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Temozolomide is the most common antineoplastic agent used for
glioblastoma therapy. Some patients can develop early resistance to this
compound. Overcoming chemoresistance could be an important challenge to improve
the prognosis and increase the survival of these patients. The action of some
efflux transporters localized on the blood-brain barrier seems to be the main
mechanism involved in the resistance. An intriguing member of this resistance
mechanism is the P-glycoprotein, an ABC transporter.
In this review, we focus on discussing the role of P-glycoprotein in
temozolomide resistance of glioblastoma multiforme. We summarize the current literature
on structure, localization and activity of this protein, highlighting its role
on the distribution of different drugs used for the treatment of brain tumors
and other cancers.
Keywords: P-gp,
Temozolomide, Chemoresistance, Glioblastoma, Blood-brain barrier, Multidrug
resistance
Abbreviations: P-gp/ABCB1/MDR1:
Permeability glycoprotein; GBM: Glioblastoma Multiforme; TMZ: Temozolomide;
BBB: Blood-brain Barrier; CNS: Central Nervous System; ABC Transporter:
ATP-binding Cassette Transporter; MDR: Multidrug Resistance; BCRP/ABCG2: Breast
Cancer Resistance Protein; MRPs: Multidrug Resistance-Associated Proteins; OS:
Overall Survival; MGMT: O6-methlyguanine-DNA-methyltransferase; MMR: Mismatch
Repair; TMDs: Transmembrane Domains; THMs: Transmembrane α-Helices; NBDs:
Nucleotide Binding Domains; CPT-11: Irinotecan; TKIs: Tyrosine kinase
Inhibitors; EGFR: Epidermal Growth Factor Receptor; ECF: Extracellular Fluid;
siRNA: Small Interfering RNA; RNAi: RNA Interference; lncRNAs: Long Non-Coding
RNAs; NPs: Nanoparticles; EGF: Epidermal Growth Factor
INTRODUCTION
GBM is
the most common and aggressive primary malignant brain tumor [1,2] with an
incidence of 3 cases per 100,000 individuals
each year and a median OS less than one year [1,3].
Current standard of care for GBM consists of surgical resection,
radiation therapy and chemotherapy. TMZ represents the frontline chemotherapy
treatment for GBM [4-6], TMZ together with surgical resection and radiotherapy
has improved the prognosis for GBM patients [1,7-10]; however, despite
improvements in therapeutic treatment, quality of life and prognosis remain
very poor. Moreover the management of GBM patients is complicated by the presence
of drug resistance mechanisms that are a common cause for therapeutic failure
of several drugs, including TMZ.
TMZ is an oral alkylating chemotherapeutic compound that is able to
cross the BBB and acts generating O6-methylguanine adducts which introduce mis-pairs
with thymine; it is not possible to repair these adducts which thus create DNA
damage resulting in cell cycle arrest, cell death and senescence [4,11-13].
An understanding of the molecular processes associated to resistance is
critical to find and develop mechanisms to sensitize GBM cells to TMZ. Several
studies try to explain TMZ resistance; MGMT and the MMR system appear to be
involved in the failure of TMZ treatment [4,13-17].
A possible candidate responsible of resistance to antineoplastic
agents, including TMZ, in GBM patients is the P-gp which belongs to the ABC
transporter family [18].
P-gp (ABCB1 or MDR1) is an ATP-driven efflux pump which
utilizes ATP hydrolysis to transport various substrates across the plasma membrane
of several tissues [4]; protein expression has been reported not only in
healthy tissues but also in many tumors, including brain tumors [18-23].
Concerning cancer, P-gp is a potent efflux-pump, which through its mechanism of
action, is involved in the expulsion of several drugs out of the tumor cells:
this mechanism provides an explanation for the resistance of tumor cells to
multiple antineoplastic agents known as MDR [4,18,24].
The present review is focused on the role played by P-gp in TMZ
resistance of GBM analyzing the molecular and biological mechanisms through
which this efflux pump could represent a limiting factor for success of TMZ
treatment.
Structure and Function of P-gp
BBB is the greatest challenge in the treatment of CNS tumors,
representing the primary obstacle to drug delivery into CNS. It is a dynamic
interface that separates the brain from the blood ensuring CNS homeostasis and
protecting the brain from potentially harmful substances [18,25,26].
