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Current
Cancer Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 10, Number 7, November 2010
Contents
Bone-Targeted Doxorubicin-Loaded Nanoparticles as a Tool for the Treatment of Skeletal Metastases Pp. 649-659
M. Salerno, E. Cenni, C. Fotia, S. Avnet, D. Granchi, F. Castelli, D. Micieli, R. Pignatello, M. Capulli, N. Rucci, A. Angelucci, A. Del Fattore, A. Teti, N. Zini, A. Giunti and N. Baldini
[Abstract] [Purchase
Article]
Oxaliplatin-mediated Inhibition of Survivin Increases Sensitivity of
Head and Neck Squamous Cell Carcinoma Cell Lines to Paclitaxel Pp. 660-669
Z. Khan, N. Khan, A.K. Varma, R.P. Tiwari, S. Mouhamad, G.B.K.S. Prasad and P.S. Bisen
[Abstract] [Purchase
Article]
The Role of Oxidative Stress and Anti-Oxidant Treatment in Platinum-Induced Peripheral Neurotoxicity Pp. 670-682
V.A. Carozzi, P. Marmiroli and G. Cavaletti
[Abstract] [Purchase
Article]
Is Src a Viable Target for Treating Solid Tumours? Pp. 683-694
B. Elsberger, B. Stewart, O. Tatarov and J. Edwards
[Abstract] [Purchase
Article]
Modular Branched Neurotensin Peptides for Tumor Target Tracing
and Receptor-Mediated Therapy: A Proof-of-Concept Pp. 695-704
C. Falciani, B. Lelli, J. Brunetti, S. Pileri, A. Cappelli, A. Pini, C. Pagliuca, N. Ravenni, L. Bencini, S. Menichetti, R. Moretti, M. De Prizio, M. Scatizzi and L. Bracci
[Abstract] [Purchase
Article] [Supplementary Material]
Paclitaxel Efficacy is Increased by Parthenolide via Nuclear
Factor-KappaB Pathways in In Vitro and In Vivo Human Non–Small Cell Lung Cancer Models Pp. 705-715
Z.W. Gao, D.L. Zhang and C.B. Guo
[Abstract] [Purchase
Article]
Wnt/β-Catenin/LEF-1 Signaling in Chronic Lymphocytic Leukemia
(CLL): A Target for Current and Potential Therapeutic Options Pp. 716-727
R.K. Gandhirajan, S.J. Poll-Wolbeck, I. Gehrke and K.-A. Kreuzer
[Abstract] [Purchase
Article]
New Insights of CTLA-4 into Its Biological Function in Breast Cancer Pp. 728-736
H. Mao, L. Zhang, Y. Yang, W. Zuo, Y. Bi, W. Gao, B. Deng, J. Sun, Q. Shao and X. Qu
[Abstract] [Purchase
Article]
Dynamic Simulations of Pathways Downstream of ERBB-Family,
Including Mutations and Treatments: Concordance with Experimental Results Pp. 737-757
N. Castagnino, L. Tortolina, A. Balbi, R. Pesenti, R. Montagna, A. Ballestrero, D. Soncini, E. Moran, A. Nencioni and S. Parodi
[Abstract] [Purchase
Article] [Supplementary Material]
DNA Topoisomerase II Enzymes as Molecular Targets for Cancer
Chemotherapy Pp. 758-771
K. Chikamori, A.G. Grozav, T. Kozuki, D. Grabowski, R. Ganapathi and M.K. Ganapathi
[Abstract] [Purchase
Article]
Concomitant CXCR4 and CXCR7 Expression Predicts Poor
Prognosis in Renal Cancer Pp. 772-781
C. D'Alterio, C. Consales, M. Polimeno, R. Franco, L. Cindolo, L. Portella, M. Cioffi, R. Calemma, L. Marra, L. Claudio, S. Perdonà, S. Pignata, G. Facchini, G. Cartenì, N. Longo, L. Pucci, A. Ottaiano, S. Costantini, G. Castello and S. Scala
[Abstract] [Purchase
Article]
Cancer Therapy By Targeting Hypoxia-Inducible Factor-1 Pp. 782-796
Y. Li and D. Ye
[Abstract] [Purchase
Article]
Abstracts
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Bone-Targeted Doxorubicin-Loaded Nanoparticles as a Tool for the Treatment of Skeletal Metastases
M. Salerno, E. Cenni, C. Fotia, S. Avnet, D. Granchi, F. Castelli, D. Micieli, R. Pignatello, M. Capulli, N. Rucci, A. Angelucci, A. Del Fattore, A. Teti, N. Zini, A. Giunti and N. Baldini
Bone metastases contribute to morbidity in patients with common
