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Current
Cancer Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 11, Number 3, March 2011
Contents
Hot Topic
Targeting Tumor Uniquitin-Proteasome Pathway with
New and Old Drugs
Guest Editors: Q. Ping Dou
Editorial
Pp. 236-238
Bortezomib as the First Proteasome Inhibitor Anticancer Drug:
Current Status and Future Perspectives Pp. 239-253
D. Chen, M. Frezza, S. Schmitt, J. Kanwar and
Q.P. Dou
[Abstract] [Purchase
Article] [PMID:
21247388 PubMed - indexed for MEDLINE]
Marizomib, a Proteasome Inhibitor for
All Seasons: Preclinical Profile and a Framework for Clinical
Trials Pp. 254-284
B.C. Potts, M.X. Albitar, K.C. Anderson, S. Baritaki,
C. Berkers, B. Bonavida, J. Chandra, D. Chauhan, J.C. Cusack
Jr., W. Fenical, I.M. Ghobrial, M. Groll, P.R. Jensen, K.S.
Lam, G.K. Lloyd, W. McBride, D.J. McConkey, C.P. Miller, S.T.C.
Neuteboom, Y. Oki, H. Ovaa, F. Pajonk, P.G. Richardson, A.M.
Roccaro, C.M. Sloss, M.A. Spear, E. Valashi, A. Younes
and M.A. Palladino
[Abstract]
[Purchase
Article] [PMID:
21247382 PubMed - indexed for MEDLINE]
Second Generation Proteasome Inhibitors:
Carfilzomib and Immunoproteasome-Specific Inhibitors (IPSIs)
Pp. 285-295
D.J. Kuhn, R.Z. Orlowski and C.C. Bjorklund
[Abstract] [Purchase
Article]
[PMID:
21247387 PubMed - indexed for MEDLINE]
Green Tea Polyphenols as Proteasome Inhibitors: Implication
in Chemoprevention Pp. 296-306
H. Yang, K. Landis-Piwowar, T.H. Chan and Q.P.
Dou
[Abstract] [Purchase
Article]
[PMID:
21247384 PubMed - indexed for MEDLINE]
Targeting Proteasomes with Naturally
Occurring Compounds in Cancer Treatment Pp. 307-324
V. Cecarini, M. Cuccioloni, M. Mozzicafreddo, L. Bonfili,
M. Angeletti and A.M. Eleuteri
[Abstract] [Purchase
Article] [PMID:
21265733 PubMed - indexed for MEDLINE]
Clioquinol – A Novel Copper-Dependent and Independent
Proteasome Inhibitor Pp. 325-331
A.D. Schimmer
[Abstract] [Purchase
Article] [PMID:
21247386 PubMed - indexed for MEDLINE]
Targeting Malignancies with Disulfiram (Antabuse):
Multidrug Resistance, Angiogenesis, and Proteasome
Pp. 332-337
B. Cvek
[Abstract] [Purchase
Article] [PMID:
21247389 PubMed - indexed for MEDLINE]
Disulfiram, and Disulfiram Derivatives as Novel Potential
Anticancer Drugs Targeting the Ubiquitin-Proteasome System
in Both Preclinical and Clinical Studies Pp. 338-346
F.R. Kona, D. Buac and A.M. Burger
[Abstract] [Purchase
Article] [PMID:
21247383 PubMed - indexed for MEDLINE]
SCF E3 Ubiquitin Ligases as Anticancer Targets Pp.
347-356
L. Jia and Y. Sun
[Abstract] [Purchase
Article] [PMID:
21247385 PubMed - indexed for MEDLINE]
General Articles
Autophagy: Molecular Mechanisms and their Implications
for Anticancer Therapies Pp. 357-379
S. Meschini, M. Condello, P. Lista and G. Arancia
[Abstract] [Purchase
Article] [PMID:
21247381 PubMed - indexed for MEDLINE]
Peptidyl Prolyl Isomerase, Pin1 is a Potential Target
for Enhancing the Therapeutic Efficacy of Etoposide Pp.
380- 392
R. Mathur, S. Chandna, P.N. Kapoor and B.S. Dwarakanath
[Abstract] [Purchase
Article] [PMID:
21247380 PubMed - indexed for MEDLINE]
Abstracts
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Article]
[PMID:
21247388 PubMed - indexed for MEDLINE]
Bortezomib as the First Proteasome Inhibitor Anticancer
Drug: Current Status and Future Perspectives
D. Chen, M. Frezza, S. Schmitt, J. Kanwar and
Q.P. Dou
Targeting the ubiquitin-proteasome pathway has
emerged as a rational approach in the treatment of human cancer.
