Current
Cancer Drug Targets
ISSN: 1568-0096
Current Cancer Drug Targets
Volume 7, Number 8, December 2007
Contents
Tubulin/Microtubule System as an Anti-Cancer Drug
Target
Guest Editor: A/Prof. Maria Kavallaris Ph.D.
Editorial Pp. 696
Tubulin Folding Pathways: Implication in the Regulation
of Microtubule Dynamics Pp. 697-703
A. Beghin, C.M. Galmarini and C. Dumontet
[Abstract]
Looking at Drug Resistance Mechanisms for MicrotubuleInteracting
Drugs: Does TUBB3 Work? Pp. 704-712
Cristiano Ferlini, Giuseppina Raspaglio, Lucia Cicchillitti,
Simona Mozzetti, Silvia Prislei, Silvia Bartollino and Giovanni
Scambia
[Abstract]
Microtubules in Apoptosis Induction: Are They Necessary?
Pp. 713-729
M.-A. Estève, M. Carré and D. Braguer
[Abstract]
How Do Microtubule-Targeted Drugs Work? An Overview
Pp. 730-742
Mary Ann Jordan and Kathy Kamath
[Abstract]
General Articles
Molecular and Cellular Regulators of Cancer Angiogenesis
Pp. 743-758
P.P. Goh, D.M. Sze and B.D. Roufogalis
[Abstract]
Radiosensitization of Prostate Cancer by Soy Isoflavones
Pp. 759-765
Julian J. Raffoul, Fazlul H. Sarkar and Gilda G. Hillman
[Abstract]
Novel Mitotic Targets and Their Small-Molecule
Inhibitors Pp. 766-784
Alexandre V. Ivachtchenko, Alex S. Kiselyov, Sergey E. Tkachenko,
Yan A. Ivanenkov and Konstantin V. Balakin
[Abstract]
IAPs as a Target for Anticancer Therapy Pp. 785-794
S. Danson, E. Dean, C. Dive and M. Ranson
[Abstract]
Beneficial Action of Citrus Flavonoids on
Multiple Cancer Related Biological Pathways
Pp. 795-809
O. Benavente-García, J. Castillo, M. Alcaraz, V.
Vicente, J.A. Del Río and A. Ortuño
[Abstract]
Abstracts
[Back to top]
Editorial: Tubulin/Microtubule
System as an Anti-Cancer Drug Target
The tubulin/microtubule system is an integral component of
the cytoskeleton. Microtubules are highly dynamic structures
that play a critical role in orchestrating the separation
and segregation of chromosomes during mitosis. This makes
microtubules highly valued as anticancer drug targets. Tubulin-binding
agents (also known as anti-microtubule, microtubule-binding,
microtubule-targeting drugs) are derived from natural sources
and include a large number of agents with diverse chemical
structures. What all tubulin-binding agents share in common
is their ability to disrupt microtubule dynamics, induce mitotic
arrest and cell death. The best known of these agents are
the vinca alkaloids and taxanes, which at high doses
cause microtubule destabilisation and microtubule stabilisation,
respectively.
Improvements in our understanding of the mechanisms of action
and resistant to tubulin-binding agents has continued to drive
a strong interest in identifying and developing new derivatives
of tubulin-binding agents. Well over 200 of these agents are
under various stages of development. Despite the fact that
the first tubulin-binding agents, were clinically introduced
in the 1960’s, there are still many aspects of these
agents that are not understood and in recent years, previously
unknown cellular effects and protein interactions have begun
to be discovered.
It has been known for some time that tubulin-binding agents
disrupt microtubule dynamics, but the differences between
the different classes of tubulin-binding agents and their
effects on microtubule dynamics and mitosis have been difficult
to pinpoint. Jordan and Kamath give a valuable overview of
microtubule dynamics, endogenous regulators of microtubule
function and the effect of different classes of tubulin-binding
agents on microtubule dynamics.
The role of microtubule binding proteins in the regulation
of microtubule dynamics and drug response have been studied,
yet limited attention has been given to the role of tubulin
folding pathways as a means to regulate microtubule dynamics.
Beghin, Galmarini and Dumontet, review current understanding
regarding tubulin-folding pathways, their relation to disease,
and discuss their potential influence on microtubule dynamics
and their value as new drug targets.
Despite the clinical success of tubulin-binding agents, drug
resistance can emerge as a significant clinical problem. There
has been much interest in recent years associated with alterations
in the cellular target of these agents, the tubulin/microtubule
system. The mechanisms mediating resistance in the clinic
are not well understood. Ferlini et al. review resistance
mechanisms and discuss the benefits of targeting TUBB3 (also
known as class III β-tubulin
or βIII-tubulin),
a β-tubulin
isotype commonly increased in drug resistant epithelial cancers.