cancers, and conventional therapy provides only palliation
and can induce systemic side effects. The development of nanostructured
delivery systems that combine carriers with bone-targeting
molecules can potentially overcome the drawbacks presented
by conventional approaches. We have recently developed biodegradable,
biocompatible nanoparticles (NP) made of a conjugate between
poly (D,L-lactide-co-glycolic) acid and alendronate, suitable
for systemic administration, and directly targeting the site
of tumor-induced osteolysis. Here, we loaded NP with doxorubicin
(DXR), and analyzed the in vitro and in vivo activity of the
drug encapsulated in the carrier system. After confirming
the intracellular uptake of DXR-loaded NP, we evaluated the
anti-tumor effects in a panel of human cell lines, representative
for primary or metastatic bone tumors, and in an orthotopic
mouse model of breast cancer bone metastases. In vitro, both
free DXR and DXR-loaded NP, (58-580 ng/mL) determined a significant
dose-dependent growth inhibition of all cell lines. Similarly,
both DXR-loaded NP and free DXR reduced the incidence of metastases
in mice. Unloaded NP were ineffective, although both DXR-loaded
and unloaded NP significantly reduced the osteoclast number
at the tumor site (P = 0.014, P = 0.040,
respectively), possibly as a consequence of alendronate activity.
In summary, NP may act effectively as a delivery system of
anticancer drugs to the bone, and deserve further evaluation
for the treatment of bone tumors.
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Oxaliplatin-mediated Inhibition of Survivin Increases Sensitivity of
Head and Neck Squamous Cell Carcinoma Cell Lines to Paclitaxel
Z. Khan, N. Khan, A.K. Varma, R.P. Tiwari, S. Mouhamad, G.B.K.S. Prasad and P.S. Bisen
The present study deals with the evaluation of the
efficacy of oxaliplatin and paclitaxel combination as a potential
strategy in controlling HNSCC cell proliferation and the assessment
of correlation between occurrence of apoptosis and changes
in expression of survivin (IAP). The panel cell lines included
two HNSCC cell lines (Cal27 and NT8e) and one normal cell
line (293) with differential level of survivin expression
in accordance with chemosensitivity. The cytotoxicity and
effect of drugs on apoptosis was determined, separately and
in combination. Combined treatment of cells with paclitaxel
and oxaliplatin resulted in significantly higher cytotoxicity
as compared to individual single drug treatment. Cytotoxicity
was prominent in paclitaxel to oxaliplatin (pacl-oxal) sequence
treatment with an approximate two-fold increase in apoptosis
as compared to oxaliplatin to paclitaxel (oxal-pacl) sequence
treatment. Paclitaxel treatment also caused increased survivin
expression showing reduced apoptosis at low concentration.
Oxaliplatin, when combined with paclitaxel, decreased the
survivin level with increased cell death. Inhibition of survivin
by a small interfering RNA (siRNA) method also increased the
sensitivity of the cancer cell lines to paclitaxel whereas
over-expression of survivin in the transfected 293-cell line
provided resistance. In conclusion, the interaction between
drugs was synergistic and schedule-dependent. Survivin played
a critical role in paclitaxel resistance through the suppression
of apoptosis, and a significant induction of apoptosis was
observed when oxaliplatin was combined with paclitaxel at
least in part by the down-regulation of survivin.