BBB consists of capillary endothelial cells not fenestrated, joined
together by tight junctions limiting the passage of solutes [18,27-29].
Moreover brain endothelial cells are characterized by the presence of specific
transport systems that regulate the entry of compounds [30]. The major
transport system is represented by the ABC transporter family. These efflux
transporters are responsible of MDR phenotype, binding and hydrolyzing ATP; BBB
is therefore strongly protective for the CNS, but at the same time becomes a
limiting factor to treatment of CNS diseases regulating the entry of drugs into
the brain.
ABC transporter family is an evolutionarily conserved family of
proteins suggesting its paramount role in survival of the species
[19,21,31-33]; so far, 49 ABC transporters have been identified and classified
in different human tissues [33-36]. The prominent members of this family are
P-gp, BCRP (or ABCG2) and MRPs.
P-gp was the first of these transporters to be identified and analyzed
[37,38]; it is currently the best known efflux-pump in humans, probably for its
significant role in cancer cells chemoresistance. P-gp is coded by the multiple
drug resistance MDR1 gene localized on chromosome 7, it is a single 170
kDa polypeptide [33]. The protein is made of two TMDs, each consisting of six
highly hydrophobic TMHs, and two NBDs involved in the binding and hydrolysis of
ATP [33,39-41].
P-gp is expressed preferentially in organs with excretory role and in
tissues with barrier function, particularly in the apical membrane of
epithelial cells including liver, kidney, intestine and apical membrane of
endothelial cells of the capillaries of the brain [33]: protein localization
suggests a role in the defense of susceptible organs, such as the brain, from
toxic compounds and in the secretion of metabolites or xenobiotics [33,42]. In
addition P-gp expression was also found in pancreas, adrenal gland, placenta, testis
and on the surface of hematopoietic cells [33,43].
P-gp is a plasma membrane protein able to interact with several
compounds including chemotherapeutic drugs, immunosuppressive agents, calcium
channel blockers and natural products, among many others, pumping them out of
the cells [18,33,39,41,44-46]. P-gp
substrates differ in size, structure and function, even if most of them are
weakly amphipathic and relatively hydrophobic [33,41]. This broad substrate
specificity is in agree with P-gp role as efflux pump involved in removing
substrates from the inner to the outer side of cell plasma membrane or directly
into the extracellular space, preventing the accumulation inside tissues of a
variety of compounds, such as drugs, xenobiotics, toxins and metabolites
[19,47].
P-gp Influences CNS
Distribution of Chemical Agents
Several mechanisms seem to be involved in the poor response of brain tumors
to chemotherapy, drugs delivery to the CNS continues to be a clinical
challenge.
Some studies have shown the role of P-gp and other ABC transporters, especially
BCRP, in preventing therapeutic agents penetration into the brain, including
conventional antitumor compounds such as vinca alkaloids, anthracyclines and
taxanes [19,48-52]; indeed the expression of these transporters is associated
with inherent or acquired MDR [53]. Moreover, recent literature suggests that
P-gp and BCRP work together and cooperate at the BBB with a synergistic effect,
reducing significantly brain penetration of drugs and consequently their
effectiveness [18,54-58].
CPT-11 is an antineoplastic agent which acts inhibiting DNA
topoisomerase I, a nuclear enzyme involved in DNA replication, repair and
transcription [59, 60]. This compound is strongly used for colorectal cancer
treatment and shows an interesting activity against other type of tumors,
including GBM [59, 61]. In vivo and in vitro studies suggested that CPT-11
is able to cross the BBB, but its activity is strongly limited by P-gp action
that reduces brain penetration not only of CPT-11, but also of its active
metabolite [59].
de Vries et al. demonstrated that BCRP and P-gp work together to reduce
plasma exposure and brain penetration of topotecan in a knockout mice model
[57]. Topotecan, inhibitor of topoisomerase I, is a derivative of camptothecin;
its efficacy is confirmed in the treatment of ovarian, lung, and cervical
cancer and seems to have a moderate effect also in adults with primary
malignant glioma [57,62].