Based on positive preclinical and clinical studies, bortezomib
was subsequently approved for the clinical use as a front-line
treatment for newly diagnosed multiple myeloma patients and
for the treatment of relapsed/refractory multiple myeloma
and mantle cell lymphoma, for which this drug has become the
staple of treatment. The approval of bortezomib by the US
Food and Drug Administration (FDA) represented a significant
milestone as the first proteasome inhibitor to be implemented
in the treatment of malignant disease. Bortezomib has shown
a positive clinical benefit either alone or as a part of combination
therapy to induce chemo-/radio sensitization or overcome drug
resistance. One of the major mechanisms of bortezomib associated
with its anticancer activity is through upregulation of NOXA,
which is a proapoptotic protein, and NOXA may interact with
the anti-apoptotic proteins of Bcl-2 subfamily Bcl-XL
and Bcl-2, and result in apoptotic cell death in malignant
cells. Another important mechanism of bortezomib is through
suppression of the NF-κB
signaling pathway resulting in the down-regulation of its
anti-apoptotic target genes. Although the majority of success
achieved with bortezomib has been in hematological malignancies,
its effect toward solid tumors has been less than encouraging.
Additionally, the widespread clinical use of bortezomib continues
to be hampered by the appearance of dose-limiting toxicities,
drug-resistance and interference by some natural compounds.
These findings could help guide physicians in refining the
clinical use of bortezomib, and encourage basic scientists
to generate next generation proteasome inhibitors that broaden
the spectrum of efficacy and produce a more durable clinical
response in cancer patients. Other desirable applications
for the use of proteasome inhibitors include the development
of inhibitors against specific E3 ligases, which act at an
early step in the ubiquitin-proteasome pathway, and the discovery
of less toxic and novel proteasome inhibitors from natural
products and traditional medicines, which may provide more
viable drug candidates for cancer chemoprevention and the
treatment of cancer patients in the future.
[Back to top]
[Purchase
Article]
[PMID:
21247382 PubMed - indexed for MEDLINE]
Marizomib, a Proteasome Inhibitor for All Seasons:
Preclinical Profile and a Framework for Clinical Trials
B.C. Potts, M.X. Albitar, K.C. Anderson, S. Baritaki,
C. Berkers, B. Bonavida, J. Chandra, D. Chauhan, J.C. Cusack
Jr., W. Fenical, I.M. Ghobrial, M. Groll, P.R. Jensen, K.S.
Lam, G.K. Lloyd, W. McBride, D.J. McConkey, C.P. Miller, S.T.C.
Neuteboom, Y. Oki, H. Ovaa, F. Pajonk, P.G. Richardson, A.M.
Roccaro, C.M. Sloss, M.A. Spear, E. Valashi, A. Younes
and M.A. Palladino
The proteasome has emerged as an important clinically
relevant target for the treatment of hematologic malignancies.
Since the Food and Drug Administration approved the first-in-class
proteasome inhibitor bortezomib (Velcade®)
for the treatment of relapsed/refractory multiple myeloma
(MM) and mantle cell lymphoma, it has become clear that new
inhibitors are needed that have a better therapeutic ratio,
can overcome inherent and acquired bortezomib resistance and
exhibit broader anti-cancer activities. Marizomib (NPI-0052;
salinosporamide A) is a structurally and pharmacologically
unique ß-lactone-γ-lactam
proteasome inhibitor that may fulfill these unmet needs. The
potent and sustained inhibition of all three proteolytic activities
of the proteasome by marizomib has inspired extensive preclinical
evaluation in a variety of hematologic and solid tumor models,
where it is efficacious as a single agent and in combination
with biologics, chemotherapeutics and targeted therapeutic
agents. Specifically, marizomib has been evaluated in models
for multiple myeloma, mantle cell lymphoma, Waldenstrom’s
macroglobulinemia, chronic and acute lymphocytic leukemia,
as well as glioma, colorectal and pancreatic cancer models,
and has exhibited synergistic activities in tumor models in
combination with bortezomib, the immunomodulatory agent lenalidomide
(Revlimid®),
and various histone deacetylase inhibitors. These and other
studies provided the framework for ongoing clinical trials
in patients with MM, lymphomas, leukemias and solid tumors,
including those who have failed bortezomib treatment, as well
as in patients with diagnoses where other proteasome inhibitors
have not demonstrated significant efficacy. This review captures
the remarkable translational studies and contributions from
many collaborators that have advanced marizomib from seabed
to bench to bedside.