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The Role of Oxidative Stress and Anti-Oxidant Treatment in Platinum-Induced Peripheral Neurotoxicity
V.A. Carozzi, P. Marmiroli and G. Cavaletti
Platinum-based anticancer drugs are a cornerstone
of the current antineoplastic treatment. However, their use
is limited by the onset of peripheral nervous system dysfunction,
which can be severe and persistent over a long period of time.
Among the several hypothesis proposed to explain this side
effect, evidence is increasing that dorsal root ganglia (DRG)
oxidative stress can be an important pathogenetic mechanism
and, possibly, a therapeutic target to limit the severity
of platinum-induced peripheral neurotoxicity but preserving
the anticancer effectiveness.
In fact, DRG energy failure has been suggested as a result
of mitochondrial DNA-platinum binding and several antioxidant
drugs have been tested in pre-clinical experiments and clinical
trials.
In this review, an update on the current knowledge on the
relationship existing between oxidative stress and platinum
drugs peripheral neurotoxicity will be given.
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Is Src a Viable Target for Treating Solid Tumours?
B. Elsberger, B. Stewart, O. Tatarov and J. Edwards
Src was the first proto-oncogene to be discovered.
Since then the role of Src has been extensively studied in
vitro. Src is a key regulator of multiple signal transduction
pathways and plays a significant part in cellular transformation.
Dysfunction of Src, through overexpression or increased activation,
has profound effects on basic cellular functions. Elevated
Src expression and/or activation is evident across a wide
range of solid tumour types, highlighting its place in carcinogenesis
and making it an attractive therapeutic target.
In this review, we discuss in vitro and in vivo data examining the role of Src in the different cellular processes
involved in oncogenesis and metastasis, covering the association
of Src with increased cell proliferation and survival, decreased
cellular adhesion, increased cell motility and invasiveness,
accelerated/advanced angiogenesis and pathogenic bone activity.
We also review evidence gathered from human tumour tissue
and translational research studies that further substantiates
the role of Src in oncogenesis. A summary of Src inhibitors
currently being developed and trialled as therapeutic agents
is provided to underline Src as a potential molecular target
for solid tumour therapy. Further clinical data are needed
to conclusively demonstrate that Src inhibitors have clinical
utility in the treatment of solid tumors.
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Article] [Supplementary Material]
Modular Branched Neurotensin Peptides for Tumor Target Tracing
and Receptor-Mediated Therapy: A Proof-of-Concept
C. Falciani, B. Lelli, J. Brunetti, S. Pileri, A. Cappelli, A. Pini, C. Pagliuca, N. Ravenni, L. Bencini, S. Menichetti, R. Moretti, M. De Prizio, M. Scatizzi and L. Bracci
The aim of this study was to demonstrate that oligo-branched
peptides can be effective either for spotlighting tumor cells
that overexpress peptide receptors, or for killing them, simply
by exchanging the functional moiety coupled to the conserved
receptor-targeting core. Tetra-branched peptides containing
neurotensin (NT) sequence are described here as selective
targeting agents for human colon, pancreas and prostate cancer.
Fluorophore-conjugated peptides were used to measure tumor
versus healthy tissue binding in human surgical samples, resulting
in validation of neurotensin receptors as highly promising
tumor-biomarkers. Drug-armed branched peptides were synthesized
with different conjugation methods, resulting in uncleavable
adducts or drug-releasing molecules. Cytotoxicity on human
cell lines from colon (HT-29), pancreas (PANC-1) or prostate
(PC-3) carcinoma indicated branched NT conjugated with MTX
and 5-FdU as the most active agents on PANC-1 (EC50 4.4e-007
M) and HT-29 (1.1e-007 M), respectively. Tetra-branched NT
armed with 5-FdU was used for in vivo experiments in HT-29-xenografted
mice and produced a 50% reduction in tumor growth with respect
to animals treated with the free drug. An unrelated branched
peptide carrying the same drug was completely ineffective. In vitro and in vivo results indicated that branched peptides
are valuable tools for tumor selective targeting.