Lapatinib, antineoplastic agent, is a member of the
4-anilinoquinazoline class of TKIs; different studies on lapatinib and other
TKIs reported the involvement of the efflux transporters of the BBB, among
which P-gp, as responsible of low brain concentration of these compounds
[63-66]. Regarding TKIs, in another study Agarwal et al. suggested the
involvement of P-gp and BCRP on the distribution of an EGFR inhibitor,
gefitinib, to the CNS [54]. In vivo
and in vitro experiments showed that
both transporters are able to reduce the intracellular accumulation of
gefitinib favoring its outflow. As confirmation of these results, brain distribution
of gefitinib improved and increased when it was co-administered with a dual
P-gp and BCRP inhibitor, suggesting a combined therapy of gefitinib and this
type of inhibitors as a novel opportunity for cancer treatment [54].
Another inhibitor of EGFR, erlotinib, is a known substrate of P-gp which
prevents its brain penetration; unfortunately erlotinib does not seem to be
successful in different clinical trials for GBM [67].
In vivo preclinical studies showed that
P-gp reduces the brain penetration of alkaloid compounds too and especially of
vinblastine, an antineoplastic agent able to bind to tubulin and inhibit
microtubule formation, resulting in disruption of mitotic spindle assembly and
arrest of the cell cycle [68]. In particular, the authors compared the
pharmacokinetics of vinblastine in P-gp knockout and wild type mice. They
observed an increase of drug accumulation in tissues, especially in the brain,
and a reduction in drug excretion in P-gp knockout mice, suggesting
consequently an involvement of P-gp in the efficacy of vinblastine.
Finally by in vivo and in vitro studies, P-gp appeared to
interfere with novel anticancer molecules too, such as vemurafenib, a BRAF
inhibitor approved for the treatment of patients with metastatic melanoma;
active efflux of vemurafenib by P-gp and BCRP strongly reduces its brain
distribution [69]. These observations could be very useful for the assessment
of vemurafenib in the treatment of brain metastasis.
P-gp and Anticancer Strategies
MDR phenomenon in cancer cells is associated to their resistance to a
wide range of anticancer compounds, even if structurally and functionally
different [33,70,71]. Intrinsic or acquired resistance could be associated to
several mechanisms and biological processes such as action of efflux systems,
including P-gp and other ABC transporters, enhanced DNA repair, alteration in
apoptosis and metabolic modifications [72,73].
Several research studies are conducted with the purpose to find
strategies to sensitize cancer cells to chemotherapeutic agents overcoming drug
resistance, in particular P-gp inhibitors/modulators have been developed
representing a significant opportunity in clinical setting for P-gp-mediated
drug resistance.
Different P-gp inhibitors have been identified and some of these
compounds may be efficient in cancer treatment in association with other
antineoplastic drugs, such as vincristine and daunorubicin [31, 33]. The P-gp
inhibitors are classified in different groups depending on potency, selectivity
and drug-drug interaction potential; currently it is possible to distinguish
four generations of P-gp inhibitors.
About first-generation inhibitors, many compounds belong to this group
among which calcium channel blockers, immunosuppressants, anti-hypertensives,
antiarrhythmics and antiestrogens [33]. In 1981, Tsuruo et al. using leukemia
cells observed that verapamil, a calcium channel blocker, could reverse drug
resistance [74]. Verapamil and cyclosporine A are two important examples of
early discovery of P-gp inhibitors/modulators, both are P-gp substrates and act
competing with other P-gp substrates for efflux by a mechanism of competitive
inhibition [33,45]. Unfortunately, the combination of first-generation MDR
inhibitors with anticancer drugs leads to toxic side effects, especially
serious cardiovascular toxicity; this aspect makes their use clinically difficult,
therefore they were
replaced by second generation inhibitors [33,45].
Second generation inhibitors were developed in order to increase
inhibitory effects and reduce toxicity at the same time. These compounds are
analogues of the first generation inhibitors and they were synthesized by
structurally modifications of first generation inhibitors. Valspodar is the
best known second generation inhibitor, it has been evaluated in association
with anticancer drugs in several clinical trials [33,75-90]. Other examples of
second-generation inhibitors are non-immunosuppressive analogues of cyclosporin
A, R-enantiomer of verapamil and dexverapamil [33]. Despite second-generation
P-gp inhibitors have a better pharmacological profile compared to the
first-generation ones, unfortunately these compounds show some disadvantages, indeed they may be responsible of
unexpected drug-drug interactions and they are able to inhibit cytochrome P450
resulting in an increase of drug toxicity [74,91-93].