[Back to top]
[Purchase
Article]
[PMID:
21247387 PubMed - indexed for MEDLINE]
Second Generation Proteasome Inhibitors: Carfilzomib
and Immunoproteasome-Specific Inhibitors (IPSIs)
D.J. Kuhn, R.Z. Orlowski and C.C. Bjorklund
The ubiquitin-proteasome pathway (UPP) is an attractive
chemotherapeutic target due to its intrinsically stringent
regulation of cell cycle, pro-survival, and anti-apoptotic
regulators that disproportionately favor survival and proliferation
in malignant cells. A reversible first-in-class proteasome
inhibitor, bortezomib, is Food and Drug Administration approved
for multiple myeloma and relapsed/refractory mantle cell lymphoma
and has proven to be extremely effective, both as a single
agent and in combination. An irreversible second generation
proteasome inhibitor, carfilzomib, has shown preclinical effectiveness
against hematological and solid malignancies both in vitro
and in vivo. Carfilzomib, a peptidylepoxyketone functions
similarly to bortezomib through primary inhibition of chymotrypsin-like
(ChT-L) activity at the β5
subunits of the core 20S proteasome. Carfilzomib is also currently
achieving successful response rates within the clinical setting.
In addition to conventional proteasome inhibitors, a novel
approach may be to specifically target the hematological-specific
immunoproteasome, thereby increasing overall effectiveness
and reducing negative off-target effects. The immunoproteasome-specific
inhibitor, IPSI-001, was shown to have inhibitory preference
over the constitutive proteasome, and display enhanced efficiency
of apoptotic induction of tumor cells from a hematologic origin.
Herein, we discuss the preclinical and clinical development
of carfilzomib and explore the potential of immunoproteasome-specific
inhibitors, like IPSI-001, as a rational approach to exclusively
target hematological malignancies.
[Back to top]
[Purchase
Article] [PMID:
21247384 PubMed - indexed for MEDLINE]
Green Tea Polyphenols as Proteasome Inhibitors: Implication
in Chemoprevention
H. Yang, K. Landis-Piwowar, T.H. Chan and Q.P.
Dou
Next to water, tea is the most popular beverage in the world.
The most abundant and active compound in green tea is (-)-epigallocatechin-3-gallate
(EGCG), which is extensively studied for its cancer-preventive
and anti-cancer activities as well as its cellular targets.
One potential molecular target of EGCG is the proteasome.
While molecular docking and structure-activity relationship
(SAR) analysis suggests that the ester carbon of EGCG is important
for mediating its proteasome-inhibitory activity, EGCG is
very unstable under physiological conditions. Therefore, a
series of analogs were synthesized aiming to improve stability
and bioavailability of EGCG. Among them, peracetate-protected
or the prodrug of EGCG was found to have increased bioavailability,
stability, and proteasome-inhibitory activities against various
human cancer cells and tumors compared to EGCG, suggesting
its potential use for cancer prevention and treatment. Epidemiological
studies have indicated that green tea consumption is associated
with the reduced risk of cancers, especially associated with
the reduced risk of late stage of cancers. This risk reduction
may be attributed not only to proteasome inhibition, but also
to numerous other intracellular molecules targeted by EGCG
that are involved in cell cycle regulation, apoptosis, angiogenesis,
and metastasis.
[Back to top]
[Purchase
Article] [PMID:
21265733 PubMed - indexed for MEDLINE]
Targeting Proteasomes with Naturally Occurring Compounds in
Cancer Treatment
V. Cecarini, M. Cuccioloni, M. Mozzicafreddo, L. Bonfili,
M. Angeletti and A.M. Eleuteri
Aberrant cellular proliferation and compromised apoptotic
pathways are hallmarks of cancer aggressiveness, and in this
framework, the role of protein degradation machineries have
been extensively dissected.
