Current Cancer
Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 6, Number 1, February 2006
Contents
Rho GTPases: Promising Cellular Targets
for Novel Anticancer Drugs Pp. 1-14
Gerhard Fritz and Bernd Kaina
[Abstract]
Anti-Cancer Therapy: Targeting the Mevalonate Pathway
Pp. 15-37
Kelly M. Swanson and Raymond J. Hohl
[Abstract]
Estrogen Receptor Alpha: Impact of Ligands on
Intracellular Shuttling and Turnover Rate in Breast Cancer
Cells Pp. 39-64
Guy Leclercq, Marc Lacroix, Ioanna Laïos
and Guy Laurent
[Abstract]
The Stem Cell Factor Receptor/c-Kit as a Drug
Target in Cancer Pp. 65-75
J. Lennartsson and L. Rönnstrand
[Abstract]
Disruption of Metabolic Pathways – Perspectives
for the Treatment of Cancer Pp. 77-87
Eliana P. Araujo, José B. Carvalheira and Licio
A. Velloso
[Abstract]
Abstracts
[Back to top]
Rho GTPases: Promising Cellular Targets for Novel
Anticancer Drugs
Gerhard Fritz and Bernd Kaina
Ras-homologous (Rho) GTPases play a pivotal role in the regulation
of numerous cellular functions associated with malignant transformation
and metastasis. Rho GTPases are localized at membranes and
become activated upon stimulation of cell surface receptors.
In their GTP-bound (= active) state, Rho proteins bind to
effector proteins, thereby triggering specific cellular responses.
Members of the Rho family of small GTPases are key regulators
of actin reorganization, cell motility, cell-cell and cell-extracellular
matrix (ECM) adhesion as well as of cell cycle progression,
gene expression and apoptosis. Each of these functions is
of importance for the development and progression of cancer.
Furthermore, Rho guanine exchange factors (GEFs) are often
oncogenic and the expression level of Rho GTPases frequently
increases with malignancy. Rho proteins also affect cellular
susceptibility to DNA damaging agents, including antineoplastic
drugs and ionizing radiation (IR). Thus, modulation of Rho
driven mechanisms may influence the therapeutic efficiency
and/or the side effects of conventional antineoplastic therapy.
Because of their pleiotropic functions, Rho proteins appear
to be promising targets for the development of novel anticancer
drugs. Experimental approaches to inhibit Rho (and Ras) have
focused on the attenuation of their C-terminal isoprenylation.
This is because C-terminal lipid modification is required
for correct intracellular localization and function of Rho/Ras.
Inhibitors of farnesyltransferase (FTI), geranylgeranyltransferase
(GGTI) as well as of HMG-CoA-reductase (i. e. statins) have
been investigated with respect to their usefulness in tumor
therapy. The studies showed that these compounds affect tumor
progression and furthermore have impact on the frequency of
cell death induced by tumor therapeutics. A possible drawback
of inhibitors of isoprenylation is their poor selectivity
for individual Rho GTPases. Therefore, specific inhibitors
of individual Rho functions (notably RhoA-, RhoB-, Rac1- or
Cdc42-related functions) are predicted to be of great therapeutic
benefit. Indeed, compounds developed as specific inhibitors
of the RhoA-effector molecule Rho-kinase (ROK) have been demonstrated
to exert anti-metastatic activity in vivo.
[Back to top]
Anti-Cancer Therapy: Targeting the Mevalonate Pathway
Kelly M. Swanson and Raymond J. Hohl
The mevalonate pathway has become an important target for
anti-cancer therapy. Manipulation of this pathway results
in alteration of malignant cell growth and survival in cell
culture and animal models, with promising potential for application
in human cancers. Mevalonate is synthesized from 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA). Mevalonate is further metabolized to
farnesyl pyrophosphate (FPP), which is the precursor for sterols.