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Paclitaxel Efficacy is Increased by Parthenolide via Nuclear
Factor-KappaB Pathways in In Vitro and In Vivo Human Non–Small Cell Lung Cancer Models
Z.W. Gao, D.L. Zhang and C.B. Guo
The focus of this study was to develop additive or synergistic
agents to chemosensitize the existing chemotherapeutic drug
in human non–small cell lung cancer (NSCLC). In this
study employing analyses of the NF-κB/
I-κB
kinase (IKK) signal cascade in a number of NSCLC cell lines,
we report the identification and characterization of parthenolide.
Parthenolide is a sesquiterpene lactone that can antagonize
paclitaxel-mediated NF-κB
nuclear translocation and activation through selectively targeting
I-κB
kinase (IKK) activity. Our results showed that parthenolide
dramatically lowered the effective dose of Paclitaxel needed
to induce cytotoxicity of a wide range of NSCLC cell lines.
An examination of pathways common to Paclitaxel and parthenolide
signaling revealed that this synergy was related to modulation
of the NF-κB/
I-κB
kinase (IKK) signal cascade through IKKβ.
Parthenolide alone induced apoptosis via the mitochondria/caspase
pathway. Moreover, in a human orthotopic NSCLC xenograft model,
a well-tolerated combination induces tumor regression. These
data strengthen the rationale for the use of parthenolide
to decrease the apoptotic threshold via a caspase-dependent
process and support the use of concurrent low doses of paclitaxel
in the treatment of NSCLC with paclitaxel chemoresistance.
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Wnt/β-Catenin/LEF-1 Signaling in Chronic Lymphocytic Leukemia
(CLL): A Target for Current and Potential Therapeutic Options
R.K. Gandhirajan, S.J. Poll-Wolbeck, I. Gehrke and K.-A. Kreuzer
There is a growing body of evidence that Wnt signaling, which
is already known to play a critical role in various types
of cancer, also has a vital function in B cell neoplasias,
particularly in chronic lymphocytic leukemia (CLL). It is
known that Wnt proteins are overexpressed in primary CLL cells
and several physiological inhibitors are partly inactivated
in this disease. Furthermore, β-cateninis
upregulated upon Wnt stimulation and cooperates with the transcription
factor lymphoid enhancer binding factor-1 (LEF-1). LEF-1 is excessively overexpressed in CLL cells by more
than 3,000-fold compared to normal B cells. Moreover, LEF-1
could be identified as an important regulator of pathophysiologically
relevant genes in CLL, and several Wnt/β-cateninsignaling
components substantially influence CLL cell survival.
In this review we summarize the current state of knowledge
about Wnt/β-catenin/LEF-1
signaling in CLL. Following a short overview of current treatment
concepts in CLL, we briefly describe Wnt signaling in human
cancers. We then discuss recent progress in understanding
regulation of the Wnt/β-catenin/LEF-1signaling
pathway in this disease. Based on the present scientific evidence
we highlight which components of this important signaling
pathway could serve as therapeutic targets in CLL. We then
present previous results gained from experimental approaches
to target different parts of the Wnt/β-catenin/LEF-1
cascade. Together with potentially promising approaches we
also critically reflect on the kind of difficulties and problems
that may arise using such strategies.
