Current Cancer Drug Targets, Volume 3, No. 2, 2003
Contents
Energy Dependent Transport of Xenobiotics and
Its Relevance to Multidrug Resistance Pp.89-107
Rajendra
Sharma, Yogesh C. Awasthi, Yusong Yang, Abha Sharma, Sharad S. Singhal and
Sanjay Awasthi
Increasing Complexity of Farnesyltransferase
Inhibitors Activity: Role in Chromosome Instability Pp.109-118
Carla
Falugi, Sonya Trombino, Pierluigi Granone, Stefano Margaritora and Patrizia Russo
Phage Display Selection and Evaluation of
Cancer Drug Targets
Pp.119-129
Victor
I. Romanov
Survivin: Role in
L.
O’Driscoll, R. Linehan and M. Clynes
Induction of Senescent-Like Growth Arrest as
a New Target in Anticancer Treatment Pp.153-159
Xianghong
Wang, Sai-Wah Tsao, Yong-Chuan Wong and Annie L.M. Cheung
[Back to top] Energy
Dependent Transport of Xenobiotics and Its Relevance to Multidrug Resistance
Rajendra Sharma, Yogesh C. Awasthi, Yusong Yang, Abha Sharma, Sharad S. Singhal and Sanjay Awasthi
Transport
mechanisms for the exclusion of toxic xenobiotics and their metabolites from
cellular environment are crucial for living organisms. Accumulation of these
toxins may affect a number of regulatory and other functions, ultimately
leading to cell death. This trafficking of toxins and their metabolites is an
energy dependent, primary active process, involving the hydrolysis of
nucleotide triphosphates (ATP or GTP), while transferring substrate molecules
across the cell membrane, against a concentration gradient of the substrate.
Therefore, specific membrane associated proteins, known as efflux pumps, are
required to remove these undesirable molecules from the cellular environment.
These transport proteins have diverse structural characteristics with molecular
weights ranging from 28 kDa to 190 kDa and a broad substrate specificity
ranging from anionic to weakly cationic compounds. While these transport
mechanisms constitute an important part of the cellular defense machinery, they
also pose a formidable threat to the efficacy of chemotherapy against
pathogenic bacteria and cancer cells. In cancer cells, the over expression of
these proteins may confer a multidrug resistance (MDR) phenotype. This problem
of MDR in cancer cells has so far been attributed to the two major families of
efflux pumps, P-glycoprotein (Pgp) and multidrug resistance associated proteins
(MRP), which belong to the ATP-binding cassette (ABC) super family. However,
the existence of these pumps has not been able to explain all types of acquired
MDR. Therefore, the importance of transport mechanisms other than these
ABC-transporters cannot be ruled out. One such transporter is DNP-SG ATPase,
whose identity has recently been established with RLIP76, a Ral binding GTPase
activating protein known to be involved in the Ras-Rho-Ral mediated signaling
mechanism. In the present article, we review the comparative functional,
structural, and molecular characteristics of some transporters and discuss
their role in xenobiotic transport and multidrug resistance.
[Back to top] Increasing Complexity of Farnesyltransferase
Inhibitors Activity: Role in Chromosome Instability
Carla
Falugi, Sonya Trombino, Pierluigi Granone, Stefano Margaritora and Patrizia Russo
Oncogenic Ras
proteins have been seen as an important target for novel anticancer drugs. Due
to the functional role of Ras farnesylation, fanesyltransferase (FTase)
inhibition was thought to be a strategy for interfering with Ras-dependent
transformation. When farnesylation is blocked, the function of Ras protein is
severely impaired because of the inability of the nonfarnesylated protein to
anchor to the membrane. Although it has been clearly demonstrated that FTase
inhibitors (FTIs) inhibit Ras farnesylation, it is uncertain whether the
antiproliferative effects of these compounds result exclusively from the
effects on Ras. Moreover, no consensus has been reached as to the relevant
targets(s) of FTIs that can explain their mosaic pharmacology. In searching for
downstream targets for FTIs effects, CENP-E and CENP-F/mitosin were identified.
Different studies showed that the inhibition of farnesylation interferes with
CENP-E-microtubule association. In the presence of FTIs, chromosome alignment
to the metaphase plate is delayed, suggesting that farnesylated proteins are
involved in a step critical to bipolar spindle formation and chromosome
alignment. An important question is whether these biological effects might
contribute to the chemotherapeutic effects of the FTIs. However, FTIs,
triggering the spindle checkpoint, might elevate the rate of cellular
missegregation to levels that are incompatible with cell viability, as well as
have a reduced (but still significant?) effect on checkpointproficient normal
cells. As an example, RPR-115135 induced micronuclei (MN) increase in cancer
cells displaying high chromosome instability (CIN) levels, whereas in normal
cells it is devoid of activity. Cancer cells showing high CIN level might
represent an ideal target for the activity of some FTIs.
