# Potential of Peroxisome Proliferator-Activated Receptor Gamma  Antagonist Compounds  as Therapeutic Agents for a Wide Range of Cancer Types

Authors: Jack D. Burton; David M. Goldenberg; Rosalyn D. Blumenthal
Journal: PPAR Research
 (2008)

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## Abstract

PPARγ  is a therapeutic target that has been exploited for
treatment of type II diabetes mellitus (T2DM) with agonist drugs.
Since PPARγ  is expressed by many hematopoietic, mesodermal and
epithelial cancers, agonist drugs were tested and shown to have
both preclinical and clinical anticancer activities.  While
preclinical activity has been observed in many cancer types,
clinical activity has been observed only in pilot and phase II
trials in liposarcoma and prostate cancer.  Most studies address
agonist compounds, with substantially fewer reports on anticancer
effects of PPARγ  antagonists.  In cancer model systems, some
effects of PPARγ  agonists were not inhibited by PPARγ  antagonists,
suggesting noncanonical or PPARγ-independent mechanisms.  In
addition, PPARγ  antagonists, such as T0070907 and GW9662, have
exhibited antiproliferative effects on a broad range of
hematopoietic and epithelial cell lines, usually with greater
potency than agonists.   Also, additive antiproliferative effects
of combinations of agonist plus antagonist drugs were observed.
Finally, there are preclinical in vivo data showing that
antagonist compounds can be administered safely, with favorable
metabolic effects as well as antitumor effects.  Since PPARγ
antagonists represent a new drug class that holds promise as a
broadly applicable therapeutic approach for cancer treatment, it
is the subject of this review.


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## Body

## 1. Introduction

PPARγ  is one of the three known peroxisome
proliferator-activated receptors and is a member of the nuclear receptor (NR)
superfamily.  Since it has a
predominantly nuclear location, regardless of whether cognate ligands are
present, it is classified as a type II NR.
It functions as a transcription factor by heterodimerizing with the
retinoid X receptor (RXR), after which this complex binds to specific DNA
sequence elements called peroxisome proliferator response elements
(PPREs) [1]. In order to become fully
active as a transcription factor, PPARγ must be bound by ligand. RXR can be affected
by binding its own cognate ligands, usually resulting in incremental increases
in transcriptional activity. After the PPARγ/RXR heterodimer binds to PPREs in promoter
regions of target genes, coactivator proteins, such as p300 (CBP),
SRC-1, and Drip205 (or TRAP220) family members, are recruited to this complex
to modulate gene transcription [2–4]. Different
PPARγ ligands appear to be able to recruit different coactivators, which may explain differences in the biological activity
between ligands [5].The cardinal biologic activity of PPARγ is the induction of differentiation of
adipocytes, the cell type that expresses the highest levels of PPARγ amongst normal tissues. Lower levels of PPARγ are, however, found in other normal tissues
and cell types such as skeletal muscle, liver, breast, prostate,
colon, type 2 alveolar pneumocytes, some endothelial cells as well as monocytes,
and B-lymphocytes. There are three PPARγ mRNA isoforms (γ1, γ2, and γ3) and two major protein species (γ1 and γ2). The
mRNA isoforms are generated by alternate promoter usage, resulting in an
additional 28 amino acids at the N-terminus of PPARγ2 compared with PPARγ1. Most tissues express PPARγ1, whereas the PPARγ2 isoform is expressed mostly by adipocytes.
The longer N-terminal domain of PPARγ2 may affect function, since this isoform was
shown to confer a higher level of ligand-independent transcriptional activity,
which was further increased by physiologic concentrations of insulin [6]. High
levels of PPARγ expression by fat and its role in adipogenesis
led to the recognition that agonistic PPARγ ligands have antidiabetic effects. The
chemical class of PPARγ agonists known as thiazolidinediones (TZDs)
demonstrated high-affinity binding to PPARγ [7] as well as favorable therapeutic
properties, and such drugs were eventually registered for the treatment of type
II diabetes mellitus (T2DM). Three TZD
drugs have been registered in the U.S.: rosiglitazone (Avandia), pioglitazone (Actos), and troglitazone(Rezulin).
Subsequent to its marketing and widespread use, troglitazone was
associated with idiosyncratic and, in rare cases, fatal hepatic toxicity, and,
thus, was withdrawn from the market. The former two drugs, however, have remained
as safe and effective therapeutic options for the management of T2DM.Not long after reports of the cloning of PPARγ and its expression in normal tissues [8, 9],
PPARγ expression was observed in an array of primary
cancers and derivative cell lines. Its expression was reported initially in
liposarcoma [10], and soon thereafter in colon, breast, and prostate carcinomas
and additional cancer types [11–14]. In addition
to the in vitro and preclinical in vivo anticancer effects of TZDs, pilot clinical studies using
troglitazone showed antitumor activity in patients with liposarcoma and
prostate cancer [15, 16]. Compounds from other chemical classes were also shown
to bind PPARγ and to have antiproliferative effects in
cancer models, such as the naturally occurring eicosanoid, 15-deoxy-Δ12,14-prostaglandin J2(15-d-PGJ2), the N-aryl tyrosine derivative, GW1929 [17], and the
triterpenoid, 2-cyano-3,12-dioxooleana-1,9-diene-28-oic acid, CDDO [18]. While
compounds that exhibit PPARγ agonist activity, such as TZDs, have PPARγ-dependent antiproliferative effects, they have
also been shown to have antiproliferative effects in cell types that are
genetically PPARγ-null [19]. Also, uncertainty about mechanisms
of anticancer effects of PPARγ ligands has resulted from variability in the
classification of some compounds (e.g., bisphenol A diglycidyl ether [BADGE], which has been
shown to have both agonist and antagonist activities) [20, 21].