In addition, the farnesyl moiety from FPP is utilized for
post-translational modification of proteins including small
GTPases, such as Ras and Ras related proteins, which play
a role in malignant transformation of cells. FPP is a precursor
for geranylgeranyl pyrophosphate (GGPP), which is similarly
involved in post-translational modification of proteins. There
has been intense interest in manipulating the pathway through
HMG-CoA reductase inhibition. More recently, the focus has
been on manipulating the pathway by post-translational modification
of key regulatory proteins through farnesyl prenyl transferase
(FPTase) or geranylgeranyl prenyl transferase (GGPTase) inhibition.
This review focuses on the mevalonate pathway and the application
of rational drug therapies to manipulate this pathway. Included
in the review are a summary of agents demonstrating success
in preclinical investigations such as; farnesyl transferase
inhibitors, geranylgeranyl transferase inhibitors, dual inhibitors,
statins, bisphosphonates, histone deacetylase inhibitors and
other compounds. While these agents have shown preclinical
success, translation to success in clinical trials has been
more difficult. These clinical trials are reviewed along with
evaluation of some of the potential problems with these agents
in their clinical application.
[Back to top]
Estrogen Receptor Alpha: Impact of Ligands on Intracellular
Shuttling and Turnover Rate in Breast Cancer Cells
Guy Leclercq, Marc Lacroix, Ioanna Laïos
and Guy Laurent
Estrogen receptors (α
and ß) are members of the steroid/thyroid nuclear receptors
superfamily of ligand-dependent transcription factors. Impact
of the α
isoform of estrogen receptor (ER) on breast cancer etiology
and progression is now well established. Current therapeutic
strategy to treat ER-positive breast cancer relies on the
blockade of ER trancriptional activity by antiestrogens. Data
accumulated during the last five years on the mechanism of
action of ER enable one to foresee new strategies. These data
indeed reveal that ER is not statically bound to DNA at promoter
sites of genes regulating cell proliferation and/or differentiation,
but rather behaves as a very mobile protein continuously shuttling
between targets located within various cellular compartments
(i.e. membrane, microsomes, nucleus...). This allows the receptor
to generate both non-genomic and genomic responses. Ligands,
growth factors and second messengers produced downstream of
activated membrane receptors modulate ER-mediated responses
by interfering with the traffic patterns of the receptor,
as well as by locally blocking its transient anchorage. Changes
in ER turnover rate associated with these regulatory processes
seem also to strongly influence the ability of the receptor
to mediate gene transactivation. The present paper surveys
these biological data and analyzes how they may be integrated
into new drug design programs aimed at expanding our therapeutic
armamentarium against breast cancer.
[Back to top]
The Stem Cell Factor Receptor/c-Kit as a Drug Target
in Cancer
J. Lennartsson and L. Rönnstrand
Tyrosine phosphorylation has a key role in intracellular
signaling. Inappropriate proliferation and survival cues in
tumor cells often occur as a consequence of unregulated tyrosine
kinase activity. Much of the current development of anti-cancer
therapies tries to target causative proteins in a specific
manner to minimize side-effects. One attractive group of target
proteins is the kinases. c-Kit is a receptor tyrosine kinase
that normally controls the function of primitive hematopoietic
cells, melanocytes and germ cells. It has become clear that
uncontrolled activity of c-Kit contributes to formation of
an array of human tumors. The unregulated activity of c-Kit
may be due to overexpression, autocrine loops or mutational
activation. This makes c-Kit an excellent target for cancer
therapies in these tumors. In this review we will highlight
the current knowledge on the signal transduction molecules
and pathways activated by c-Kit under normal conditions and
in cancer cells, and the role of aberrant c-Kit signaling
in cancer progression. Recent advances in the development
of specific inhibitors interfering with these signal transduction
pathways will be discussed.
[Back to top]
Disruption of Metabolic Pathways – Perspectives
for the Treatment of Cancer
Eliana P. Araujo, José B. Carvalheira and Licio
A. Velloso
Several growth-promoting signaling pathways have tight molecular
connections with metabolic-related signal transduction systems.
By controlling these pathways, cancer cells gain autonomy
over energy-acquiring systems and, thus, expand their potential
for proliferation. Here, we discuss the use of drug and antisense
oligonucleotide approaches to inhibit metabolic pathways in
cancer cells and their potential use in the therapeutics of
cancer.
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