Current Cancer
Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 6, Number 2, March 2006
Contents
Integrins in Cancer Treatment Pp.
89-105
Johannes A. Eble and Jörg Haier
[Abstract]
Signal Transducers and Activators of Transcription (STATs):
Novel Targets of Chemopreventive and Chemotherapeutic Drugs
Pp. 107-121
Lidija Klampfer
[Abstract]
Liposomal Muramyl Tripeptide Phosphatidylethanolamine:
Targeting and Activating Macrophages for Adjuvant Treatment
of Osteosarcoma Pp. 123-133
A. Nardin, M.-L. Lefebvre, K. Labroquère,
O. Faure and J.-P. Abastado
[Abstract]
Signaling Pathways and Intracellular Targets of
Sulforaphane Mediating Cell Cycle Arrest and Apoptosis
Pp. 135-145
L. Gamet-Payrastre
[Abstract]
Telomeres and Telomerase: Pharmacological Targetsfor
New Anticancer Strategies? Pp. 147-180
F. Pendino, I. Tarkanyi, C. Dudognon, J. Hillion, M. Lanotte,
J. Aradi and E. Ségal-Bendirdjian
[Abstract]
Abstracts
[Back to top]
Integrins in Cancer Treatment
Johannes A. Eble and Jörg Haier
Anchorage-independent growth, anoikis resistance, and most
steps of metastasis formation are integrinmediated or -dependent
processes, which are characteristics of malignant tumor cells.
Acting as oncogenes or tumor suppressor genes, integrins may
be involved in the oncogenic transformation of normal cells
and their growth into a primary tumor node. During tumorigenesis,
a switch of integrin expression can be observed, inasmuch
as growth-promoting and growth-attenuating integrins are up-
and down-regulated, respectively. ECM-ligand binding to an
integrin initiates signals, which eradiating from the integrins
are transmitted via different yet interconnecting
pathways and elicit various cell functions, such as morphological
changes, adhesion, migration and gene activation. Any of these
functions takes part in the metastatic cascade of tumor progression,
such as epithelial-to-mesenchymal transition of carcinoma
cells, tumor cell contact with the basement membrane, invasion
into neighboring tissues as well as production and activation
of ECM-degrading MMPs. Besides their direct involvement in
tumor progression as cell surface molecules on tumor cells,
integrins in normal cells surrounding a tumor, e.g.
endothelial cells, can also determine various cancer characteristics,
such as tumor-induced neoangiogenesis and immune resistance.
Hence, integrins are relevant pharmacological targets in tumor
biology. Spurred by the recent success to generate pharmaceutical
mimetics of RGD-dependent integrins and by the integrin´s
easy accessibility on the cell surface, the hope is rising
that also RGD-independent integrins, such as the collagen-
and laminin-binding integrins, can be pharmacologically manipulated
to fight integrin-dependent functions of cancer cells, which
are necessary and at least partially specific for their proliferation
and progression.
[Back to top]
Signal Transducers and Activators of Transcription
(STATs): Novel Targets of Chemopreventive and Chemotherapeutic
Drugs
Lidija Klampfer
A family of latent cytoplasmic transcription factors, signal
transducers and activators of transcription (STATs), mediates
the responsiveness of cells to several cytokines and growth
factors. Although mutations of STATs have not been described
in human tumors, the activity of several members of the family,
such as STAT1, STAT3 and STAT5, is deregulated in a variety
of human tumors. STAT3 and STAT5 acquire oncogenic potential
through constitutive phosphorylation on tyrosine, and their
activity has been shown to be required to sustain a transformed
phenotype. Disruption of STAT3 and STAT5 signaling in transformed
cells therefore represents an excellent opportunity for targeted
cancer therapy. In contrast to STAT3 and STAT5, STAT1 negatively
regulates cell proliferation and angiogenesis and thereby
inhibits tumor formation. Consistent with its tumor suppressive
properties, STAT1 and its downstream targets have been shown
to be reduced in a variety of human tumors and STAT1 deficient
mice are highly susceptible to tumor formation.
In recent years we have gained mechanistic understanding
of the pathways whereby STATs convey signals from the cytoplasm
to the nucleus. In addition, several endogenous regulators
of the JAK/STAT pathway have been described - and their mechanism
of action revealed - that profoundly affect signaling by STATs.
Both should greatly facilitate the design of drugs with potential
to modulate STAT signaling and to restore the homeostasis
in tissues where STATs have gone awry.
