# Peroxisome Proliferator-Activated Receptors (PPARs) as Potential Inducers of Antineoplastic Effects in CNS Tumors

Authors: Lars Tatenhorst; Eric Hahnen; Michael T. Heneka
Journal: PPAR Research
 (2008)

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## Abstract

The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS). The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy.


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## Body

## 1. Review Criteria

For this review we searched NCBI
PubMed articles including early-release publications. Search terms included
peroxisome proliferator-activated receptor (PPAR) in conjunction with “glioma”
or “glioblastoma” or “astrocytoma” or “neuroblastoma.” The abstracts
of retrieved citations were reviewed and prioritized by relevant content. Full
articles were obtained and references were checked for additional material when
appropriate. Only papers published in English between 1995 and 2008 were included.


## 2. PPARs

The peroxisome proliferators-activated
receptors (PPARs) are ligand-inducible transcription factors which belong to
the superfamily of phylogenetically related proteins termed nuclear hormone
receptors (NHRs). Three different PPAR isotypes (PPARα, PPARβ, also called δ,
and PPARγ) have been identified in various species and show structural homology
[1, 2]. PPARγ is found in two different
isoforms, PPARγ1 and PPARγ2 [3].PPARα, PPARβ/δ
and PPARγ show unique spatio-temporal tissue-dependent patterns of expression
during fetal development in a broad range of cell types with ectodermal,
mesodermal, or endodermal origin. PPARs are involved in several aspects of
tissue differentiation and development, such as the differentiation of the
adipose tissue, brain, placenta, and skin [4]. Therefore, it appears that the
PPAR isoforms developed from a common PPAR gene with broad ligand-binding
specificity, itself derived from the ancestral orphan receptor [5].PPARs
regulate gene expression via multiple mechanisms, thereby functioning as
obligate heterodimers with retinoid-X-receptors (RXRs). Like the other members
of the NHR superfamily, PPARs are composed of four domains. The highly
conserved DNA-binding domain together with its zinc finger domain is a common attribute of all family members.
The DNA binding domain is linked to the C-terminal ligand binding domain by the
hinge region. The E/F domain is responsible for the dimerization of PPARs with
RXRs and the ligand-dependent transactivation function of the receptor. The
N-terminal domain finally is involved in the ligand-independent regulation of
the receptor activity (reviewed in [6]).PPARs
stimulate gene expression through binding to conserved DNA sequences, termed
peroxisome-proliferator response elements (PPREs), present in the promoter
region of their target genes. In the absence of ligands, these heterodimers are
physically associated with corepressor complexes which suppress gene
transcription [4]. However, upon binding of a ligand to the
receptor, the NCor-containing corepressor complexes are dismissed and replaced
with coactivator complexes. These coactivators are then linked to the basal
transcriptional apparatus, thereby activating gene transcription [7].PPARs act prinicipally as lipid sensors and regulate whole body
metabolism in response to dietary lipid intake and direct their subsequent
metabolism and storage [8]. The prototypic member of the
family, PPARα,
was initially reported to be induced by peroxisome proliferators, and now
denotes the subfamily of three related receptors. The natural ligands of these
receptors are dietary lipids and their metabolites. The specific ligands
interacting with the individual receptors have been difficult to establish, owing
to the relatively low-affinity interactions and broad ligand specificity of the
receptors.PPARα acts primarily to regulate energy homeostasis
through its ability to stimulate the breakdown of fatty acids and cholesterol,
driving gluconeogenesis and reduction in serum triglyceride levels. This
receptor acts as a lipid sensor, binding fatty acids and intiating their
subsequent metabolism. PPARα
binds a number of lipids including fatty acids, eicosanoids, and other natural
lipid ligands. Its dominant action is to stimulate adipocyte differentiation
and to direct lipid metabolites to be deposited in this tissue. PPARγ
operates at the critical metabolic intersection of lipid and carbohydrate
metabolism. PPARγ
activation is linked to reduction in serum glucose levels, likely as a
secondary effect of its ability to regulate endocrine factors. It is this
latter activity that has led to the development of specific PPARγ agonists for the treatment of type-2 diabetes [9]. The PPARβ/δ binds and responds to
VLDL-derived fatty acids, eicosanoids including prostaglandin A1 [10] and appears to be primarily
involved in fatty acid oxidation, particularly in muscle.Binding of PPARs to their specific