Tubulin-binding agents are known to be potent inducers of
apoptosis. The link between microtubule disruption and apoptosis
induction are not clear. Estève, Carré and Braguer
give a comprehensive overview of the apoptotic processes known
to be activated following treatment of cancer cells with tubulin-binding
agents.
The tubulin/microtubule system remains one the most important
drug targets for the treatment of cancer. This special issue
provides current and new insight into the mechanisms of action
of these agents, resistance and new drug targets within the
tubulin/microtubule repertoire of microtubule dynamic regulators.
Improved insight into the mechanisms of action and resistance
to these agents will lead to improved targeting of existing
agents and the development of more effective agents to treat
resistant disease.
A/Prof. Maria Kavallaris Ph.D.
Head, Pharmacoproteomics Program
NHMRC RD Wright Fellow
Children's Cancer Institute Australia for Medical Research
High Street (P.O. Box 81)
Randwick, NSW, Australia 2031
Tel: 61-2-9382 1823
Fax: 61-2-9382 1850
E-mail: m.kavallaris@ccia.unsw.edu.au
[Back to top]
Tubulin Folding Pathways: Implication in the Regulation
of Microtubule Dynamics
A. Beghin, C.M. Galmarini and C. Dumontet
As microtubules are essential in many cell functions, they
have been used as a target of a variety of anticancer drugs
that are grouped as stabilizing (taxanes) and destabilizing
(vinca-alkaloids, colchicinoids) microtubule agents. It appears
clearly now that the dynamic behaviour more than modifications
of microtubule mass are altered by antitubulin agents in the
range of serum concentrations obtained after administration
in humans. While the role of microtubule associated proteins
in the regulation of microtubule dynamics has been extensively
studied, there is a growing body of data suggesting that tubulin
folding could also play an important role in microtubule dynamics.
We review the current knowledge regarding tubulin folding
pathways, their relation to disease, and their possible influence
on microtubule dynamics.
[Back to top]
Looking at Drug Resistance Mechanisms for MicrotubuleInteracting
Drugs: Does TUBB3 Work?
Cristiano Ferlini, Giuseppina Raspaglio, Lucia Cicchillitti,
Simona Mozzetti, Silvia Prislei, Silvia Bartollino and Giovanni
Scambia
Vinca alkaloids and taxanes represent the mainstay
of medical treatment of hematological and solid tumors. Unfortunately,
a major clinical problem with these agents is drug resistance.
Although a plethora of mechanisms of drug resistance have
been described, only a few of them have been validated in
clinical trials. Among these, the one involving the protein
TUBB3 seems to represent a promising target for studying drug
resistance. In fact, it seems that this protein is a factor
promoting cell survival and represents an endogenous element
of an inherent drug-resistance program built into cells to
counteract the activity of microtubule-interacting drugs.
Its pivotal role has been ascertained in clinical trials in
lung, breast, and ovarian cancer, three diseases that can
be successfully treated with microtubule-interacting drugs.
Although TUBB3 is probably not a unique factor in drug resistance,
the hope is that direct targeting of this protein will increase
the response to microtubule-interacting drugs, thereby overcoming
an important element in the growth of drug resistance.
[Back to top]
Microtubules in Apoptosis Induction: Are They Necessary?
M.-A. Estève, M. Carré and D. Braguer
Microtubule-Targeting Agents (MTAs) constitute a class of
drugs largely used in cancer treatment. Among them, both taxanes
and Vinca-alkaloids are known to inhibit cancer cell
proliferation by inducing cell cycle arrest and subsequent
apoptosis. These agents modify the cytoskeleton by affecting
the tubulin/microtubule system. In cancer cells, both classes
suppress microtubule dynamics through inhibition of microtubule
dynamic instability and treadmilling, and commonly induce
diverse signals responsible for cell death initiation and
execution via the mitochondrial intrinsic pathway.
However, links between microtubule network disturbance and
the involvement of mitochondria in apoptosis are not obvious,
and one may think that they could be independent. Nevertheless,
several intracellular proteins could connect microtubules
and the apoptotic machinery. The aim of the present review
is to provide elements that could answer to the question :
is microtubule disruption dispensable for MTA-induced apoptosis?
