| Current
Cancer Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 9, Number 5, August 2009
Contents
Ribonucleotide Reductase
as One Important Target of [Tris(1,10-phenanthroline)lanthanum(III)]
Trithiocyanate (KP772) Pp. 595-607
P. Heffeter, A. Popovic-Bijelic, P. Saiko,
R. Dornetshuber, U. Jungwirth, N. Voevodskaya, D. Biglino,
M.A. Jakupec, L. Elbling, M. Micksche, T. Szekeres, B.K. Keppler,
A. Gräslund and W. Berger
[Abstract] [Purchase
Article]
Deacetylase Inhibitors Modulate the Myostatin/Follistatin
Axis without Improving Cachexia in Tumor-Bearing Mice
Pp. 608-616
A. Bonetto, F. Penna, V.G. Minero, P. Reffo,
G. Bonelli, F.M. Baccino and P. Costelli
[Abstract] [Purchase
Article]
P-Selectin Glycoprotein Ligand-1 as a
Potential Target for Humoral Immunotherapy of Multiple Myeloma
Pp. 617-625
C. Tripodo, A.M. Florena, P. Macor, A. Di
Bernardo, R. Porcasi, C. Guarnotta, S. Ingrao, M. Zerilli,
E. Secco, M. Todaro, F. Tedesco and V. Franco
[Abstract] [Purchase
Article]
Targeting the Mevalonate Pathway for
Improved Anticancer Therapy Pp. 626-638
G. Fritz
[Abstract] [Purchase
Article]
The Role of Fibroblast Growth Factors
in Tumor Growth Pp. 639-651
M. Korc and R.E. Friesel
[Abstract] [Purchase
Article]
Importance of Influx and Efflux Systems
and Xenobiotic Metabolizing Enzymes in Intratumoral Disposition
of Anticancer Agents Pp. 652-674
B. Rochat
[Abstract] [Purchase
Article]
Targeting of Hsp32 in Solid Tumors and
Leukemias: A Novel Approach to Optimize Anticancer Therapy
Pp. 675-689
K.V. Gleixner, M. Mayerhofer, A. Vales,
A. Gruze, G. Hörmann, S. Cerny-Reiterer, E. Lackner,
E. Hadzijusufovic, H. Herrmann, A.K. Iyer, M.-T. Krauth, W.F.
Pickl, B. Marian, R. Panzer-Grümayer, C. Sillaber, H.
Maeda, C. Zielinski and P. Valent
[Abstract] [Purchase
Article]
Emerging Strategies to Strengthen the
Anti-Tumour Activity of Type I Interferons: Overcoming Survival
Pathways Pp. 690-704
M. Caraglia, M. Marra, P. Tagliaferri, S.W.J.
Lamberts, S. Zappavigna, G. Misso, F. Cavagnini, G. Facchini,
A. Abbruzzese, L.J. Hofland and G. Vitale
[Abstract] [Purchase
Article]
Abstracts
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Ribonucleotide
Reductase as One Important Target of [Tris(1,10-phenanthroline)lanthanum(III)]
Trithiocyanate (KP772)
P. Heffeter, A. Popovic-Bijelic, P. Saiko,
R. Dornetshuber, U. Jungwirth, N. Voevodskaya, D. Biglino,
M.A. Jakupec, L. Elbling, M. Micksche, T. Szekeres, B.K. Keppler,
A. Gräslund and W. Berger
KP772 is a new lanthanum complex containing three 1,10-phenathroline
molecules. Recently, we have demonstrated that the promising
in vitro and in vivo anticancer properties
of KP772 are based on p53-independent G0/G1
arrest and apoptosis induction. A National Cancer Institute
(NCI) screen revealed significant correlation of KP772 activity
with that of the ribonucleotide reductase (RR) inhibitor hydroxyurea
(HU). Consequently, this study aimed to investigate whether
KP772 targets DNA synthesis in tumor cells by RR inhibition.
