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Current
Cancer Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 10, Number 4, June 2010
Contents
Inhibitors of the Sphingosine Kinase Pathway as Potential
Therapeutics Pp. 354-367
M.R. Pitman and S.M. Pitson
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Pharmacological Inhibition of Poly(ADP-ribose)
Polymerase (PARP) Activity in PARP-1 Silenced Tumour Cells
Increases Chemosensitivity to Temozolomide and to a N3-Adenine
Selective Methylating Agent Pp. 368-383
L. Tentori, A. Muzi, A.S. Dorio, M. Scarsella, C. Leonetti,
G.M. Shah, W. Xu, E. Camaioni, B. Gold, R. Pellicciari, F.
Dantzer, J. Zhang and G. Graziani
[Abstract] [Purchase
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Targeting CREB for Cancer Therapy: Friend
or Foe Pp. 384-391
X. Xiao, B.X. Li, B. Mitton, A. Ikeda and K.M. Sakamoto
[Abstract] [Purchase
Article]
Molecular Pathways in the Progression of Hormone-Independent
and Metastatic Prostate Cancer Pp. 392-401
B. Wegiel, S. Evans, R. Hellsten, L.E. Otterbein, A. Bjartell
and J.L. Persson
[Abstract] [Purchase
Article]
Recent Advances in Understanding Hormonal
Therapy Resistant Prostate Cancer Pp. 402-410
K.V. Donkena, H. Yuan and C.Y. Young
[Abstract] [Purchase
Article]
Human Mesenchymal Stem Cells (hMSCs) as Targets of
DNA Damaging Agents in Cancer Therapy Pp.
411-421
S. Cruet-Hennequart, Á.M. Prendergast, F.P. Barry and
M.P. Carty
[Abstract] [Purchase
Article]
Tyrosine Kinase Inhibitors Gefitinib, Lapatinib and
Sorafenib Induce Rapid Functional Alterations in Breast Cancer
Cells Pp. 422-431
S. Carloni, F. Fabbri, G. Brigliadori, P. Ulivi, R. Silvestrini,
D. Amadori and W. Zoli
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Article]
Abstracts
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Inhibitors of the Sphingosine Kinase Pathway as Potential
Therapeutics
M.R. Pitman and S.M. Pitson
Sphingosine kinase (SK) 1 and 2 are lipid kinases that
phosphorylate sphingosine to form sphingosine-1 phosphate,
a potent signalling molecule with pleiotrophic effects. SK1
is commonly up-regulated in tumours and its inhibition or
genetic ablation has been shown to slow tumour growth as well
as sensitise cancer cells to other chemotherapeutics. Therefore,
SK1 is of particular interest as a target therapeutic intervention
in cancer. Initial SK inhibitors were sphingos-ine derivatives
and displayed efficacy in a number of disease models, establishing
a premise for SK inhibition for anti-proliferative and anti-inflammatory
therapies, even though these compounds had questionable specificity.
More recently, a number of new SK inhibitors have been developed
that display higher affinities and greater specificity for
the SKs. Here we summarise the current small molecule inhibitors
and related approaches for targeting the SKs, and their in
vitro and in vivo efficacy. Furthermore, we
highlight findings demonstrating the success of SK inhibition
in cancer and a range of other disease models that promotes
the continued interest in targeting the SKs for therapeutic
benefit.
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Pharmacological Inhibition of Poly(ADP-ribose)
Polymerase (PARP) Activity in PARP-1 Silenced Tumour Cells
Increases Chemosensitivity to Temozolomide and to a N3-Adenine
Selective Methylating Agent
L. Tentori, A. Muzi, A.S. Dorio, M. Scarsella, C. Leonetti,
G.M. Shah, W. Xu, E. Camaioni, B. Gold, R. Pellicciari, F.