## 2. Effects of PPARγ Antagonist Compounds in Epithelial Cancer Model Systems: Cell Growth and Apoptosis

The initial report of Fehlberg et al. [22] showed an inhibitory effect of this class of agents on
a colon cancer and a lymphoma cell line using the compound, BADGE, which as
noted has been classified as both an agonist and antagonist. This initial study
did not examine effects on proliferation, but showed that apoptotic effects, such
as increases in annexin-V binding and reductions in DNA content as assessed by propidium
iodide staining, required 50–100μM concentrations of BADGE, which
would tend to increase off-target effects. Subsequently, Seargent et al. [23] showed that a
higher affinity, selective PPARγ antagonist, GW9662, had direct antiproliferative
effects on three breast cancer cell lines of differing phenotypes (ER+, ER−,
and p53-null). This antagonist compound was somewhat more potent in its effects
than an agonist (rosiglitazone). In this report, the role of PPARγ in mediating growth inhibition was addressed,
but not fully elucidated. All three cell lines expressed it and the predicted,
canonical PPARγ-related transactivation effects were
demonstrated, with the agonist inducing transactivation and the antagonist suppressing
it, thus excluding PPARγ-mediated transactivation as the mechanism of
this effect. There are data, however, that
suggest that antagonist-type compounds may also act via other PPARγ-dependent pathways. Lea et al. reported similar results using
a range of agonist and antagonist compounds on both murine and human cell lines
[24]. Schaefer et al. showed
that the antiproliferative effect of the PPARγ antagonist, T0070907, on
hepatocellular carcinoma cell lines was attenuated by knockdown of PPARγ by siRNA [25].
These data are consistent with a PPARγ-mediated transrepression mechanism, which has
been demonstrated with respect to anti-inflammatory effects of PPARγ ligands mediated by the NF-κB signaling pathway.  Pascual et al. showed  similar
effects of a pure agonist (rosiglitazone) and a mixed agonist/antagonist (GW0072)
on the repression of a NF-κB-regulated gene, iNOS, suggesting that pure antagonists may also be capable of
mediating this effect [26].There are also data that PPARγ ligands (both agonist and antagonist) exert PPARγ-independent effects suggesting other cellular
targets of these compounds. This was demonstrated clearly by Palakurthi
et al., who demonstrated in
vitro and in vivo growth
inhibition of two agonist compounds, troglitazone and ciglitazone, in
experiments utilizing PPARγ-/- and PPARγ+/+ embryonic stem cell lines (ES),
both of which exhibited very similar sensitivity to these compounds [19]. This
effect was shown to be mediated in part by the inhibition of the initiation of
protein translation, since these TZD compounds increased the phosphorylation
and consequent inactivation of elongation-initiation factor 2 (eIF2) both in
cells that expressed and were null for PPARγ. The
effect of antagonist compounds on this pathway has not been reported. As noted, BADGE had similar proapoptotic
effects in a colon cancer line expressing PPARγ and a T-lymphoma line that showed no
detectable expression of it (by immunoblotting and RT-PCR) of this target [22].
But, given the variable classification of this compound as both an antagonist
and agonist, the mechanism underlying this effect and its attribution are unclear.