Indeed, KP772 treatment led to significant reduction of cytidine
incorporation paralleled by a decrease of deoxynucleoside
triphosphate (dNTP) pools. This strongly indicates disruption
of RR activity. Moreover, KP772 protected against oxidative
stress, suggesting that this drug might interfere with RR
by interaction with the tyrosyl radical in subunit R2. Additionally,
several observations (e.g. increase of transferrin receptor
expression and protective effect of iron preloading) indicate
that KP772 interferes with cellular iron homeostasis. Accordingly,
co-incubation of Fe(II) with KP772 led to generation of a
coloured iron complex (Fe-KP772) in cell free systems. In
electron paramagnetic resonance (EPR) measurements of mouse
R2 subunits, KP772 disrupted the tyrosyl radical while Fe-KP772
had no significant effects. Moreover, coincubation of KP772
with iron-loaded R2 led to formation of Fe-KP772 suggesting
chelation of RR-bound Fe(II). Summarizing, our data prove
that KP772 inhibits RR by targeting the iron centre of the
R2 subunit. As also Fe-KP772 as well as free lanthanum exert
significant -though less pronounced- cytotoxic/static activities,
additional mechanisms are likely to synergise with RR inhibition
in the promising anticancer activity of KP772.
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Deacetylase Inhibitors Modulate the Myostatin/Follistatin
Axis without Improving Cachexia in Tumor-Bearing Mice
A. Bonetto, F. Penna, V.G. Minero, P. Reffo,
G. Bonelli, F.M. Baccino and P. Costelli
Muscle wasting, as occurring in cancer cachexia, is primarily
characterized by protein hypercatabolism and increased expression
of ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1.
Myostatin, a member of the TGFβ
superfamily, negatively regulates skeletal muscle mass and
we showed that increased myostatin signaling occurs in experimental
cancer cachexia. On the other hand, enhanced expression of
follistatin, an antagonist of myostatin, by inhibitors of
histone deacetylases, such as valproic acid or trichostatin-A,
has been shown to increase myogenesis and myofiber size in
mdx mice. For this reason, in the present study we
evaluated whether valproic acid or trichostatin-A can restore
muscle mass in C26 tumor-bearing mice.
Tumor growth induces a marked and progressive loss of body
and muscle weight, associated with increased expression of
myostatin and ubiquitin ligases. Treatment with valproic acid
decreases muscle myostatin levels and enhances both follistatin
expression and the inactivating phosphorylation of GSK-3β,
while these parameters are not affected by trichostatin-A.
Neither agent, however, counteracts muscle atrophy or ubiquitin
ligase hyperexpression.
Therefore, modulation of the myostatin/follistatin axis in
itself does not appear sufficient to correct muscle atrophy
in cancer cachexia.
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P-Selectin Glycoprotein Ligand-1 as a Potential Target for
Humoral Immunotherapy of Multiple Myeloma
C. Tripodo, A.M. Florena, P. Macor, A. Di
Bernardo, R. Porcasi, C. Guarnotta, S. Ingrao, M. Zerilli,
E. Secco, M. Todaro, F. Tedesco and V. Franco
Monoclonal antibodies (mAbs), successfully adopted in
the treatment of several haematological malignancies, have
proved almost ineffective in multiple myeloma (MM), because
of the lack of an appropriate antigen for targeting and killing
MM cells.
Here, we demonstrate that PSGL1, the major ligand of P-Selectin,
a marker of plasmacytic differentiation expressed at high
levels on normal and neoplastic plasma cells, may represent
a novel target for mAb-mediated MM immunotherapy.
The primary effectors of mAb-induced cell-death, complement-mediated
lysis (CDC) and antibody-dependent cell-mediated cytotoxicity
(ADCC), were investigated using U266B1 and LP1 cell-lines
as models. Along with immunological mechanisms, the induction
of apoptosis by PSGL1 cross-linking was assessed.
The anti-PSGL1 murine mAb KPL1 induced death of MM cells in
a dose- and time-dependent fashion and mediated a significant
amount of ADCC. KPL1 alone mediated C1q deposition on target
cells but proved unable to induce CDC due to inhibition of
the lytic activity of complement by membrane complement regulators
(mCRP) expressed on the cell surface. Consistently, CDC was
induced by KPL1 upon mCRP blockage.
Our results suggest a role for PSGL1 in MM humoral immunotherapy
and support further in vivo studies assessing the
effects of anti-PSGL1 mAbs on MM growth and interaction with
the bone marrow microenvironment.