Dantzer, J. Zhang and G. Graziani
We recently demonstrated that poly(ADP-ribose)
polymerase (PARP)-1 is involved in angiogenesis and tumour
aggressiveness. In this study we have compared the influence
of abrogation of PARP-1 expression by stable gene silencing
to that of the pharmacological inhibition of cellular PARP
activity using PARP-1/-2 inhibitors on the chemosensitivity
of tumour cells to the wide spectrum methylating agent temozolomide
(TMZ) and to the N3-adenine selective methylating agent {1-methyl-4-[1-methyl-4-(3-methoxysulfonylpropanamido)pyrrole-2-carboxamido]-pyrrole-2-carboxamido}propane
(Me-Lex). Silencing of PARP-1 in melanoma or cervical carcinoma
lines enhanced in vitro sensitivity to TMZ and Me-Lex,
and induced a higher level of cell accumulation at the G2/M
phase of cell cycle with respect to controls. GPI 15427, which
inhibits both PARP-1 and PARP-2, increased sensitivity to
TMZ and Me-Lex both in PARP-1-proficient and -deficient cells.
However, it induced different cell cycle modulations depending
on PARP-1 expression, provoking a G2/M
arrest only in PARP-1 silenced cells. Treatment of PARP-1
silenced cells with TMZ or Me-Lex resulted in a more exten-sive
phosphorylation of Chk-1 and p53 as compared to PARP-1 proficient
cells. The combination of the methylating agents with GPI
15427 increased Chk-1 and p53 phosphorylation both in PARP-1
proficient or deficient cells. When mice challenged with PARP-1
silenced melanoma cells were treated with the TMZ and PARP
inhibitor combination there was an additional reduction in
tumour growth with respect to treatment with TMZ alone. These
results suggest the involvement of PARP-2 or other PARPs,
in the repair of DNA damage provoked by methylating agents,
highlighting the importance of targeting both PARP-1 and PARP-2
for cancer therapy.
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Targeting CREB for Cancer Therapy: Friend
or Foe
X. Xiao, B.X. Li, B. Mitton, A. Ikeda and
K.M. Sakamoto
The cyclic-AMP response element-binding protein (CREB)
is a nuclear transcription factor activated by phosphorylation
at Ser133 by multiple serine/threonine (Ser/Thr) kinases.
Upon phosphorylation, CREB binds the transcriptional co-activator,
CBP (CREB-binding protein), to initiate CREB-dependent gene
transcription. CREB is a critical regulator of cell differentiation,
proliferation and survival in the nervous system. Recent studies
have shown that CREB is involved tumor initiation, progression
and metastasis, supporting its role as a proto-oncogene. Overexpression
and over-activation of CREB were observed in cancer tissues
from patients with prostate cancer, breast cancer, non-small-cell
lung cancer and acute leukemia while down-regulation of CREB
in several distinct cancer cell lines resulted in inhibition
of cell proliferation and induction of apoptosis, suggesting
that CREB may be a promising target for cancer therapy. Although
CREB, as a transcription factor, is a challenging target for
small molecules, various small molecules have been discovered
to inhibit CREB phosphorylation, CREB-DNA, or CREB-CBP interaction.
These results suggest that CREB is a suitable transcription
factor for drug targeting and therefore targeting CREB could
represent a novel strategy for cancer therapy.
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Molecular Pathways in the Progression of
Hormone-Independent and Metastatic Prostate Cancer
B. Wegiel, S. Evans, R. Hellsten, L.E. Otterbein, A. Bjartell
and J.L. Persson
Once prostate cancer becomes castration resistant, cancer
cells may rapidly gain the ability to invade and to metastasize
to lymph nodes and distant organs. The progression through
hormone-dependent to hormone-independent/castration-resistant
and metastatic PCa is poorly understood. In this review paper,
we provide an overview on the cellular and molecular mechanisms
underlying the process of tumor cell invasion and metastasis
in prostate cancer. We specifically presented the most recent
findings on the role of multiple cellular signaling pathways
including androgen receptor (AR), mitogen-activated protein
kinases (MAPK), Akt, transforming growth factor
β (TGFβ),
interleukin-6 (IL-6) and vascular endothelial growth factor
(VEGF) in the development of hormone-independent/castration-resistant
prostate cancer. In addition, we also discussed the recent
findings on signatures of gene expression during prostate
cancer progression. Our overviews on the novel findings will
help to gain better understanding of the complexity of molecular
mechanisms that may play an essential role for the development
of castration-resistant and metastatic prostate cancer. It
will also shed light on the identifying specific targets and
design effective therapeutic drug candidates.