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New Insights of CTLA-4 into Its Biological Function in Breast Cancer
H. Mao, L. Zhang, Y. Yang, W. Zuo, Y. Bi, W. Gao, B. Deng, J. Sun, Q. Shao and X. Qu
CTLA-4 is a negative regulator of the proliferation and the
effector function of T-cells. Therefore, it might be
important to determine its expression on tumor cells and T-lymphocytes
from cancer patients, to investigate its role in initiating
and maintaining the neoplastic pathogenesis. CTLA-4 expression
was detected in breast tissue by immunohistochemical staining
and RT-PCR in 60 patients with breast cancer and 30 normal
controls. The levels of CTLA-4 on T lymphocytes in 33 of the
patients and 27 of the control group were determined by flow
cytometry. Isolated peripheral blood mononuclear cells (PBMCs)
were stimulated with phytohaemagglutinin (PHA). Stimulation
index and IL-2 level in the cell culture supernatant were
measured by MTT assay and ELISA method, respectively. Patients
showed strong expression of CTLA-4 in the tumor cells of all
specimens at both the protein and mRNA level, but only weakly
positive or negative expression in normal breast tissue. Patients
with higher mRNA level of CTLA-4 had obvious axillary lymph
nodes metastases and higher clinical stage. Spontaneous expression
of CD3+CTLA-4+ on PBMCs of tumor patients was also significantly
higher than that of the controls. Moreover, PBMCs derived
from patients with high expression of CD3+CTLA-4+ T-cells
showed poor responsiveness to PHA stimulation and lower IL-2
production. Therefore, abnormal expression and dysregulation
of CTLA-4 could partly explain the mechanism of evasion of
anti-tumor immune responses in breast cancer patients and
therefore highlight its importance in the development and
progression of breast cancer.
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Article] [Supplementary Material]
Dynamic Simulations of Pathways Downstream of ERBB-Family,
Including Mutations and Treatments: Concordance with Experimental Results
N. Castagnino, L. Tortolina, A. Balbi, R. Pesenti, R. Montagna, A. Ballestrero, D. Soncini, E. Moran, A. Nencioni and S. Parodi
The pathways downstream of ErbB-family proteins
are very important in BC, especially when considering treatment
with onco-protein inhibitors. We studied and implemented dynamic
simulations of four downstream pathways and described the
fragment of the signaling network we evaluated as a Molecular
Interaction Map. Our simulations, enacted using Ordinary Differential
Equations, involved 242 modified species and complexes, 279
reversible reactions and 111 catalytic reactions. Mutations
within a single pathway tended to be mutually exclusive; only
inhibitors acting at, or downstream (not upstream), of a given
mutation were active. A double alteration along two distinct
pathways required the inhibition of both pathways. We started
an analysis of sensitivity / robustness of our network, and
we systematically introduced several individual fluctuations
of total concentrations of independent molecular species.
Only very few cases showed significant sensitivity. We transduced
the ErbB2 over-expressing BC line, BT474, with the HRAS (V12)
mutant, then treated it with ErbB-family and phosphorylated
MEK (MEKPP) inhibitors, Lapatinib and U0126, respectively.
Experimental and simulation results were highly concordant,
showing statistical significance for both pathways and for
two respective endpoints, i.e. phosphorylated active forms
of ERK and Akt, p one tailed = .0072 and = .0022, respectively.
Working with a complex 39 basic species signaling network
region, this technology facilitates both comprehension and
effective, efficient and accurate modeling and data interpretation.
Dynamic network simulations we performed proved to be both
practical and valuable for a posteriori comprehension of biological
networks and signaling, thereby greatly facilitating handling,
and thus complete exploitation, of biological data.
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DNA Topoisomerase II Enzymes as Molecular Targets for Cancer
Chemotherapy
K. Chikamori, A.G. Grozav, T. Kozuki, D. Grabowski, R. Ganapathi and M.K. Ganapathi
DNA topoisomerase II enzymes regulate essential cellular processes
by altering the topology of chromosomal DNA. These
enzymes function by creating transient double-stranded breaks
in the DNA molecule that allow the DNA strands to pass through
each other and unwind or unknot tangled DNA. Because
of the integral role of topoisomerases in regulating DNA metabolism,
these enzymes are vital for cell survival. Several clinically
active antitumor agents target these enzymes. Mammalian
cells contain two topoisomerase II isozymes that are encoded
by different genes: topoisomerase IIα and IIβ Although, both isozymes are homologous and exhibit similar
catalytic activity, they are differentially regulated and
are involved in distinct biological functions. The topoisomerase
IIα and topoisomerase IIβ enzymes are regulated by post-translational modifications,
including sumoylation, ubiquitination and phosphorylation.