ligands leads to conformational changes which allow co-repressor release and
co-activator recruitment. Even though all PPARs can be attributed to a common
ancestral nuclear receptor, each PPAR isotype has its own properties with
regard to ligand binding. Synthetic thiazolidinediones (TZDs), which are
commonly prescribed for the treatment of type-2 diabetes, are selective PPARγ
ligands. Naturally occurring PPARγ ligands include eicosanoids and the
cyclopentenone prostaglandin 15d-PGJ2. The best characterized PPARγ
agonists are the TZDs including pioglitazone (Actos) and rosiglitazone
(Avandia), which are Food and Drug Association (FDA) approved for treatment of
type-2 diabetes. The
TZD troglitazone (Rezulin) was introduced in the late 1990s but turned out to
be associated with an idiosyncratic reaction leading to drug-induced hepatitis.
It was withdrawn from the US
market in 2000, and from other markets soon afterwards. There are a number of
non-TZD-based PPARγ agonists, such as GW78456 and
others that have been developed. PPARα ligands include fibrates that are
commonly used for the treatment of hypertriglyceridemia and the synthetic
agonists WY14,643 and GW7647. PPARβ/δ agonists include the prostacyclin
PGI2, and synthetic agents including GW0742, GW501516, and GW7842.
All three PPAR isotypes can be activated by polyunsaturated fatty acids with
different affinities and efficiencies [8, 11]. An overview addressing the
affinity of several natural and synthetic ligands has been summarized recently [12].All PPARs have been described in the
adult and developing brain as well as in the spinal cord. Furthermore, it has
been suggested that PPAR activation in neurons may directly influence neuron
cell viability and differentiation [13–17]. While PPARβ/δ has been found in neurons of
numerous brain areas, PPARα and γ have been localized to more restricted brain
areas [18, 19]. The localization of PPARs has also
been investigated in purified cultures of neural cells. PPARβ/δ is expressed in immature
oligodendrocytes where its activation promotes differentiation, myelin
maturation and turnover [20, 21]. The γ isotype is the dominant isoform in microglia.
Astrocytes possess all three PPAR isotypes, although to different degrees
depending on the brain area and animal age [22, 23].The role of PPARs in the CNS is mainly related to lipid metabolism; however,
these receptors have been implicated in neural cell differentiation and death
as well as in inflammation and neurodegeneration. The expression of PPARγ in the brain has been extensively
studied in relation to inflammation and neurodegeneration [14]. PPARα has been suggested to be involved
in the acetylcholine metabolism [24] and to be related to excitatory
amino acid neurotransmission and oxidative stress defense [18]. However, mice lacking PPARα
function appear healthy and fertile and do not show neurological phenotypes,
suggesting that PPARα
is dispensable for brain development [25]. In contrast, loss of PPARγ
has been shown to be embyonically lethal [26]. Whereas PPARβ/δ remains highly expressed in the rat
CNS, the expression of PPARα and γ decreases postnatally in the brain [27]. In retina, all three receptors are
expressed [23, 27, 28]. Even though this pattern of
expression, which is isotype-specific and regulated during development,
suggests that the PPARs may play a role during the formation of the CNS, their
function in this tissue is still poorly understood. Both in vitro and in vivo observations show that PPARβ/δ is the prevalent isoform in the
brain beeing found in all cell types, whereas PPARα is expressed at very low levels
predominantly in astrocytes [29]. Acyl-CoA synthetase 2, which is
crucial in fatty acid utilization, is regulated by PPARβ/δ at the transcriptional level,
providing a facile measure of PPARβ/δ action. This observation strongly
suggests that PPARβ/δ participates in the regulation of
lipid metabolism in the brain. This hypothesis is further supported by the
observation that PPARβ/δ null mice exhibit an altered
myelination of the corpus callosum. Such a defect was not observed in other
regions of the central nervous system, and the expression of mRNA encoding
proteins involved in the myelination process remained unchanged in the brain [30].As mentioned above, PPARs were at first identified as controllers of
lipid metabolism. Presently, it turned out that PPARs also play a role in
controlling important cellular functions like energy homeostasis, diabetes,
cell proliferation and cell death, differentiation, inflammation, and even
cancer [6, 31]. Especially PPARγ and its agonists have been demonstrated to
induce antineoplastic effects in several types of cancer (reviewed in [7]). In the following we focus on the role of PPARs as
potential inducers of antineoplastic effects in highly abundant CNS tumors,
namely astroglioma and neuroblastoma.