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Targeting the Mevalonate Pathway for Improved Anticancer Therapy
G. Fritz
The mevalonate pathway is important for the generation
of isoprene moieties, thereby providing the basis for the
biosynthesis of molecules required for maintaining membrane
integrity, steroid production and cell respiration. Additionally,
isoprene precursors are indispensable for the prenylation
of regulatory proteins such as Ras and Ras-homologous (Rho)
GTPases. These low molecular weight GTP-binding proteins play
key roles in numerous signal transduction pathways stimulated
upon activation of cell surface receptors by ligand binding.
Thus, Ras/Rho proteins eventually regulate cell proliferation,
tumor progression and cell death induced by anticancer therapeutics.
Lipid modification of Ras/Rho proteins at their C-terminal
CAAX-box is essential for their correct intracellular localization
and function. Therefore, pharmacological inhibition of the
isoprene metabolism is anticipated to impact the manifold
biological functions attributed to Ras/Rho proteins. Here,
the pros and cons of compounds that interfere with the mevalonate
pathway for cancer treatment are summarized and discussed.
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The Role of Fibroblast Growth Factors in Tumor Growth
M. Korc and R.E. Friesel
Biological processes that drive cell growth are exciting
targets for cancer therapy. The fibroblast growth factor (FGF)
signaling network plays a ubiquitous role in normal cell growth,
survival, differentiation, and angiogenesis, but has also
been implicated in tumor development. Elucidation of the roles
and relationships within the diverse FGF family and of their
links to tumor growth and progression will be critical in
designing new drug therapies to target FGF receptor (FGFR)
pathways. Recent studies have shown that FGF can act synergistically
with vascular endothelial growth factor (VEGF) to amplify
tumor angiogenesis, highlighting that targeting of both the
FGF and VEGF pathways may be more efficient in suppressing
tumor growth and angiogenesis than targeting either factor
alone. In addition, through inducing tumor cell survival,
FGF has the potential to overcome chemotherapy resistance
highlighting that chemotherapy may be more effective when
used in combination with FGF inhibitor therapy. Furthermore,
FGFRs have variable activity in promoting angiogenesis, with
the FGFR-1 subgroup being associated with tumor progression
and the FGFR-2 subgroup being associated with either early
tumor development or decreased tumor progression. This review
highlights the growing knowledge of FGFs in tumor cell growth
and survival, including an overview of FGF intracellular signaling
pathways, the role of FGFs in angiogenesis, patterns of FGF
and FGFR expression in various tumor types, and the role of
FGFs in tumor progression.
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Importance of Influx and Efflux Systems and Xenobiotic Metabolizing
Enzymes in Intratumoral Disposition of Anticancer Agents
B. Rochat
In this review, intratumoral drug disposition will be
integrated into the wide range of resistance mechanisms to
anticancer agents with particular emphasis on targeted protein
kinase inhibitors. Six rules will be established: 1. There
is a high variability of extracellular/intracellular drug
level ratios; 2. There are three main systems involved in
intratumoral drug disposition that are composed of SLC, ABC
and XME enzymes; 3. There is a synergistic interplay between
these three systems; 4. In cancer subclones, there is a strong
genomic instability that leads to a highly variable expression
of SLC, ABC or XME enzymes; 5. Tumor-expressed metabolizing
enzymes play a role in tumor-specific ADME and cell survival
and 6. These three systems are involved in the appearance
of resistance (transient event) or in the resistance itself.
In addition, this article will investigate whether the overexpression
of some ABC and XME systems in cancer cells is just a random
consequence of DNA/chromosomal instability, hypo- or hypermethylation
and microRNA deregulation, or a more organized modification
induced by transposable elements. Experiments will also have
to establish if these tumor-expressed enzymes participate
in cell metabolism or in tumor-specific ADME or if they are
only markers of clonal evolution and genomic deregulation.
Eventually, the review will underline that the fate of anticancer
agents in cancer cells should be more thoroughly investigated
from drug discovery to clinical studies. Indeed, inhibition
of tumor expressed metabolizing enzymes could strongly increase
drug disposition, specifically in the target cells resulting
in more efficient therapies.
