL) tumor suppressor gene is the cause of VHL
disease, a rare multisystemic autosomal dominant disorder characterized by the
development of hypervascular tumors in a number of organs, including the
retina, brain, spine, pancreas, adrenal gland, and the kidney. Recent
discoveries have demonstrated that the VHL gene product pVHL serves as a
substrate-recognition component of an E3 ubiquitin ligase complex that targets
hypoxia-inducible factor (HIF) transcription factor for polyubiquitination and
subsequent degradation. Accordingly, tumor cells devoid of functional pVHL show
an inappropriate accumulation of HIF, as well as downstream HIF-target genes,
such as vascular endothelial growth factor (VEGF), a potent angiogenic
factor. Furthermore, HIF has been found to be elevated in many human cancers
further underscoring its common significance in oncogenesis. These and other
related recent findings have shed significant insight into the mechanisms governing
mammalian cellular oxygen homeostasis and how disruptions in this
oxygen-sensing pathway can lead to tumorigenesis. Next generation anti-cancer
drugs will undoubtedly emerge from our understanding of the molecular pathways
governing normal cellular metabolism, growth and differentiation that have gone
awry during neoplastic transformation, and studies in VHL disease will serve as
one of the proving grounds for the efficacy of ‘designer’ anti-cancer drugs
tailored against the VHL-HIF pathway.
[Back to top] The Therapeutic Potential of 4-1BB (CD137) in
Cancer
Kyung-Ok Nam, Woo Jin Kang, Byoung S. Kwon, Sung Jin Kim
and Hyeon-Woo Lee
Techniques
for modulating immune cells for cancer therapy have been widely studied. One
key approach that is being clinically tested is developing tumor-destructive
cell-mediated immune responses by regulating co-stimulatory molecules. 4-1BB
(CD137), a member of the TNF receptor family, is expressed following activation of T and NK cells. Recently,
it has been reported that DCs also express 4-1BB. Crosslinking of 4-1BB
provides a potent co-stimulatory signal for lymphocytes via signal
transduction pathways that modulate a number of cellular responses. One
remarkable response is stimulation of anti-tumor activity in vivo and in
vitro. We here review the potential role of 4-1BB in cancer immunotherapy
focusing on the cellular and molecular mechanisms involved.
[Back to top] The MCM Complex: Its Role in DNA Replication
and Implications for Cancer Therapy
Ming
Lei
The MCM complex
controls the once per cell cycle DNA replication in eukaryotic cells. In a
process known as DNA replication licensing, it primes chromatin for DNA
replication by binding origins of DNA replication during the late M to early G1
phase of the cell cycle. Activated by S phase promoting protein kinases, the
origin-bound MCM complexes unwind the double stranded DNA at the origins,
recruit DNA polymerases and initiate DNA synthesis. Coupled with the initiation
of DNA replication in the S phase, the MCM complexes move away from replication
origins as a component of the DNA replication fork, likely serving as DNA
helicases. Their departure deprives replication origins the ability to
re-initiate DNA replication for the reminder of the cell cycle. Because of its
vital role in genome duplication in proliferating cells, deregulation of the
MCM function results in chromosomal defects that may contribute to
tumorigenesis. The MCM proteins are highly expressed in malignant human cancers
cells and pre-cancerous cells undergoing malignant transformation. They are not
expressed in differentiated somatic cells that have been withdrawn from the
cell cycle. Therefore, these proteins are ideal diagnostic markers for cancer
and promising targets for anti-cancer drug development. In this article, I will
overview the structures and functions of the MCM complex with an effort to
integrate insights from recent biochemical and structural studies. Discussions
will also cover activities and structures of the complex that may be useful for
the development of drug screens.