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Recent Advances in Understanding Hormonal
Therapy Resistant Prostate Cancer
K.V. Donkena, H. Yuan and C.Y. Young
Androgen deprivation therapy has been the major treatment
for advanced prostate cancer (PCa) and has shown to prolong
life. However, remissions are temporary and patients almost
inevitably progress to become castration-resistant prostate
cancer (CRPC). CRPC is almost incurable even when treated
with docetaxel that may have a slight life prolonging effect
on CRPC patients. Interestingly, most of CRPC still express
androgen receptor (AR) and depend on the AR for growth. Recently
it has been suggested that AR may act as a tumor suppressor
in normal prostatic epithelial cells, while in PCa cells AR
becomes oncogenic, even under androgen deprivation states.
The mechanisms for the latter are still under intensive investigations.
A number of studies showed that, in fact, AR signaling is
increased under an androgen-depleted environment. The mechanisms
suggested in these studies including AR mutations, AR overexpression
by gene amplifica-tion and other mechanisms that allow activation
by low androgen levels or by other endogenous steroids, increased
local de novo synthesis of androgens will be discussed. Moreover,
developments and tests in clinical trials in CRPC of a number
of novel agents interrupting AR signaling mediated PCa growth
will also be discussed.
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Human Mesenchymal Stem Cells (hMSCs) as Targets of
DNA Damaging Agents in Cancer Therapy
S. Cruet-Hennequart, Á.M. Prendergast, F.P. Barry and
M.P. Carty
Human mesenchymal stem cells (hMSCs) consist of cells
that can differentiate into mesenchymal tissues, including
osteoblasts, adipocytes and chondrocytes. hMSCs constitute
a particular stem cell niche in the stromal compartment of
the bone marrow, and play a role in maintaining the normal
function of haematopoietic stem cells. Furthermore, hMSCs
localise to solid tumours, and can modulate cancer cell function
through secretion of paracrine signals. While hMSCs, either
in the bone marrow, or in the microenvironment of a tumour,
will be targeted by DNA damaging agents used in cancer therapy,
the response of the hMSC population to DNA damage is not well
understood. As progenitor cells, genomic DNA damage to hMSCs
during cancer therapy could generate a population of surviving
cells that can go on to give rise to secondary tumours. A
better understanding of the response of hMSCs to DNA damage
could provide new in-sights into the effects of cancer treatments,
as well as into the development of treatment-associated secondary
cancers. This article reviews the relationship of hMSCs to
cancer, with a focus on the response of hMSCs to DNA damaging
agents.
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Tyrosine Kinase Inhibitors Gefitinib, Lapatinib and
Sorafenib Induce Rapid Functional Alterations in Breast Cancer
Cells
S. Carloni, F. Fabbri, G. Brigliadori, P. Ulivi, R. Silvestrini,
D. Amadori and W. Zoli
Alterations in tyrosine kinase expression or functionality
have been linked to tumor growth, and detailed analysis of
tyrosine kinase pathways has led to the development of novel
anticancer drugs based on their inhibition. The aim of the
present work was to examine the cytotoxicity and cellular
alterations correlated with multidrug resistance mechanisms
induced by three tyrosine kinase inhibitors, lapatinib, sorafenib
and gefitinib. The study was performed on three breast cancer
cell lines (BRC-230, MCF-7 and SkBr3). Drug-induced growth
inhibition was detected by Sulforhodamine B analysis. Apoptosis,
cytosolic calcium alteration, extrusion pump activity and
mitochondrial membrane depolarization were assessed by flow
cytometry. Drug efflux-related gene expression was analyzed
by RT-PCR and drug target protein expression was evaluated
by Western Blot. Lapatinib and gefitinib induced a cytotoxic
effect and mitochondrial mem-brane depolarization in BRC-230
and SkBr3 cells, while sorafenib induced apoptosis and a high
and rapid dissipation of mitochondrial potential in all cell
lines. Moreover, all three drugs produced a rapid cytosolic
calcium mobilization from endoplasmic reticulum stores in
the investigated cell lines and a strong decrease in multidrug
transporter activity in BRC-230 and MCF-7 cells. Mitochondrial
membrane depolarization and inhibition of multidrug transporter
activity induced by tyrosine kinase inhibitors were independent
of cytosolic calcium mobilization. These data suggest that
the investigated drugs possess mechanisms of action that are
independent of drug target expression, opening up further
possibilities for the development of new therapeutic strategies.
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