The first section is focused on the mechanisms responsible
for the MTA-mediated apoptosis. Then, links between cell cycle
regulators and apoptosis are underlined since MTA induce cell
cycle arrest by inhibiting microtubules. In the third part,
the potential involvement of microtubule-sequestered and/or
-transported proteins in apoptotic signalisation is discussed.
Lastly, the possible role of the tubulin/microtubule system
in direct effects of MTAs on mitochondria is summarized. Thus,
it becomes clear that microtubule network and apoptosis are
deeply linked in MTA effectiveness, through a cascade of cellular
events. It could lead to identification of new biomarkers
of MTA effectiveness, that could improve combinatorial therapy
with MTAs and provide crucial arms to circumvent resistance
of cancer cells.
[Back to top]
How Do Microtubule-Targeted Drugs Work? An Overview
Mary Ann Jordan and Kathy Kamath
The importance of microtubules in mitosis makes them a superb
target for a group of highly successful, chemically diverse
anticancer drugs. Knowledge of the mechanistic differences
among the many drugs of this class is vital to understanding
their tissue and cell specificity, the development of resistance,
the design of novel improved drugs, optimal scheduling of
treatment, and potential synergistic combinations. This overview
covers microtubule assembly dynamics, the exquisite regulation
of microtubule dynamics in cells by endogenous regulators,
the important role of microtubule dynamics in mitosis, the
diversity and number of microtubule-targeted drugs undergoing
clinical development, the antimitotic mechanisms of microtubule-targeted
drugs with emphasis on suppression of microtubule dynamics
by vinblastine and taxol, the role of drug uptake and retention
in the efficacy of microtubule-targeted drugs, and the anti-angiogenic
and vascular-disrupting mechanisms of microtubule targeted
drugs. In view of the success of this class of drugs, it has
been argued that microtubules represent the single best cancer
target identified to date, and it seems likely that drugs
in this class will continue to remain an important chemotherapeutic
class of drugs even as more selective chemotherapeutic approaches
are developed.
[Back to top]
Molecular and Cellular Regulators of Cancer Angiogenesis
P.P. Goh, D.M. Sze and B.D. Roufogalis
Current cancer chemotherapeutic drugs have limited efficacy
due to the fact that tumour cells are a rapidly changing target
characterised by genomic instability. Unlike tumour cells,
activated endothelial cells (ECs) required for angiogenesis,
a process indisputably crucial to tumour growth and metastasis,
were originally considered to be ideal therapeutic targets
free of drug resistance. Additionally, unlike preclinical
studies in mice using inhibitors targeting the powerful EC
mitogen- vascular endothelial growth factor (VEGF)- overall
survival benefit with anti-VEGF therapy used as monotherapy
has yet to be demonstrated in phase III clinical trials. In
contrast, VEGF-specific antibodies combined with current chemotherapy
have resulted in improved outcomes in certain previously untreated
cancers. This has led some researchers to hypothesize that
combined treatments targeting other angiogenic molecules besides
VEGF, and/or targeting not only ECs but other angiogenic non-EC
types, may offer alternative but effective therapeutic options
for eradicating malignant tumours. A rational approach to
effective anti-angiogenic combination therapy will, however,
require further understanding of the molecular and cellular
mechanisms which undergird tumour vascularisation. Recent
studies involving judicious use of powerful new genetic approaches
have provided unprecedented insights into how different molecular
and cellular mechanisms cooperate to build, branch and mature
the growing vessel network so pivotal to tumour growth and
survival. This review covers our current understanding of
how the various key players - the tumour cells, stromal cells,
endothelial cells and pericytes, and bone-marrow-derived haematopoietic
and putative endothelial progenitors interact via
their cell-derived pro- or anti-angiogenic factors to regulate
tumour angiogenesis.
[Back to top]
Radiosensitization of Prostate Cancer by Soy Isoflavones
Julian J. Raffoul, Fazlul H. Sarkar and Gilda G. Hillman
A trend in investigating the use of several nutritional
compounds for cancer chemoprevention has revealed that phytochemicals
demonstrated anti-cancer properties by inhibiting signal transduction
pathways essential for cancer cell proliferation, tumor growth,
invasion and metastasis. Emerging evidence suggests that the
anti-proliferative and anti-oxidant effects of some of these
dietary agents could be utilized to both potentiate the response
of cancer cells to radiotherapy and reduce radiation-induced
toxicity to normal surrounding tissues. Using pre-clinical
orthotopic models of prostate cancer, studies on the combination
of soy isoflavones with tumor irradiation demonstrate a synergistic
anti-cancer effect between these two modalities and emphasize
the potential and safety of dietary factors to improve conventional
radiotherapy for a better control of tumor growth and metastasis.