## 3. Other Effects of PPARγ Antagonist Compounds

PPARγ antagonist compounds have also
been shown to affect cell shape, adhesion, and invasiveness of cancer cell
lines. Masuda et al. evaluated
the effects of the PPARγ antagonists, BADGE, GW9662 and
T0070907, on four squamous carcinoma cell lines derived from tumors of the oral
cavity. Antiproliferative effects were
shown for the three antagonists, but not for the agonist, pioglitazone [27]. Effects of these agents on adhesion and
anoikis were also evaluated. Antagonists
were found to inhibit adhesion and induce cell death related to loss of
adhesion (known as anoikis) under normal tissue culture conditions on untreated
plastic dishes. T0070907 induced similar inhibition of adhesion to
fibronectin-coated plates, and this was significantly reversed by coincubation
of cells with this antagonist and the agonist, pioglitazone, suggesting a PPARγ-dependent effect. Since adhesion
and detachment are related to cytoskeletal structure and function, this was
assessed by fluorescent staining of F-actin.
Using confocal microscopy, T0070907 was shown to cause dose-dependent
disruption of F-actin, associated with rounding of the cells. Additional
experiments showed inhibition of FAK and MEK-ERK signaling pathways, as well as
decreased expression of integrin α5 and CD151, both of which are adhesion
proteins that have been implicated in cancer cell invasion and metastasis. Schaefer
et al. showed similar effects
of PPARγ antagonists on hepatocellular
carcinoma cell lines including inhibition of adhesion, induction of anoikis, and
inhibition of phosphorylation and activation of FAK [25]. These effects were shown to be dependent on
the degree of PPARγ inhibition, and could be mediated
by the antagonist or knockdown of PPARγ via specific, cognate siRNA.
T0070907 was also shown to have substantially greater growth inhibitory effects
on the HepG2 line compared with the agonist drugs, troglitazone, and
rosiglitazone. Takahashi et al. demonstrated anti-invasive and
growth inhibitory effects of the antagonists, GW9662 and
T0070907, on
esophageal cancer cell lines. The anti-invasive effects were observed at levels
substantially lower than those required for growth inhibition [28]. In summary, all of these studies addressing
anticancer effects of PPARγ antagonist compounds have show
effects on cell growth, adhesion, and invasion in multiple epithelial cancer
models.Some of these effects
are PPARγ-dependent, but the potential role of other
targets is suggested by the similar effects of BADGE on a PPARγ+ colon cancer line and a PPARγ-negative T-lymphoma line. Also, the
substantially different concentrations of PPARγ antagonists needed to induce anti-invasive
effects versus growth inhibition in esophageal cancer lines suggest different
mechanisms with differing degrees of PPARγ dependence or lack of involvement of the PPARγ-signaling pathway for some effects. A PPARγ-independent effect of antagonists on
colorectal cancer cell lines and in an in
vivo tumor xenograft derived from one of the lines was shown in a more
recent report by Schaefer et al.
[29]. A decrease in tubulin levels was observed
that was independent of PPARγ, PPARδ,
and proteasome function. This downregulation of tubulins α and β may explain
the antimigratory, anti-invasive, and antimetastatic effects that were
observed. Thus, in summary, PPARγ antagonist compounds with varying chemical
structures (though GW9662 and T0070907 are similar) have several significant
anticancer effects in vitro and
in vivo in epithelial cancer
model systems including breast, colon, aerodigestive squamous cell, and
hepatocellular.