In order to improve the features of P-gp modulators/inhibitors, a
third-generation of inhibitors with high affinity for ABC transporters, high
specificity and potency has been developed. Third generation includes compounds
such as tariquidar and elacridar [33]; tariquidar binds to P-gp through a non-competitive
mechanism, while elacridar acts by binding to the allosteric site of P-gp
[33,94].
Some studies show that the inhibition of P-gp improves brain drug
delivery of some anticancer compounds and consequently the treatment of CNS tumors;
Fellner et al. demonstrated that P-gp inhibition by valspodar increases
paclitaxel brain levels in nude mice with intracerebrally implanted human U-118
MG glioblastoma [18,95]. Even if in vitro
and in vivo studies report that
these drugs are associated to an enhancement of chemosensitivity, unfortunately
they do not appear associated with an improvement of OS in cancer patients
[72,96,97], moreover they continue to show unexpected toxic effects [33,71].
Probably side effects and drug-drug interactions may be responsible of
ABC transporter inhibitors failure, limiting their clinical application and
their translation from animal model to patient. In addition, inhibiting a
specific transporter, the remaining ABC transporters, that are coexpressed in
the tumor, could compensate by their biological activity, interfering with
inhibition and reducing the effectiveness of the drug inhibitor.
Some research studies tried to develop novel P-gp inhibitors which
constitute the fourth generation [33,71]; substances belonging to this group
are natural agents and their derivatives, surfactants and lipids,
peptidomimetics. Surfactants are responsible of alteration of membrane lipids
integrity and are able to modify P-gp structure [33,98] determining loss of
P-gp function [33,98]; other substances act through other mechanisms such as
limitation of P-gp ATPase activity [33,99]. Finally other agents associate
transporters inhibition with another favorable biological function (dual
ligands), for example some aminated thioxanthones were able to inhibit cell
growth and P-gp activity at the same time [33,100].
Despite all the efforts to develop P-gp inhibitors, only few compounds
have been evaluated for their capacity to enhance drug delivery into the CNS;
currently researchers are trying to identify new approaches and to find new
P-gp inhibitors or novel mechanisms of action, among which natural compounds,
small molecule inhibitors, RNA interference and epigenetic regulation [72].
For instance, several TKIs are ABC transporters modulators and have
been examined to allow drugs to overcome the BBB increasing their bioavailability;
probably many TKIs are very functional for their capacity to inhibit both P-gp
and BCRP at the same time. Intriguingly, gefitinib, a TKI, increased topotecan penetration into the brain ECF
likely via inhibition of BCRP and P-gp [101-105]. Some in vivo or in vitro
studies described other TKIs, such as nilotinib and icotinib, which appeared
able to inhibit ABC transporters enhancing chemotherapeutic drugs efficacy
[72,106-108].
Flavonoids, alkaloids, coumarins and terpenoids are natural compounds
that in vitro or in vivo studies seem to be associated with P-gp downregulation and
decrease of proteins expression; their application is promoted by low cost, low
toxicity and action extended to other ABC transporters too [72,109-114]. Among
these compounds curcumin, active principle of Curcuma longa, was
examined in some in vitro models of
breast, colon and prostate cancer and appeared to be associated to an increase
of sensitivity to some drugs [72,115-118].
Another very interesting approach to fight multidrug resistance is
given by the possibility to block and silence ABC transporters expression
through siRNA or RNAi mechanisms, approaches which involve RNA molecules to
inhibit gene expression or translation. RNAi technology
was used for the first time in 2003 in human cancer cells to knockdown the P-gp encoding mRNA reversing
chemoresistance [72]. Since then several in
vitro studies, especially on gastric, pancreatic, lung and ovarian cancer,
designed stable vectors to overcome chemoresistance decreasing P-gp and other
ABC transporter expression, sensitizing cells to antineoplastic compounds and
promoting drug accumulation [72,119-120]. LncRNAs is a novel class of
transcripts which includes important regulators of transcriptional processes.
The lncRNAs have a wide range of functions in cellular and developmental
processes and are able to regulate several genes including genes associated to
anticancer resistance.