The goal of this review is to focus on the role of soy isoflavones
as potent radiosensitizers for prostate cancer and other malignancies.
We will discuss molecular pathways regulated by soy isoflavones
that inhibit survival pathways activated by radiation and
ultimately drive the cells to cell death both in vitro
and in vivo in pre-clinical models.
[Back to top]
Novel Mitotic Targets and Their Small-Molecule
Inhibitors
Alexandre V. Ivachtchenko, Alex S. Kiselyov, Sergey E. Tkachenko,
Yan A. Ivanenkov and Konstantin V. Balakin
With several successful anticancer drugs on the market and
numerous compounds in clinical developments, antimitotic agents
represent an important category of anticancer agents. However,
clinical utility of the tubulin-binding agents is somewhat
limited due to multiple drug resistance (MDR), poor pharmacokinetics
and therapeutic index. There is ongoing need for the modulators
of other intracellular targets that result in the same anti-mitotic
effect without adverse effects of “traditional”
tubulin binders. This review describes progress made to-date
in development of novel and emerging biotargets affecting
the mitotic events, and their small-molecule modulators.
[Back to top]
IAPs as a Target for Anticancer Therapy
S. Danson, E. Dean, C. Dive and M. Ranson
The avoidance of apoptosis is one of the hallmarks of cancer
cells. In addition, failure to induce apoptosis by anticancer
agents, either due to limitations of the drug or the tumour
cell evading apoptosis, is a reason for chemotherapeutic failure.
Two general pathways for apoptotic cell death have been characterised,
the extrinsic and intrinsic pathways which merge in the final
common pathway. X-linked inhibitor of apoptosis protein (XIAP)
is an anti-apoptotic protein in the final common pathway that
inhibits caspases and suppresses apoptosis. XIAP is over-expressed
in many cancer cell lines and cancer tissues. High XIAP expression
has been correlated with resistance to chemotherapy and radiotherapy
and to poor clinical outcome by some investigators.
Manipulation of apoptosis is an attractive therapeutic concept.
Much effort has been spent on inhibiting the anti-apoptotic
protein, B cell lymphoma gene 2 (Bcl-2) which is part of the
intrinsic pathway. Now attention is turning to inhibition
of XIAP as a cancer drug target. It has been argued that it
is more effective to block the final common pathway rather
than just the intrinsic arm. Inhibition of XIAP can be with
either antisense oligonucleotides (ASO) or small molecule
inhibitors. In vitro, XIAP antagonists produce XIAP
knockdown and apoptosis which is associated with sensitisation
of tumour cells to radiotherapy and cytotoxic drugs. In
vivo, XIAP antagonists have antitumour effects and sensitise
tumours to the effects of chemotherapy.
This review will summarise the preclinical data for both ASO
and small molecule inhibition of XIAP and discuss emerging
Phase I data. Future strategies for manipulation of XIAP and
the clinical development of XIAP inhibitors will be discussed.
[Back to top]
Beneficial Action of Citrus Flavonoids on
Multiple Cancer Related Biological Pathways
O. Benavente-García, J. Castillo, M. Alcaraz, V.
Vicente, J.A. Del Río and A. Ortuño
Attempts to control cancer involve a variety of means,
including the use of suppressing, blocking and transforming
agents. Suppressing agents prevent the formation of new cancers
from pro-carcinogens, blocking agents prevent carcinogenic
compounds from reaching critical initiation sites, while transformation
agents act to facilitate the metabolism of carcinogenic components
into less toxic materials or to prevent their biological actions.
Flavonoids can act as all three types of agent.
Epidemiological and animal studies suggest that flavonoids
have a protective effect against cardiovascular diseases and
some types of cancer. Although flavonoids have been studied
for about 50 years, the cellular mechanisms involved in their
biological action are still not completely understood. In
recent years, experimental studies have provided growing evidence
supporting the beneficial action of flavonoids on multiple
cancer-related biological pathways (carcinogen bio-activation,
cell-signaling, cell cycle regulation, angiogenesis and inflammation).
Within the last decade, reports on flavonoid activity have
largely associated with enzyme inhibition and anti-proliferative
activity. Many of these studies have pointed to a structural-functional
relationship, in that the antioxidant, enzyme-inhibition or
antiproliferative activities of flavonoids are dependent on
particular structural motifs. Our own studies have shown that
structural factors would explain the antioxidant, antiproliferative
and antimetastasic properties of some citrus flavonoids.
In this paper we discuss the relation between each structural
factor and the anticancer activity of Citrus flavonoids.
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