## 4. Effects of PPARγ Antagonists in Hematopoietic Cancer Model Systems

Studies were conducted
in our lab to assess the effects of PPARγ antagonists on hematopoietic cell lines. Initial screening showed that several
myeloma (MM) cell lines had the greatest sensitivity to the antiproliferative
effects of the antagonists, GW9662 and T0070907. Thus multiple MM lines were
tested, including one that is IL-6-dependent, for sensitivity to these
compounds as well as to the agonist, pioglitazone. MM lines as well as
non-Hodgkin lymphoma (NHL) lines showed significantly greater sensitivity to
the growth inhibitory effects of the two antagonist drugs compared with the
agonist [30]. As a group, the MM lines were more sensitive than the other
groups of cancer cell lines to the antiproliferative effects of the
antagonists, particularly T0070907. Other goals were to directly compare the
sensitivity of previously tested epithelial cancer types (breast and colon) to
hematopoietic lines (MM and NHL) as well as to evaluate a chemoresistant
epithelial cancer type (renal cell). These experiments showed that in all the
epithelial and hematopoietic cell lines tested, the antagonists were
significantly more potent in their growth inhibitory effects compared with the
agonist drug.The IC50 values for the panel of 16 cell lines
tested in these studies are shown in Table 1. For each of the cell lines in the panel, significant
differences in the IC50 values of the antagonist
compounds and the agonist drug, pioglitazone, were observed (P values ranging from <.04 to
<.001, with 12 of 16 lines at <.001). While the MM lines showed the
greatest sensitivity to the antagonists, similar degrees of sensitivity to the
antagonists were also seen in the subset of breast cancer lines, which included
two lines that are estrogen receptor-negative. Though not quite as sensitive as
a subset, significant differences between the antagonists and the agonist were
also observed in the renal cell lines, which are among the most chemoresistant
epithelial lines. The differential sensitivities within and across cell lines
did not appear to be related to the levels of PPARγ expression. Also, neither the agonist nor the
antagonist induced significant upregulation of PPARγ as has been reported in some studies with PPARγ ligands. Consistent with prior reports, combinations
of the agonist and with each of the antagonists did not result in attenuation
of growth inhibitory effects. In fact, schedule-dependent increases in growth
inhibition were observed, particularly when the antagonists were added to cells
24 hours prior to the agonist. Aspects of the mechanisms of cytotoxicity of the
antagonists and agonists were also compared. It was shown that both classes of PPARγ ligand-induced apoptotic effects, but this
effect was found to be caspase-independent for the agonist, pioglitazone [30].Table 1
Mean IC50 values (μM) for the PPARγ ligands.
Cell linesPioglitazoneT0070907GW9662ColonMoser#26.5±2.615.9±1.020.1±0.3HT29§53.0±4.711.2±0.014.1±0.5LS174T#38.7±7.47.8±1.99.5±0.5HCT-15§53.1±2.513.0±0.519.0±0.8RCCA498#38.9±4.924.3±0.729.1±0.3ClearCa-2§56.4±3.120.8±1.921.5±0.7BreastZR75-30§77.9±7.03.9±0.310.6±0.9MCF7§54.8±3.910.2±1.916.6±2.4MDA-MB-231§78.7±3.520.1±1.126.8±1.0MMCAG*62.4±9.912.2±1.213.8±0.1KMS12-BM§33.2±5.13.2±0.611.8±1.6KMS12-PE§56.4±1.54.3±0.39.5±0.9OPM6§48.9±1.84.1±0.311.5±0.1U266B1§56.6±1.39.9±0.229.7±1.5NHLRamos§66.5±7.412.7±0.715.1±0.1SU-DHL6§53.1±1.411.8±0.414.8±0.3Mean IC50 values from replicate experiments with this panel of cells for each of