Another strategy to fight MDR is represented by the use of microRNAs,
which are endogenous, nonprotein-coding, short RNAs of 20–22 nucleotides,
involved in gene expression regulation by the ability to bind mRNA and silence
genes. The genes inhibited by microRNAs are involved in different biological
processes such as embryogenesis, cell development, proliferation and apoptosis
[121,122]. Interestingly, microRNAs are dysregulated in cancer. Researchers are
investigating about the possibility of using these molecules as diagnostic or
predictive or prognostic biomarkers in different tumors. Their alterations are
involved at various levels of chemoresistance mechanism. Some studies
identified a pattern of microRNAs responsible of the inhibition of P-gp expression
in MCF-7 breast cancer cells and esophageal squamous carcinoma cells
[74,123-125]. Other microRNAs are involved in ABC transporters inhibition
improving sensitivity to antineoplastic agents, for example miR-122 in
hepatocellular carcinoma cells [72,126], miR-19a and miR-19b in gastric cancer
cells [72,127], miR-145 in ovarian cancer cells [72,128], miR-137 in
neuroblastoma cells in which for instance it regulates the response to
doxorubicin treatment [72,129]; intriguingly, miR-21 represents another
molecule involved in the response, in particular it appears to promote
doxorubic in resistance in GBM T98G cells [130].
Recently some studies identified a role of epigenetic modifications,
such as DNA methylation and histone modifications, in the regulation of gene
expression associated to chemosensitivity and resistance [72,131].
Finally, nanotechnology-based approach is being developed to overcome
multidrug resistance, this approach consisting in constructs with the function
to deliver chemical compounds, including drugs, such P-gp inhibitors, or miRNA
or RNAi, to specific target cells. These constructs include liposomes, polymer
and peptide/protein conjugates, polymeric micelles, polymeric, lipid and
inorganic NPs; they show differences in structure, for instance liposomes are
small artificial vesicles consisting of lipid bilayers, while NPs are carriers
with natural or synthetic polimeric matrix. Concerning these constructs in general,
even if they have different conformation, they all function as vehicle of
chemical compounds without giving problems associated to high dosage, cell
toxicity, low specificity and uptake. Delivery of antitumor molecules to cancer
cells through a nanotechnology-based approach could be an interesting novel
opportunity to inhibit P-gp expression enhancing intracellular drug
concentration [72,74].
P-gp Contributes to
Chemoresistance in Glioblastoma
Resistance to antineoplastic agents is the main reason for treatment
failure of brain tumors, in particular resistance to TMZ is often quickly
acquired by GBM cells; for this reason different studies try to understand
molecular mechanisms underlying TMZ resistance with the aim of developing
strategies to sensitize GBM cells to TMZ.
The first predictive and prognostic molecular biomarker linked to TMZ
resistance is the enzyme MGMT implicated in DNA damage repair associated to TMZ
action. According to Hegi et al., hypermethylation of MGMT promoter gene, and
consequently its silencing, is observed in about 50% of GBM cases and is
associated to a better prognosis and a longer survival regardless of the
treatment [132]. Moreover, a
major survival benefit was observed in patients with methylatated MGMT promoter
treated with a combination of TMZ and radiotherapy compared to patients treated
with radiotherapy only, suggesting an association between MGMT methylation and
response to TMZ treatment in adult GBM patients.
Unfortunately, chemoresistance is a very complex mechanism linked to
different biological processes; therefore MGMT promoter methylation status is
not the only marker in GBM resistance. Sardi et al. studying methylation status
of MGMT promoter and analyzing the expression of MGMT in pediatric brain tumors
treated with TMZ, showed that MGMT was nearly always unmethylated in contrast
to what is observed in adult brain tumors [133]; moreover the expression level
of MGMT appeared variable. The unmethylated status of MGMT along with the
involvement of other DNA repair mechanisms could justify the reduced efficacy
of TMZ in pediatric brain tumors.
Another factor associated to chemoresistance in CNS tumors is the
expression and the activity of efflux pump proteins, among these P-gp is the
first identified xenobiotic drugs ATP-dependent efflux pump and the most
examined.
Some studies investigated about the role of P-gp in TMZ resistance.
Schaich et al. in GBM patients treated with TMZ, in order to investigate the
possible involvement of MDR1 gene variants in patient’s survival, discovered
that the exon 12 C1236T polymorphism is predictive of the outcome independently
from MGMT status [134]. This observation suggests that this polymorphism could
play a role in patient response to TMZ; according to some hypotheses this effect
could be associated to the genetic mechanism of linkage disequilibrium or to an
altered affinity of P-gp for TMZ. In addition, in vitro analysis showed an increase of cytotoxicity and cell death
in MDR1 negative cells after exposure to TMZ compared to MDR1-expressing cells.