[Back to top] Phage Display Selection and Evaluation of
Cancer Drug Targets
Victor I. Romanov
Techniques for the
construction of phage display libraries of combinatorial proteins have
dramatically improved. This has allowed researchers to expand the applications
to the field of cancer biology. The most direct use of protein phage-displayed
libraries is the selection of ligands for individual proteins. This includes
identification of peptide ligands for receptor signaling molecules: integrins,
cytokine and growth factor receptors. Selected peptides may be used as
competitors for natural ligands and for the mapping of binding epitopes. This
approach has been exploited for delineation of intracellular signal
transduction pathways and for the selection of enzyme substrates and inhibitors.
Recently, more complicated biological systems were used as targets for
biopanning. This includes combination of soluble proteins, cellular surfaces
and even the vasculature of whole organs. cDNA expression libraries in
phage-based vectors have been recently introduced. The use of phage as a vector
for targeted gene therapy is also considered. These and other applications of
phage display for cancer research will be reviewed.
[Back to top] Survivin: Role in Normal Cells and in
Pathological Conditions
L. O’Driscoll, R.
Linehan and M. Clynes
Survivin, an
inhibitor of apoptosis (IAP) containing one baculovirus IAP repeat (BIR)
domain, has been reported to be capable of regulating both cellular
proliferation and apoptotic cell death. Survivin splice variants, survivin-D.Ex3 and survivin-2B, have apparently
retained and lost anti-apoptotic potential, respectively. As survivin was first
discovered due to its high homology with effector cell protease receptor
(EPR-1), a protein involved in blood coagulation, it has been suggested (but
not proven) that EPR-1 may act as a natural anti-sense to survivin in cells.
Survivin homologs have been found in non-human species. Survivin expression has
been described during embryonic development and in adult cancerous tissues,
with greatly reduced expression in adult normal differentiated tissues,
particularly if their proliferation index is low. Survivin has been defined as
a universal tumor antigen and as the fourth most significant transcriptosome
expressed in human tumors. Although survivin is usually located in the cell
cytoplasmic region and associated with poor prognosis in cancer, nuclear
localisation, indicative of favorable prognosis, has also been reported.
Survivin expression has also been reported in a number of proliferating normal
adult tissues.
Extensive research
has been conducted, aimed at increasing our understanding of survivin, by
determining its sub-cellular structure and location, mechanism(s) of action and
control of expression. While much important information on this molecule has
been accumulated, there are still many areas of controversy or limited
information. Further research may enable exploitation of survivin overexpression
in cancer compared to normal tissues, making survivin a potentially attractive
target for cancer therapeutics.
[Back to top] Induction of Senescent-Like Growth Arrest as
a New Target in Anticancer Treatment
Xianghong Wang,
Sai-Wah Tsao, Yong-Chuan Wong and Annie L.M. Cheung
Replicative
senescence is a programmed cellular response in normal cells, the induction of
which depends on the accumulated number of cell divisions. Unlike cells
undergoing apoptosis, senescent cells have a large and flat morphology, express
acidic b-galactosidase (b-gal) and show a permanent cell cycle G1
phase arrest. Recently, senescent-like growth arrest has been observed in many
types of tumor cell lines after exposure to certain chemotherapeutic drugs.
These senescent-like cancer cells show similar morphology, growth arrest and b--gal expression to normal cells undergoing
replicative senescence. However, unlike replicative senescence during the aging
process, the chemodrug-induced senescent-like growth arrest is independent of
cell cycle distribution, telomere length or cell cycle inhibitors. These
observations suggest that induction of senescentlike response may provide a
novel target leading to permanent growth arrest in cancer cells. So far, cell
lines derived from more than 14 types of cancers have shown senescent-like
growth arrest by either introduction of tumor suppressor genes or treatment
with chemotherapeutic drugs. In addition, the drug-induced b -gal expression has been correlated with
cancer cells undergoing terminal senescent-like growth arrest, which provides a
possible marker for this process. This review will describe the evidence on
senescent-like growth arrest in human cancer cells and the molecular changes
that differ between chemodrug-induced senescent-like growth arrest and
apoptosis. In addition, the possible factors and mechanisms involved in this
process are also discussed. Finally, the implications on how senescent-like
growth arrest might be exploited as a possible new target for anti-cancer drugs
are addressed.