the three PPARγ ligands are shown above, expressed in μM±SEM. Cell lines are grouped according to
cancer type. IC50 values from each cell line were compared by single
factor ANOVA analysis, with all lines showing significant differences as
indicated: P§<.0001;P*<.005;P#<.04.Another question that
was addressed was the impact of IL-6 on the responses of the MM lines to PPARγ antagonists, since this is a cytokine that
plays a central role in the pathogenesis and progression of MM, as well as
other cancer types. For these studies, 4 of the 5 MM lines that were utilized
were IL-6-independent in order to follow up on a previous
report of Wang et al. that
analyzed the responses of three MM lines to the PPARγ agonists, 15-d-PGJ2 and
troglitazone. This report showed that growth
inhibition and certain downstream signaling events were PPARγ-dependent, and also
that two IL-6-dependent MM lines expressed PPARγ while an IL-6-independent line did not [31].
Also, GW9662 was reported to block the effects of the agonists, and had no antiproliferative activity on its own. We utilized five
different MM lines, of which four are IL-6 independent (CAG, KMS12-BM, KMS12-PE,
and OPM-6) as well as a fifth that is dependent on an IL-6 autocrine loop
(U266B1). In contrast to the prior report cited above, of the lines analyzed,
CAG expressed PPARγ, while the autocrine IL-6-dependent line,
U266B1, did not express PPARγ by immunoblotting. Also, three of the four of IL-6-independent MM lines were more sensitive to the growth
inhibitory effects of both of the two PPARγ antagonist compounds compared with the
IL-6-dependent line, U266B1 (see Table 1).In MM cell lines, which
are more often IL-6 dependent compared with other B cell lines, the strict dependence
on exogenous IL-6 is indicative of ongoing requirement for this signaling
pathway, which in pathophysiologic states, such as MM, usually depends on production
of this cytokine by stromal cells. In
MM, clinically more aggressive or treatment-resistant disease is associated
with production of IL-6 by the myeloma cell themselves as opposed to the bone
marrow stroma [32]. MM lines show a spectrum of IL-6 dependence, with some
being dependent on exogenous IL-6, others being dependent on its autocrine
production, and yet others being IL-6-independent for their growth. Even those
MM lines that are not strictly dependent on IL-6 for their growth (exogenous or
autocrine) can still be affected by the addition of exogenous IL-6 [33] (also
shown in one of the lines tested, OPM-6, [34]). Addition of IL-6 to such MM
lines has been shown to induce either incremental stimulation of proliferation or
induction of resistance to various agents such as dexamethasone, standard chemotherapy
drugs such as melphalan and other agents. Thus the interaction of IL-6 and PPARγ antagonist compounds were examined in two MM
lines (KMS12-PE and OPM-6). MTT assays were performed in the
presence and absence of exogenous IL-6 (5 ng/mL). For both of these MM lines,
addition of IL-6 did not induce resistance, but instead appeared to increase
the sensitivity of these lines to T0070907, with a similar trend observed with
GW9662 [30].