In the same study, as confirmation of the involvement of MDR1 in the resistance
to TMZ, the authors observed a trend to restoration of chemosensitivity to the
drug in MDR1-expressing cells when treated with a combination of TMZ and
MDR1-inhibitor/modulator, especially cyclosporine A. Finally Schaich et al.,
reported a significant P-gp expression not only in parenchymal tissue but also
in GBM vessels suggesting that drug delivery to the brain and drug resistance
are influenced by the activity of P-gp of endothelial cells too [134].
In another study, using in vivo
and in vitro models, authors tried to
investigate the mechanisms underlying P-gp-mediated resistance to TMZ in GBM
[135]. The authors distinguished an active and an inactive form of P-gp, both expressed in GBM cells; TMZ induced the
active form of P-gp, indeed an increase of active P-gp was observed when GBM
cells were treated with TMZ even if for a short time, the increase was greater
for chronical treatment of GBM cells with TMZ. In the study was observed that
the increase of active P-gp was induced by TMZ through a bifasic mechanism
accomplished by two steps. Firstly, TMZ treatment promoted the traffic of
active intracellular P-gp to the cell membrane directly; in a second phase the
increase of P-gp was associated to an increase of transcription of MDR1 gene,
induced by TMZ-mediated production of EGF, and subsequently to an increase of
P-gp protein synthesis.
Regarding P-gp cellular traffiking, TMZ treatment reduced subcellular
P-gp level and at the same time increased the active P-gp in the cell membrane,
the activation of P-gp requiring a conformational change; moreover the increase
of P-gp protein expression appeared to be time-dependent.
As far as the transcription of MDR1 gene is concerned, TMZ promoted
this molecular mechanism increasing firstly production and release of EGF, thus
promoting enhancement of EGFR signaling, resulting in the activation of the
heterodimeric transcription factor AP-1 which in the end promotes the transcription
of MDR1 gene. An increase of transcription MDR1 gene protected GBM cells from
TMZ treatment with consequent increase of cell survival; as confirmation of
these results MDR1 knockdown cells showed an increase of cytotoxicity with a
decrease of survival when treated with TMZ. Therefore through an autocrine
mechanism TMZ-resistant GBM cells expressed EGFR and in the presence of TMZ
produced EGF at the same time, in this way EGF stimulated the same cells
inducing MDR1 gene expression through AP-1 activation.
In the same study, the authors observed also that on the other hand the
use of kinase inhibitors, such as erlotinib, to block EGFR signaling in
combination with TMZ reduced P-gp expression and promoted the action of TMZ on
GBM cells, confirming the role and the involvement of EGFR signaling in the
induction of MDR1 expression [135].Therefore concerning in vivo models they reported that combined therapy of erlotinib
with TMZ promoted a decrease of tumor volumes, confirming the results obtained in vitro.
To summarize, TMZ activates cell surface P-gp, promotes protein
expression and the enhancement of the function; combined therapy of TMZ with
EGFR inhibitors prevents P-gp activation sensitizing GBM cells to TMZ treatment
(Figure 1). In another report Munoz
et al., using in vitro model,
investigated about the interaction between P-gp and TMZ, in particular they co-administered
P-gp fluorescent target with TMZ observing a competitive mechanism between TMZ
and the other P-gp substrates [5]. According to the study, competitive
mechanism was useful for combined treatment of GBM cells especially of TMZ with
P-gp inhibitors, this association resulted in an increase of Caspase 3 activity
reducing cell survival. Finally, using a computer modeling system, authors
identified a specific region of interaction between TMZ and P-gp localized in
the same area of interaction of other P-gp targets, and especially near ATP
binding site.
Another study reported the involvement of miRNA-9 in TMZ resistance in
GBM cancer stem cells CD133+ (prominin-1), this miRNA appeared connected to
MDR1 gene [5,136]. In particular the authors observed that TMZ chemoresistance
was associated to an increased level of miRNA-9 which promoted upregulation of
MDR1 expression through activation of the SHH/PTCH1/MDR1 axis. Experiments
carried out by targeted siRNA confirmed the involvement of SHH pathway in MDR1
upregulation. In general in brain tumors, some microRNAs appear involved in
drug sensitivity/resistance. Giunti et al., using in vitro models, showed that miR-21, an oncogenic miRNA
overexpressed in human breast cancer, was associated with resistance to
doxorubicin in GBM T98G cells [130]; the authors observed a greater sensitivity
of GBM T98G cells to doxorubicin, with an increase of apoptosis, when they were
transfected with anti-miR-21 inhibitor compared to not trasfected control
cells.