## 3. Astroglioma

Malignant astrocytic gliomas
represent the largest proportion of all primary brain tumors in adults [32, 33]. The characteristic feature of
glioma cells is a high proliferation rate, accompanied by the ability to invade
far into the healthy brain tissue. According to the WHO classification of
tumors of the nervous system [32], gliomas are ranked with increasing
malignancy in four classes from WHO grade I to WHO grade IV. The vast
resistance against irradiation and chemotherapy and the prevalent recurrence
after surgical resection are the main reasons for the poor prognosis in
treatment of malignant astrocytic gliomas. Despite
multimodal therapeutic approaches, the mean survival time of patients with WHO
grade IV glioblastoma multiforme, which is also the most frequent brain tumor,
is only about one year after diagnosis [33]. Although medical research has been
intensified in the past decades, the overall survival of patients with
malignant astrocytic gliomas was not essentially improved [34].All isoforms
of PPARs are expressed in the brain [35, 36] as well as in a variety of rat and
human astroglial cell lines [7, 37–44]. PPARγ has been shown to be expressed at
high levels in human glioblastomas [31, 37, 45, 46]. Based on findings in other
neoplastic disease, several natural and synthetic ligands of PPARs have been
tested for their efficacy in the treatment of astroglioma. Bezafibrate and
gemfibrozil, both PPARα
agonists, inhibited the cellular viability of glioblastoma cell lines [47]. A different effect was observed
when human T98G glioblastoma cells were treated with other PPARα ligands, clofibrate and Wy-14,643. These
ligands strongly downregulated the expression of semaphorin 6B, a member of the
semaphorin family of axon guidance molecules [39], suggesting suppression of glioma
invasion mechanisms by these PPARα
agonists. However, no direct influence of Wy-14,643 on proliferation or induced
cell death was observed in either human or rat glioma cells [43].Treatment
with conjugated linoleic acid (CLA) inhibited growth in primary human
glioblastoma cells as well as ADF glioblastoma cells [13, 40, 48]. In ADF cells this was associated
with an increase of PPARα
and a decrease of PPARβ/δ
expression, whereas PPARγ
levels were unaltered [40]. Cimini et al. found that CLA and
the PPARγ-specific
agonist GW347845 reduced glioma cell growth and induced apoptosis [13, 48]. The authors suggested that this
effect was mediated by PPARγ
activation. This conclusion was supported by the finding that the PPARγ
antagonist GW259662 completely prevented both the CLA and GW347854X-induced
effects on cell growth and apoptosis. Furthermore, PPARγ agonists reduced cell
adhesion, cell migration, and tumor invasion which was associated with a
decrease in matrix metalloproteinase 2 (MMP2) levels. The authors stated that
activation of PPARγ
is likely to be responsible for these latter effects, since the PPARγ
antagonist GW259662 completely abolished these effects [13]. Furthermore, treatment with CLA
and GW347845 significantly decreased VEGF isoforms, indicating that PPARγ
may also inhibit angiogenesis in gliomas [48].Pérez-Ortiz
et al. reported that generation of reactive oxygen species (ROSs) was likely to
be responsible for glitazone-induced glial cell death [35, 49], which is in line with findings of
Kang et al. [50]. Interestingly, in four different glioma cell lines (A172, U87-MG, M059K,
M059J) rosiglitazone led to inhibition of proliferation and induction of
apoptosis in a PPARγ-dependent
way since there the antagonist GW9662 partially reverted this effect [46]. Ciglitazone and the putative
natural PPARγ
ligand PGJ2 inhibited proliferation and induced apoptotic cell death
in human [38] and rat glioma cells, and apoptotic
cell death was correlated with the upregulation of Bax and Bad protein levels [43]. Similar effects have been
described by Zang et al. [44], who also reported that a combination
of pioglitazone with all-trans