[Back to top]
Liposomal Muramyl Tripeptide Phosphatidylethanolamine:
Targeting and Activating Macrophages for Adjuvant Treatment
of Osteosarcoma
A. Nardin, M.-L. Lefebvre, K. Labroquère,
O. Faure and J.-P. Abastado
About one third of osteosarcoma patients develop lung metastasis
refractory to chemotherapy. Recent studies indicate that biological
response modifiers activating the patient’s immune system
may help controlling minimal residual disease via
pathways distinct from those used by cytotoxic drugs, and
therefore prove effective against tumor resistance. Muramyl
tripeptide phosphatidylethanolamine (MTP-PE) is a synthetic
lipophilic glycopeptide capable of activating monocytes and
macrophages to a tumoricidal state. When intercalated in multilamellar
liposomes (L-MTP-PE) and injected intravenously, it targets
lung, liver, and spleen macrophages. Therapeutic activity
of L-MTP-PE was demonstrated in several preclinical models
of experimental lung metastasis and in clinical trials in
dogs with osteosarcoma. Although macrophage activation was
shown to be directly involved in the in vivo anti-metastatic
activity of this molecule, cytokine and chemokine secretion
by activated macrophages could induce recruitment and stimulation
of other immune cells, which may in turn indirectly contribute
to the anti-tumor effect. L-MTP-PE has undergone clinical
development in humans. In early trials, most side effects
of L-MTP-PE were minimal. L-MTP-PE showed signs of efficacy
in treatment of patients with recurrent osteosarcoma and the
encouraging results from phase II studies led to a phase III
trial conducted by the Children’s Oncology Group in
patients with newly diagnosed high-grade osteosarcoma. Patients
were treated with or without L-MTP-PE in combination with
multi-drug chemotherapy in adjuvant setting; significantly
higher overall survival and disease free survival were observed
in the group receiving L-MTP-PE..
[Back to top]
Signaling Pathways and Intracellular Targets of Sulforaphane
Mediating Cell Cycle Arrest and Apoptosis
L. Gamet-Payrastre
Epidemiological studies have revealed an inverse correlation
between the intake of cruciferous vegetables and the risk
of certain types of cancer. In animal studies, results suggest
that the anti-cancerous effect of cruciferous vegetables is
due to isothiocyanates that exist as thioglucoside conjugates
in a variety of edible plants, including broccoli cabbage
for example. Among isothiocyanates (ITC), Sulforaphane (SF)
has received a great deal of interest due to its potent anti-tumoral
properties in carcinogen-treated animals. The molecular pathways
mediating the effects of SF have not been fully elucidated.
However, many studies have shown that SF (as well as other
ITCs) can induce phase II drug metabolizing enzymes in
vitro as well as in animals. This commonly occurs via
the activation of a basic leucine zipper transcription factor,
Nrf2. In addition, accumulating evidence now indicates that
SF can inhibit the proliferation of cancer cells in culture
through the induction of cell cycle arrest via the
regulation of cell cycle protein levels and/or cyclin-dependent
kinase activity, tubulin polymerization and histone acetylation.
Furthermore, ITCs have been shown to induce apoptotic cell
death via a P53 dependent or independent pathway.
Here, it is proposed to review the different intracellular
targets involved in the in vitro effects of SF in
various cancer cell lines. The relationship will then be discussed
that exists between the various cell signaling pathways involved
in this effect, and finally, the important aspects will be
identified that must be addressed to fully understand the
exact mechanism of action of SF.
[Back to top]
Telomeres and Telomerase: Pharmacological Targetsfor
New Anticancer Strategies?
F. Pendino, I. Tarkanyi, C. Dudognon, J. Hillion, M. Lanotte,
J. Aradi and E. Ségal-Bendirdjian
Telomeres are located at the ends of eukaryotic chromosomes.
Human telomerase, a cellular reverse transcriptase, is a ribonucleoprotein
enzyme that catalyzes the synthesis and extension of telomeric
DNA. It is composed of at least, a template RNA component
(hTR; human Telomerase RNA) and a catalytic subunit, the telomerase
reverse transcriptase (hTERT). The absence of telomerase is
associated with telomere shortening and aging of somatic cells,
while high telomerase activity is observed in over 85% of
human cancer cells, strongly indicating its key role during
tumorigenesis. Several details regarding telomere structure
and telomerase regulation have already been elucidated, providing
new targets for therapeutic exploitation. Further support
for anti-telomerase approaches comes from recent studies indicating
that telomerase is endowed of additional functions in the
control of growth and survival of tumor cells that do not
depend only on the ability of this enzyme to maintain telomere
length. This observation suggests that inhibiting telomerase
or its synthesis may have additional anti-proliferative and
apoptosis inducing effect, independently of the reduction
of telomere length during cell divisions. This article reviews
the basic information about the biology of telomeres and telomerase
and attempts to present various approaches that are currently
under investigation to inhibit its expression and its activity.
We summarize herein distinct anti-telomerase approaches like
antisense strategies, reverse transcriptase inhibitors, and
G-quadruplex interacting agents, and also review molecules
targeting hTERT expression, such as retinoids and evaluate
them for their therapeutic potential.
"They conceive a certain theory, and everything
has to fit into that theory. If one little fact will not fit
it, they throw it aside. But it is always the facts that will
not fit in that are significant".
“Death on the Nile”. Agatha Christie.
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