However, Zhang et al. showed in glioma cells and especially
in P-gp overexpressed cells, an increase of sensitivity to P-gp substrates
under the action of TMZ [137]. They reported that when TMZ was co-administered
with doxorubicin, TMZ affecting P-gp activity promoted an increase of
doxorubicin accumulation with a synergistic mechanism, suggesting that TMZ
could reverse doxorubicin resistance improving the treatment efficacy.
Doxorubicin is able to promote P-gp expression and in general the expression of
the ATP-binding superfamily transporter proteins. In vitro models therefore confirmed synergistic effect between
doxorubicin and TMZ showing an increase of doxorubicin accumulation in presence
of TMZ, accumulation was significantly higher in presence of high dosage of
TMZ. Analyzing the effect of TMZ on drug efflux pump, the authors showed that
TMZ does not change P-gp protein expression, but acts inhibiting P-gp directly
and especially decreasing P-gp ATPase activity. This mechanism of action could
explain synergistic effect of combination between TMZ and doxorubicin; the
mechanisms which promote accumulation of doxorubicin may represent a promising
novel strategy against malignant gliomas (Figure 2) [137].
TMZ affecting P-gp sensitizes GBM cells to
different drugs that are all substrates of P-glycoprotein; therefore in general
drugs that synergized with TMZ are substrates of P-gp.
According to Riganti et al., also in GBM
cancer stem cells TMZ promoted the accumulation of other drugs affecting P-gp activity,
in particular TMZ appeared to methylate Wnt3a gene promoter reducing its
expression [138]; Wnt3a is an important factor involved in cell growth,
tumorigenesis and stemness maintenance. The diminished expression of Wnt3a was
associated with a decrease of transcriptional activation of ABCB1 resulting in
reduced P-gp protein expression and efflux pump activity. Therefore, through
this mechanism, TMZ may sensitize GBM cancer stem cells to P-gp substrate promoting
their accumulation in tumor cells and consequently their cytotoxic and
antiproliferative effects.
Several P-gp inhibitors are not successful in
clinical trials because they show low specificity and high toxicity, for all
these reasons TMZ may represent an alternative strategy able to act as
chemotherapeutic drug and chemosensitizer agent at the same time [138].
Concluding Remarks and Future Perspective
GBM is the most common and malignant primary
brain tumor in adults with a dismal prognosis, a survival of up to 12-18 months
and a very low possibility to survive longer than 5 years [137,139].
The main cause of the frequent relapse of
this disease is due to chemoresistance of GBM stem cell. Generally GBM stem
cell resistance is associated to alterations in different biological processes
such as cell cycle, apoptosis, DNA repair; moreover, in brain tumors the BBB is
the main responsible of the difficulty for some chemotherapy agent to reach
CNS, promoting drug resistance.
Chemoresistance is mainly associated to the
activity of efflux pumps; in particular P-gp, BCRP and MRPs proteins work
together on the BBB and on the plasma membrane of brain tumors cooperating and
playing a relevant role in the MDR phenomenon.
TMZ represents the frontline treatment for
GBM, so it is very important to understand the mechanisms underlying TMZ-resistance and find novel approaches to overcome it.
Recently some studies analyzed the key role
of P-gp in drug resistance mechanism observed in GBM and especially its
implication in TMZ resistance. These reports showed the involvement of genetic
variant of MDR1 gene in response to TMZ and the implication of TMZ in P-gp activation;
in particular TMZ seems to promote P-gp expression and function. However,
targeting P-gp increases sensitivity to TMZ resulting in an increase of
apoptosis and therefore reversing the resistance to TMZ. In addition TMZ
competes with P-gp substrates, including some antineoplastic agents,
representing a promising opportunity for combined targeted therapies.
Further preclinical and clinical investigations are
necessary to better understand and overcome resistance mechanism of GBM to TMZ
associated to P-gp and other MDR mechanisms, in order to develop novel
therapeutic strategies and new molecules or optimize combined therapies for the
treatment of CNS tumors.
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