retinoic acid (ATRA) increased the cytotoxic effect. Tetradecylthioacetic acid
(TTA), a saturated fatty acid and PPAR ligand, inhibited growth of BT4Cn rat
glioma cells at increased levels as compared to the PPARγ ligand rosiglitazone [37]. Furthermore, TTA reduced tumor
growth and led to a longer survival of rats with implanted BT4Cn tumors. The
use of the PPARγ
antagonist GW9662 reversed the effect of rosiglitazone but not for TTA,
indicating that TTA might act both via PPARγ-dependent and PPARγ-independent pathways [37].Grommes et al. reported that the nonthiazolidinedione
tyrosine-based PPARγ
ligand GW7845 reduced viability of rat C6 and human glioma cells and induced
apoptotic cell death in a PPARγ-dependent
mechanism as shown by the inhibition of these effects by the specific
antagonist GW9662 [51]. Primary astrocytes were not
affected, demonstrating the specificity of the effects of GW7845 on neoplastic
cell types. GW7845 also reduced proliferation of rat C6 glioma cells and
reduced both the migration and invasion of glioma cells [51]. These investigators have
subsequently reported [52] that the PPARγ agonist pioglitazone reduced cellular
viability of rat and human glioma cell in
vitro. Furthermore proliferation in rat glioma cells was inhibited, as
measured by Ki-67 expression. Glioma cells overexpressing PPARγ-cDNA showed reduced cellular viability after
pioglitazone treatment, whereas treatment of glioma cells overexpressing a
mutant cDNA lacking transcriptional activity, showed no antineoplastic effects [52]. Grommes et al. extended these
findings to in vivo studies, using a C6 rat glioma model [52]. In this study, tumor volumes were
dramatically reduced following pioglitazone administration intracerebrally, as
well as orally, indicating that pioglitazone is able to cross the blood-brain
barrier (BBB). It has not been
established whether TZDs other than pioglitazone penetrate the BBB. However, in vitro studies provide evidence
that troglitazone is actively incorporated by the bidirectional transporter
Oatp14 (Slco1c1) expressed in brain capillary endothelial cells, which is
likely to provide homeostasis of troglitazone and may be of other TZDs [53]. Treated animals showed drug-induced apoptosis in the
tumors by activation of proapoptotic proteins. Grommes and coworkers also
observed decreased tumor invasion in
vivo which was correlated with reduced MMP9 levels. Indeed, PPARγ
agonists suppressed tumor migration in
vitro in a Boyden chamber assay. Finally, they described a
pioglitazone-induced upregulation of the astrocytic redifferentiation marker
CS-56 in tumor cells both in vivo
and in vitro. Primary astrocytes were not affected by pioglitazone, indicating the
restriction of these effects to neoplastic cell types [52]. A possible explanation for this
neoplastic specificity is given by Spagnolo et al., who showed differences in
metabolic responses in GL261 glioma cells as compared to primary astrocytes
when treated with the TZD troglitazone [54].The
same authors also presented a study exploring C57/Bl6 mice with an
intracerebral glioma derived from GL261 cells [55]. Mice were treated with a combined
therapy of interleukin (IL)-2-secreting
syngeneic/allogeneic fibroblasts administered into the tumor bed along with the
TZD pioglitazone. In contrast to the data of Grommes et al., only intracerebrally administered pioglitazone prolonged the survival of mice
harboring an intracerebral glioma, whereas pioglitazone administered orally
showed no effect. Finally, combination of pioglitazone and Il-2-secreting
fibroblasts significantly prolonged the survival of the treated mice as
compared to untreated animals [55].Using an
organotypic glioma invasion model, closely resembling extracellular
matrix environment present in the brain, Coras et al. show that micromolar
doses of troglitazone blocked glioma progression without neurotoxic damage to
the organotypic neuronal environment observed [56]. The authors stated that the