Among proteases, the proteasome is unequivocally central in
the intracellular regulation of both these processes, thus
several proteasome-directed therapies have been investigated,
aiming at controlling its activity and possibly restoring
normal cell functions. Numerous studies reported proteasome
inhibitors (both synthetic and natural occurring) to potently
and selectively induce apoptosis in many types of cancer cells.
In this review, we discuss recent advances in proteasomal
modulation by some natural occurring polyphenols, globally
providing evidence of the proteasome role as therapeutic target
in cancer treatment.
[Back to top]
[Purchase
Article] [PMID:
21247386 PubMed - indexed for MEDLINE]
Clioquinol – A Novel Copper-Dependent and Independent
Proteasome Inhibitor
A.D. Schimmer
Clioquinol (5-chloro-7-iodo-quinolin-8-ol) was used in the
1950’s-1970’s as an oral anti-parasitic agent.
More recently, studies have demonstrated that Clioquinol displays
preclinical efficacy in the treatment of malignancy. Its anti-cancer
activity relates, at least in part, to its ability to inhibit
the proteasome through mechanisms dependent and independent
of its ability to bind heavy metals such as copper. By acting
as a metal ionophore Clioquinol transports metal ions from
the extracellular environment into the cell and mobilizes
weakly bound intracellular stores. It then directs the metal
to the proteasome resulting in disruption of this enzymatic
complex. In addition, Clioquinol is capable of directly inhibiting
the proteasome at higher concentrations. Thus, Clioquinol
represents a novel therapeutic strategy to inhibit the proteasome.
Given the prior toxicology and pharmacology studies, Clioquinol
could be rapidly repositioned for a new anticancer indication.
This review highlights the mechanism of action of Clioquinol
as a proteasome inhibitor. In addition, it discusses the human
pharmacology and toxicology studies and how this information
would guide a phase I clinical trial of this agent for patients
with malignancy.
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[PMID:
21247389 PubMed - indexed for MEDLINE]
Targeting Malignancies with Disulfiram (Antabuse):
Multidrug Resistance, Angiogenesis, and Proteasome
B. Cvek
An old drug, Antabuse (disulfiram), used for decades in alcohol
aversion therapy, and its metabolite Ditiocarb were shown
from 1970s to suppress cancer growth in vivo and even in human
patients. The drug targets multidrug resistance, angiogenesis,
invasion, and proteasome. Today, there are ongoing clinical
trials of Antabuse as an adjuvant therapy against lung cancer
and as a monotherapy against cancers metastasizing to liver.
The larger clinical trials, if appropriate, will need support
from governments and charities to get the generic drug into
the clinic as a “non-profit” drug.
[Back to top]
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Article]
[PMID:
21247383 PubMed - indexed for MEDLINE]
Disulfiram, and Disulfiram Derivatives as Novel Potential
Anticancer Drugs Targeting the Ubiquitin-Proteasome System
in Both Preclinical and Clinical Studies
F.R. Kona, D. Buac and A.M. Burger
Disulfiram is a FDA approved drug for the treatment of alcoholism
and has been available for clinical use for over five decades.
Despite data from the 1970s and 80s, which showed that disulfiram
and analogs are able to enhance the activity of anticancer
cytotoxic drugs and might be useful as chemopreventative agents,
the underlying molecular mechanisms remained unknown until
recently. Large scale screening efforts for agents that can
inhibit the proteasome and be used as novel anticancer drugs
revealed that disulfiram has proteasome inhibitory activity.
Moreover, disulfiram was also found to have specific activity
against zinc fingers and RING-finger ubiquitin E3 ligases
that play an important role in cancer development. Here we
review the preclinical and clinical studies exploring disulfiram
as an anticancer agent, as well as research programs that
focus on the development of disulfiram derivatives as inhibitors
of the ubiquitin-proteasome system.