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Targeting of Hsp32 in Solid Tumors and Leukemias: A Novel
Approach to Optimize Anticancer Therapy
K.V. Gleixner, M. Mayerhofer, A. Vales,
A. Gruze, G. Hörmann, S. Cerny-Reiterer, E. Lackner,
E. Hadzijusufovic, H. Herrmann, A.K. Iyer, M.-T. Krauth, W.F.
Pickl, B. Marian, R. Panzer-Grümayer, C. Sillaber, H.
Maeda, C. Zielinski and P. Valent
Heat shock protein 32 (Hsp32), also known as heme oxygenase-1
(HO-1), is a stress-related anti-apoptotic molecule, that
has been implicated in enhanced survival of neoplastic cells
and in drug-resistance. We here show that Hsp32 is expressed
in most solid tumors and hematopoietic neoplasms and may be
employed as a new therapeutic target as evidenced by experiments
using specific siRNA and a Hsp32-targeting pharmacologic inhibitor.
This Hsp-32 targeting drug, SMA-ZnPP, was found to inhibit
the proliferation of neoplastic cells with IC50 values ranging
between 1 and 50 μM.
In addition, SMA-ZnPP induced apoptosis in all neoplastic
cells examined. Furthermore, SMA-ZnPP was found to synergize
with other targeted and conventional drugs in producing growth-inhibition.
Resulting synergistic effects were observed in all tumor-
and leukemia cells examined. Interestingly, several of the
drug partners, when applied as single agents, induced the
expression of Hsp32 in neoplastic cells, suggesting that synergistic
effects resulted from SMA-ZnPP-induced ablation of a Hsp32-mediated
survival-pathway that is otherwise used by tumor cells to
escape drug induced apoptosis. Together, Hsp32 is an important
survival factor and target in solid tumors and hematopoietic
neoplasms, and may be used to optimize anticancer therapy
by combining conventional or targeted drugs with Hsp32-inhibitors.
Based on these data, it seems desirable to explore the value
of Hsp32-targeting drugs as anti-cancer agents in clinical
trials.
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Emerging Strategies to Strengthen the
Anti-Tumour Activity of Type I Interferons: Overcoming Survival
Pathways
M. Caraglia, M. Marra, P. Tagliaferri, S.W.J.
Lamberts, S. Zappavigna, G. Misso, F. Cavagnini, G. Facchini,
A. Abbruzzese, L.J. Hofland and G. Vitale
Interferon-α
(IFN-α)
is currently the most used cytokine in the treatment of cancer.
However, the potential anti-tumour activity of IFN-α
is limited by the activation of tumour resistance mechanisms.
In this regard, we have shown that IFN-α,
at growth inhibitory concentrations, enhances the EGF-dependent
Ras→Erk
signalling and decreases the adenylate cyclase/cAMP pathway
activity in cancer cells; both effects represent escape mechanisms
to the growth inhibition and apoptosis induced by IFN-α.
The selective targeting of these survival pathways might enhance
the antitumor activity of IFN-α
in cancer cells, as shown by: i) the combination of
selective EGF receptor tyrosine kinase inhibitor (gefitinib)
and IFN-α
having cooperative anti-tumour effects; ii) the farnesyl-transferase
inhibitor R115777 strongly potentiating the anti-tumour activity
of IFN-α
both in vitro and in vivo through the inhibition
of different escape mechanisms that are dependent on isoprenylation
of intracellular proteins such as ras; iii) the cAMP reconstituting
agent (8-Br-cAMP) enhancing the pro-apoptotic activity of
IFN-α.
IFN-β
is a multifunctional cytokine binding the same receptor of
IFN-α,
but with higher affinity (10-fold) and differential structural
interactions. We recently showed that IFN-β
is considerably more potent than IFN-α
in its anti-tumour effect through the induction of apoptosis
and/or cell cycle arrest in S-phase. The emergence of long-acting
pegylated forms of IFN-β
makes this agent a promising anti-cancer drug. These observations
open a new scenario of anticancer intervention able to strengthen
the antitumor activity of IFN-α
or to use more potent type I IFNs.
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