intriguing antiglioma property of troglitazone appears to be only partially
based on its moderate cytostatic effects. Concordant with the data presented by
Grommes et al., the authors showed that troglitazone effectively inhibits glioma
cell migration and brain invasion. Interestingly,
the antimigratory effects of troglitazone could be mimicked by inhibition of
TGF-ß signaling which has shown to be intimately involved in glioma cell
migration, suggesting both mechanisms to be interlinked. In this study, the
authors identified troglitazone as a potent inhibitor of TGF-ß release,
suggesting that troglitazone reduced glioma cell motility by counteracting
TGF-ß signaling [56].More than 10
years ago, Prasanna et al. [57] reported that treatment with
lovastatin (a HMG-CoA reductase inhibitor) led to growth arrest in glioma
cells, accompanied with an increased expression of PPAR. A combination therapy
of lovastatin and the PPARγ
agonist troglitazone reduced cellular viability in the DBTRG-05MG human
glioblastoma cell line [58]. Interestingly, the combination of
lovastatin with two other PPARγ
agonists, rosiglitazone and ciglitazone, did not lead to the same effect. The
authors suggested that it may be possible that PPARγ is an essential, but not sufficient, factor in
this synergism.PPAR agonists have also been shown to exhibit
effects on tumor biology through PPAR-independent mechanisms. For example, the
PPARα/γ
dual agonist TZD 18 inhibited growth of T98G human glioblastoma cells and
induced apoptosis through PPAR-independent mechanisms, since their respective
antagonists MK-886 and GW9662 did not reverse this effect [59]. The TZD-mediated antineoplastic properties from PPARγ was argued to arise from off-target, receptor-independent
actions of the drugs as well as those of rosiglitazone and pioglitazone [35, 38, 43, 60]. The glitazones were toxic for the
human glioma cell line U251 and rat glioma cell line C6, but not for primary
rat astrocytes [43]. Indeed, PPARγ seems not to be involved in these effects of
the TZDs, since the inhibitor GW9662 had nearly no effect on attenuation of
cytotoxicity. Using PPARγ positive and PPARγ deficient
mouse embryonic stem (ES) cells, it has been demonstrated that the TZD
troglitazone inhibited the growth of tumors formed by injection
of PPARγ+ and PPARγ− cells to the same extent,
indicating that PPARγ is not essential for the
antiproliferative effects of troglitazone [60]. Moreover, troglitazone derivatives
which are unable to activate PPARγ suppress cancer cell proliferation
similar to troglitazone, giving further evidence that the antiproliferative
effects of troglitazone are at least in part PPARγ-independent [61]. Furthermore, troglitazone
sensitized human glioma cells to TRAIL-induced apoptosis in a process
independent of PPARγ [62, 63]. Troglitazone treatment led to a
marked downregulation of the antiapoptotic proteins FLIP and survivin [63] as well as Bcl-2 [62] and so could possibly counteract
the capability of tumor cells to become resistant to apoptosis. Hence a
combination therapy of troglitazone and TRAIL might be a promising experimental
approach. Conversely, in A172 human
glioma cells Kang and
colleagues showed that the TZD
ciglitazone induced cell death dependent of PPARγ, but independent of caspase and AIF.
Furthermore, the authors demonstrated that downregulation of XIAP and survivin
is involved in the cell death mechanism [50]. A possible explanation for the differentiative
effects of PPARγ
agonists was supposed
to rely on PPARγ
dysfunction. Single
strand conformational polymorphism (SSCP) analysis was carried out in different
tumor and nontumor tissues, showing somatic loss-of-function mutations in
different carcinomas [64, 65]. Genetic analysis of American patients with
glioblastoma multiforme revealed an overrepresentation of the H449H
polymorphism in the PPARγ
gene, possibly being
an important low penetrance susceptibility locus for glioneural tumors [66].