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[PMID:
21247385 PubMed - indexed for MEDLINE]
SCF E3 Ubiquitin Ligases as Anticancer Targets
L. Jia and Y. Sun
The SCF (Skp1, Cullins, F-box proteins) multisubunit E3 ubiquitin
ligase, also known as CRL (Cullin-RING ubiquitin Ligase) is
the largest E3 ubiquitin ligase family that promotes the ubiquitination
of various regulatory proteins for targeted degradation, thus
regulating many biological processes, including cell cycle
progression, signal transduction, and DNA replication. The
efforts to discover small molecule inhibitors of a SCF-type
ligase or its components were expedited by the FDA approval
of Bortezomib (also known as Velcade or PS-341), the first
(and only) class of general proteasome inhibitor, for the
treatment of relapsed/refractory multiple myeloma and mantle
cell lymphoma. Although Bortezomib has demonstrated a certain
degree of cancer cell selectivity with measurable therapeutic
index, the drug is, in general, cytotoxic due to its inhibition
of overall protein degradation. An alternative and ideal approach
is to target a specific E3 ligase, known to be activated in
human cancer, for a high level of specificity and selectivity
with less associated toxicity, since such inhibitors would
selectively stabilize a specific set of cellular proteins
regulated by this E3. Here, we review recent advances in validation
of SCF E3 ubiquitin ligase as an attractive anti-cancer target
and discuss how MLN4924, a small molecule inhibitor of NEDD8-activating
enzyme, can be developed as a novel class of anticancer agents
by inhibiting SCF E3 ligase via removal of cullin
neddylation. Finally, we discuss under future perspective
how basic research on SCF biology will direct the drug discovery
efforts surrounding this target.
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[PMID:
21247381 PubMed - indexed for MEDLINE]
Autophagy: Molecular Mechanisms and their Implications
for Anticancer Therapies
S. Meschini, M. Condello, P. Lista and G. Arancia
Autophagy is a catabolic process whereby cells maintain homeostasis
by eliminating unnecessary proteins and damaged organelles.
It may be triggered under physiological conditions, such as
nutrient starvation, or in response to a variety of stress
stimuli, such as exposure to radiations or cytotoxic compounds.
Although autophagy is basically a protective mechanism that
sustains cell survival under adverse conditions, it has been
recently demonstrated that the induction of autophagic process
may ultimately lead to cell death.
As for the role of autophagy in cancer, it is still very controversial
whether it suppresses tumorigenesis or provides cancer cells
with a rescue mechanism under unfavourable conditions. Therefore,
the dual role of autophagy in tumor progression and in the
response of cancer cells to chemotherapeutic drugs is still
open to debate.
The first part of this review describes the cellular events
occurring during the various phases of the autophagic process.
Special attention has been given to the morphological aspects
and the regulatory molecules involved in autophagic cell death.
Specifically, we have focused on the proteins necessary for
autophagosome formation, encoded by the ATG (AuTophaGy-related
gene) gene family, and their role in the regulation of the
process of autophagy. We also examined the effects of autophagy
modulators on cell survival and cell death and discussed the
recent efforts aimed at finding novel agents that activate
or inhibit autophagy by targeting regulatory molecules of
the complex autophagy pathways.
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[PMID:
21247380 PubMed - indexed for MEDLINE]
Peptidyl Prolyl Isomerase, Pin1 is a Potential Target
for Enhancing the Therapeutic Efficacy of Etoposide
R. Mathur, S. Chandna, P.N. Kapoor and B.S. Dwarakanath
The peptidyl prolyl isomerase (Pin1) that induces cis-trans
isomerization of the peptide bond involving serine/ threonine-proline
has recently been shown to regulate the activity of many phosphoproteins
including the ones involved in damage response pathways. We
investigated Pin1 as a potential target for enhancing the
efficacy of anticancer therapy by studying the effects of
juglone, a Pin1 inhibitor on the cytotoxicity of etoposide
(a widely used anticancer drug that targets topoisomerase
IIα)
in human tumor cell lines. Treatment of cells with juglone
synergistically enhanced the cytotoxicity of etoposide (loss
of clonogenicity) with a tenfold increase when etoposide treatment
preceded juglone exposure. On the other hand, the toxicity
was additive when the treatment protocol was reversed (i.e
exposure to juglone followed by etoposide treatment). This
suggests that Pin1 inhibition possibly reduces the induction
of initial DNA damage by etoposide, which was supported by
a decrease in the levels of chromatin bound topoIIα.
Increase in the etoposide induced toxicity by juglone appeared
to be mainly due to enhanced mitotic cell death linked to
cytogenetic damage, although a moderate increase in interphase
(apoptotic) death was also evident as revealed by DNA degradation
(hypodiploid population and TUNEL assay). Since the level
of Pin1 is found to be higher in cancer cells, this enzyme
could be a potential target for developing an adjuvant to
enhance the efficacy of anticancer therapies.
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