## 5. Dose-Response Effects of PPARγ Antagonist Compounds and Interaction with Other Agents

The PPARγ antagonist
compounds, GW9662 and T0070907, differ in their antiproliferative dose-response
effects compared with the agonist as well as other agents. Not only are the corresponding IC50 values for the
antagonists significantly lower than the agonist, pioglitazone, but a greater
degree of growth inhibition (85–97% versus 50–80%) was observed
with the former compounds. Also, of note was that the maximal effects of these
agents were seen at concentrations that were only 2- to 3-fold greater than the
IC50 across the entire panel of cell lines tested that included cell
lines with relative and very high levels of chemoresistance (colon and renal
cell, resp.). The dose-response curves were much steeper with the antagonist
compounds compared to the agonist, pioglitazone, and also much steeper than
what is observed with most other agents, including standard chemotherapy drugs
and other agents (see Figure 2). This dose-response relationship suggests
either a positive cooperative effect, potentially via increased, cooperative recruitment
of corepresssors, thereby increasing transrepression. The alternate possibility
is that different targets are being engaged with gradually increasing
concentrations, which together exhibit additive or supra-additive interactions.Figure 2
Dose-response curves for the MM line,
KMS12-PE, to T0070907, both in the presence and absence of the hLL1 mAb. Square symbols represent the dose-response
curve in the presence of hLL1, and diamond symbols represent the curve in the
absence of LL1. The ordinate shows percent growth inhibition values and the
abscissa the concentration of T0070907 in micromolar.Since MM lines as a group were the most sensitive of
the cell lines we tested, interaction with other novel agents for therapy of MM
were evaluated. One such agent is anti-CD74 monoclonal antibody (mAb). CD74 was
shown to be strongly expressed by the malignant plasma cells in the vast
majority of clinical MM specimens as well as the majority of MM lines [35]. It
was also shown that this mAb in unlabeled (cold) form exhibited in vitro growth inhibitory effects on both NHL and MM lines [36]. The
anti-CD74 mAb used in these studies, LL1, also showed significant therapeutic
effects in two preclinical murine NHL xenograft models. In preliminary in vitro studies, the humanized anti-CD74 mAb was combined with T0070907 in
two MM lines. These studies also evaluated a sixth MM line (KMS11), which is
IL-6 independent, expresses CD74 and is useful as a murine MM xenograft model. This line showed similar sensitivity to T0070907 as the other IL-6-independent
lines, with an (unpublished observations, J Burton). Another IL-6-independent
MM line that was used in initial studies, KMS12-PE, was also used to evaluate
interactions between T0070907 and the hLL1 mAb. While KMS11 line showed moderate
sensitivity to hLL1 (maximum growth inhibition of 50–70%), the KMS12-PE line
was resistant to single-agent hLL1 (<10% inhibition). However, in
combination with T0070907, there was a sizable shift to the left of the
dose-response curve, as is shown in one representative experiment in Figure 2.
Current data indicate that the IC50 value decreases by from a mean
value of ~4.1μM for T0070907 alone versus ~3.0μM with T0070907 in combination
with hLL1, suggestive of a supra-additive effect (25–30% observed versus <8%
expected based effect of hLL1 alone). This is a promising initial preclinical
lead given that hLL1 is now being evaluated in several phase I/II clinical
trials in B-cell cancers such as NHL and MM, and appears to be safe and well
tolerated.