These post-translational modifications influence the biologic
and catalytic activity of the enzyme and affect sensitivity
of cells to topoisomerase II-targeted drugs. In this
review, we describe how the catalytic and biologic activity
of the topoisomerase II enzyme is regulated and discuss the
mechanisms by which chemotherapeutic agents that target these
enzymes function. Given the potential importance of
site-specific modifications, in particular phosphorylation,
in regulating sensitivity to topoisomerase II-targeted drugs,
we discuss the potential role of altered topoisomerase II
phosphorylation in development of drug resistance, which is
often a limiting factor in the treatment of cancer.
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Concomitant CXCR4 and CXCR7 Expression Predicts Poor
Prognosis in Renal Cancer
C. D'Alterio, C. Consales, M. Polimeno, R. Franco, L. Cindolo, L. Portella, M. Cioffi, R. Calemma, L. Marra, L. Claudio, S. Perdonà, S. Pignata, G. Facchini, G. Cartenì, N. Longo, L. Pucci, A. Ottaiano, S. Costantini, G. Castello and S. Scala
CXCR4 is a chemokine receptor implicated in the metastatic
process. The CXCR4 ligand, CXCL12, was shown to bind also
the CXCR7 receptor, a recently deorphanized chemokine receptor
whose signalling pathway and function are still controversial.
This study was conducted to determine patients clinic-pathological
factors and outcome according to the expressions of CXCR4
and CXCR7 in renal cell carcinoma (RCC).
CXCR4 and CXCR7 expression was evaluated in 223 RCC patients
through immunohistochemistry; moreover CXCR4 and CXCR7 was
detected in 49 others consecutive RCC patients trough RT-
PCR.
CXCR4 expression was low in 42/223 RCC (18,8%), intermediate
in 71/223 (31,9%) and high in 110/223 (49,3%). CXCR7 expression
was low in 44/223 RCC patients (19,8%), intermediate in 65/223
(29,1%) and high in 114/223 (51,1%). High CXCR4 and
high CXCR7 expression predicted shorter disease free survival.
In multivariate analysis, high CXCR4 expression (p= 0.0061),
high CXCR7 (p= 0.0194) expression and the concomitant high
expression of CXCR4 and CXCR7 (p= 0.0235) are independent
prognosis factors. Through RT-PCR, CXCR4 was overexpressed
in 36/49 and CXCR7 in 33/49 samples correlating with symptoms
at diagnosis and lymph nodes status. So we can hypothesize
that CXCR4 and CXCR7, singularly evaluated and in combination,
are valuable prognostic factors in RCC patients.
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Cancer Therapy By Targeting Hypoxia-Inducible Factor-1
Y. Li and D. Ye
Tumors are invariably less well-oxygenated than the normal
tissues from which they arose. Hypoxia-inducible factor-1
(HIF-1), a key transcriptional regulator, plays a central
role in the adaptation of tumor cells to hypoxia by activating
the transcription of genes, which regulate several biological
processes including angiogenesis, cell proliferation, survival,
glucose metabolism and migration. The expression, activity
and stability of HIF-1 is not only induced in response to
reduced oxygen availability but also modulated through PI-3K,
MAPK, autocrine signaling pathways, E3 ubiquitin ligases,
and other regulators. The regulators and effects of HIF-1
in cancer have intensively provided us a new clue for the
HIF-1 targeting anticancer therapy. This review evaluates
the HIF-1 structure, the regulation mechanisms, the functions
in cancer and corresponding anticancer strategies.
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