## 4. Neuroblastoma

Neuroblastoma
is a phenotypically heterogeneous tumor, containing cells of neuronal,
melanocytic or glial/Schwann cell lineage. Regardless of the phenotype, PPARγ
is expressed in neuroblastoma cell lines [67], in primary neuroblastoma cells [7] as well as in samples of patients
harbouring neurblastoma [68]. Data about the expression of PPARβ/δ
in neuroblastomas are scarce [69–71], and only a few studies report the
expression of PPARα
at mRNA or protein level in human neuroblastoma cell lines [71–74]. Therefore, most studies that
assess the influence of PPARs on treatment of neuroblastoma evaluate the impact
of its natural or synthetic ligands.The
putative natural PPARγ
agonist 15d-PGJ2 inhibits cellular growth, decreases cellular
viability and induces apoptosis in human neuroblastoma
cells in vitro [67, 69, 74–76]. Rodway et al. [74] show that the PPARα agonist WY-14643 has no effect on the growth
of the IMR32 neuroblastoma cell line, whereas PGJ2 induces growth
inhibition in the same neuroblastoma cells. This occurs through programmed cell
death type II or autophagy, and the serum lysolipid LPA is responsible for
modulating this cellular response. In the neuroblastoma cell line ND-7, the
same group shows that the degree of PPARγ activation induced by PGJ2 is
modulated through an interaction with retinoblastoma protein (Rb) and the class
I histone deacetylase 3 (HDAC3) [75]. A combination therapy consisting
of PGJ2 and the histone deacetylase inhibitor trichostatin A (TSA)
enhanced the growth inhibition effects and is therefore proposed as a promising
new strategy in the treatment of neuroblastoma. It should be noted that the
effects of 15d-PGJ2 can also arise from its actions on the NFκB pathway [77]. Di Loreto et al. report that a
specific PPARβ
agonist as well as oleic acid induced redifferentiation in SH-SY5Y
neuroblastoma cells [70].The
best studied synthetic PPARγ
agonists are the TZD class of antidiabetic drugs, also referred to as
glitazones [7]. Valentiner et al. [78] tested four glitazones
(ciglitazone, pioglitazone, troglitazone, rosiglitazone) and reported their in vitro effects on cell growth in
seven human neuroblastoma cell lines (Kelly, LAN-1, LAN-5, LS, IMR-32, SK-N-SH,
SH-SY5Y). All the glitazones inhibited cell growth and viability of the human
neuroblastoma cell lines in a dose-dependent manner, whereas the effectiveness
of the single drugs differed strongly between cell lines. Similar results for
ciglitazone and rosiglitazone have been reported [75, 79]. Cellai et al. show that high
concentrations of rosiglitazone significantly inhibit cell adhesion in vitro, invasiveness and apoptosis
in SK-N-AS, but not in SH-SY5Y human neuroblastoma cells [79]. The authors argued that this
effect may be related to cellular differences in PPARγ transactivation. Furthermore, Jung et al.
report that the TZD rosiglitazone protects SH-SY5Y cells against MPP+ as well
as acetaldehyde-induced cytotoxicity, which may be ascribed
to the induction of the expression of antioxidant enzymes and also to the
regulation of Bcl-2 and Bax expression by rosiglitazone [80, 81].


## 5. Conclusion

The
understanding of the molecular mechanisms underlying the antineoplastic effects
mediated by PPAR agonists is still emerging. Over the past years, an increasing
number of reports were published, presenting
evidence for several involved pathways concerning cell cycle arrest, apoptosis,
redifferentiation and inhibition of invasion/migration, that have been found to
be affected by PPAR agonist treatment. Figure1 presents an overview of signal
mechanisms involved in the antineoplastic effects of PPAR ligands.
Interestingly, there are partially controverse findings regarding the receptor
dependency of the observed effects. Besides the number of natural and synthetic
ligands, as well as to the number of different tumor cell lines used, a further
explanation may be that most studies were performed on long-term cultured cell
lines which may have undergone alterations while being in cell culture.
Only few studies use primary cell cultures of tumor cells or organotypic
models, like Benedetti et al. or Coras et al. [48, 56], trying to resemble
natural conditions as close as possible. Remarkably, studies examining the effects of
PPAR agonists in vivo are just emerging for gliomas [52, 55], and are still missing for
neuroblastomas.Figure 1From all natural and synthetic PPAR
ligands, the group of thiazolidinediones is the one with the best characterized
antineoplastic properties. The fact that TZDs like pioglitazone (Actos) and
rosiglitazone (Avandia) are FDA-approved for treatment of type-2 diabetes and
therefore readily available for clinical studies may be the main reason for
this. Very recently, a phase 2 clinical study was published, presenting for the
first time a combination of low-dose chemotherapy with COX-2 inhibitors and
PPARγ
agonists in high-grade gliomas [82]. Unfortunately, the trial had to be closed
prematurely, due to the moderate efficacy as compared to other clinical trials,
which however investigated PPARγ
agonist treatment of different tumor entities. It is questionable whether the
tumor biology of astroglioma, which are extremely heterogeneous and rarely
metastasize, can be compared to these different tumors, and thus the degree of
response to a PPARγ
agonist-based therapy. Of note, depending on the particular astroglioma and
region within the tumor, the poor blood brain barrier penetration of the TZDs
may also account for limited efficacy. Therefore, further in vivo studies are
warranted to unravel the molecular mechanisms underlying the antineoplastic
effects of PPAR agonists in malignant astrocytic gliomas.Nevertheless,
agonists of PPARs, in particular the TZDs, seem to be promising candidates
for new therapeutic approaches in human CNS tumor therapy due to their profound
antiproliferative and anti-invasive effects as well as their positive effects
on apoptosis and redifferentiation.



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