## 6. Overview of Mechanisms of Action of PPARγ Agonist and Antagonist Compounds

The studies reviewed above have shown
that the effects of PPARγ ligands are mediated by various mechanisms.
Some studies show or suggest canonical PPARγ-mediated effects (i.e., via transactivation),
as exemplified by early in vitro studies with agonist compounds that
showed fat accumulation, a major PPARγ-mediated effect, in both breast cancer and
liposarcoma cell lines [10, 12]. This was
also demonstrated in liposarcoma patients in whom increased fat content within
tumors was demonstrated by serial CT scanning before and after treatment with
an agonist drug [10]. The studies of Wang et al. showed that the growth-inhibitory effects of PPARγ agonist compounds on MM lines was seen only in
lines expressing PPARγ and that these effects were reversed by
cotreatment with an antagonist compound [31]. In contrast, completely PPARγ-independent effects were demonstrated for both
agonist and antagonist compounds in reports from Palakurthi et
al. [19] and Schaefer et al. [29]. This was clearly shown for the agonist
compounds, troglitazone and ciglitazone, which showed similar antiproliferative
effects in PPARγ-wild type and PPARγ-null (knockout) embryonic stem cell lines,
both in vitro and in vivo [19]. PPARγ-independent growth inhibitory and
antimetastatic effects of several antagonist compounds were shown in both in vitro and in vivo studies using three
colon carcinoma cell lines. These effects were associated with reductions in
tubulin levels and were also shown to be independent of PPARδ and proteasome function. The PPARγ-independent effect of agonist compounds was
shown to be associated with inhibitory effects on the protein translation
pathway. The mechanism of PPARγ-independent effects of antagonist compounds on
tubulin levels has not been elucidated.The
mechanism of PPARγ-mediated transrepression may explain some of
the effects of antagonist compounds. This was suggested by the attenuation of
the effects of antagonist compounds by PPARγ knockdown by siRNA in hepatocellular carcinoma
cell lines [25]. Also, the observation that combinations of PPARγ agonist and antagonist compounds result in
additive antiproliferative effects in various cancer cell lines [24, 30] is
consistent with this mechanism. This mechanism is plausible, as it has been
shown to inhibit the NF-κB signaling pathway, which is central to inflammation and to the proliferation
and survival of multiple cancer types including hepatocellular and
colon carcinomas as well as multiple myeloma. The potential role of this and
other mechanisms remain to be determined.


## 7. Summary of Preclinical Studies of PPARγ Antagonist Compounds and Their Clinical Potential

The studies reviewed above have shown that PPARγ antagonists have in vitro and preclinical in vivo anticancer effects that are as
broad and potent as agonist compounds. These effects have been demonstrated in
a wide range of epithelial cancer cell lines as well as hematopoietic cancer
cell lines. Exploration of the
underlying mechanisms of action for antagonist compounds has shown either involvement
of PPARγ or a PPARγ-independent effect. One study suggested the
involvement of the canonical transactivation mechanism in that antagonist
effects were antagonized by coincubation with an agonist compound, pioglitazone
[27]. In another study, where knockdown of PPARγ affected responses to antagonist compounds,
the effect was not consistent with the canonical transactivation mechanism, but
may be consistent with a transrepressive mechanism [25]. Another study showed
that anticancer effects were associated with reductions in tubulin levels (a
validated cancer-related target), but this was not mediated by PPARγ, PPARδ, or the proteasome [29].While there have been numerous preclinical in vivo studies in cancer models with
PPARγ agonists, there have been relatively few with
antagonist compounds. Also agonists have been tested clinically. Some studies with
antagonists have been conducted in noncancer models at low doses (≤1 mg/kg),
which were not toxic and biologically active [37, 38]. A chemically distinct,
but selective PPARγ antagonist, SR-202, has been synthesized and evaluated
in preclinical models (Figure 1). It was given at a dose of 400 mg/kg for
periods of up to 10 weeks with favorable metabolic effects such protection
against diet-induced hyperinsulinemia and reduction in hyperinsulinemia and
hyperglycemia in genetically predisposed (ob/ob) mice [39]. In pilot studies,
we have administered moderate doses of GW9662 (15 mg/kg) and T0070907 (7.5
mg/kg) daily for 3 weeks by the intraperitoneal route to immunodeficient mice.
These doses and schedules were well tolerated and resulted in no signs of
toxicity (unpublished observations).
These data indicate that the doses of these antagonists that may be
sufficient for anticancer therapy are well tolerated, paving the way for
further development of these agents for treatment of cancer.The chemical structures of four PPARγ antagonists:
(1) GW9662, (2) T0070907, (3) SR-202, and (4) BADGE.



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