| "text": "This is an academic paper. This paper has corpus identifier PMC2528255\nAUTHORS: Jack D. Burton, David M. Goldenberg, Rosalyn D. Blumenthal\n\nABSTRACT:\nPPARγ is a therapeutic target that has been exploited for\ntreatment of type II diabetes mellitus (T2DM) with agonist drugs.\nSince PPARγ is expressed by many hematopoietic, mesodermal and\nepithelial cancers, agonist drugs were tested and shown to have\nboth preclinical and clinical anticancer activities. While\npreclinical activity has been observed in many cancer types,\nclinical activity has been observed only in pilot and phase II\ntrials in liposarcoma and prostate cancer. Most studies address\nagonist compounds, with substantially fewer reports on anticancer\neffects of PPARγ antagonists. In cancer model systems, some\neffects of PPARγ agonists were not inhibited by PPARγ antagonists,\nsuggesting noncanonical or PPARγ-independent mechanisms. In\naddition, PPARγ antagonists, such as T0070907 and GW9662, have\nexhibited antiproliferative effects on a broad range of\nhematopoietic and epithelial cell lines, usually with greater\npotency than agonists. Also, additive antiproliferative effects\nof combinations of agonist plus antagonist drugs were observed.\nFinally, there are preclinical in vivo data showing that\nantagonist compounds can be administered safely, with favorable\nmetabolic effects as well as antitumor effects. Since PPARγ\nantagonists represent a new drug class that holds promise as a\nbroadly applicable therapeutic approach for cancer treatment, it\nis the subject of this review.\n\nBODY:\n1. INTRODUCTIONPPARγ is one of the three known peroxisome\nproliferator-activated receptors and is a member of the nuclear receptor (NR)\nsuperfamily. Since it has a\npredominantly nuclear location, regardless of whether cognate ligands are\npresent, it is classified as a type II NR. \nIt functions as a transcription factor by heterodimerizing with the\nretinoid X receptor (RXR), after which this complex binds to specific DNA\nsequence elements called peroxisome proliferator response elements\n(PPREs) [1]. In order to become fully\nactive as a transcription factor, PPARγ must be bound by ligand. RXR can be affected\nby binding its own cognate ligands, usually resulting in incremental increases\nin transcriptional activity. After the PPARγ/RXR heterodimer binds to PPREs in promoter\nregions of target genes, coactivator proteins, such as p300 (CBP),\nSRC-1, and Drip205 (or TRAP220) family members, are recruited to this complex\nto modulate gene transcription [2–4]. Different\nPPARγ ligands appear to be able to recruit different coactivators, which may explain differences in the biological activity\nbetween ligands [5].The cardinal biologic activity of PPARγ is the induction of differentiation of\nadipocytes, the cell type that expresses the highest levels of PPARγ amongst normal tissues. Lower levels of PPARγ are, however, found in other normal tissues\nand cell types such as skeletal muscle, liver, breast, prostate,\ncolon, type 2 alveolar pneumocytes, some endothelial cells as well as monocytes,\nand B-lymphocytes. There are three PPARγ mRNA isoforms (γ1, γ2, and γ3) and two major protein species (γ1 and γ2). The\nmRNA isoforms are generated by alternate promoter usage, resulting in an\nadditional 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.\nThe longer N-terminal domain of PPARγ2 may affect function, since this isoform was\nshown to confer a higher level of ligand-independent transcriptional activity,\nwhich was further increased by physiologic concentrations of insulin [6]. High\nlevels of PPARγ expression by fat and its role in adipogenesis\nled to the recognition that agonistic PPARγ ligands have antidiabetic effects. The\nchemical class of PPARγ agonists known as thiazolidinediones (TZDs)\ndemonstrated high-affinity binding to PPARγ [7] as well as favorable therapeutic\nproperties, and such drugs were eventually registered for the treatment of type\nII diabetes mellitus (T2DM). Three TZD\ndrugs have been registered in the U.S.: rosiglitazone (Avandia), pioglitazone (Actos), and troglitazone(Rezulin). \nSubsequent to its marketing and widespread use, troglitazone was\nassociated with idiosyncratic and, in rare cases, fatal hepatic toxicity, and,\nthus, was withdrawn from the market. The former two drugs, however, have remained\nas 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],\nPPARγ expression was observed in an array of primary\ncancers and derivative cell lines. Its expression was reported initially in\nliposarcoma [10], and soon thereafter in colon, breast, and prostate carcinomas\nand additional cancer types [11–14]. In addition\nto the in vitro and preclinical in vivo anticancer effects of TZDs, pilot clinical studies using\ntroglitazone showed antitumor activity in patients with liposarcoma and\nprostate cancer [15, 16]. Compounds from other chemical classes were also shown\nto bind PPARγ and to have antiproliferative effects in\ncancer 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\ntriterpenoid, 2-cyano-3,12-dioxooleana-1,9-diene-28-oic acid, CDDO [18]. While\ncompounds that exhibit PPARγ agonist activity, such as TZDs, have PPARγ-dependent antiproliferative effects, they have\nalso been shown to have antiproliferative effects in cell types that are\ngenetically PPARγ-null [19]. Also, uncertainty about mechanisms\nof anticancer effects of PPARγ ligands has resulted from variability in the\nclassification of some compounds (e.g., bisphenol A diglycidyl ether [BADGE], which has been\nshown to have both agonist and antagonist activities) [20, 21].2. EFFECTS OF PPARγ ANTAGONIST COMPOUNDS\nIN EPITHELIAL CANCER MODEL SYSTEMS: CELL\nGROWTH AND APOPTOSISThe initial report of Fehlberg et al. [22] showed an inhibitory effect of this class of agents on\na colon cancer and a lymphoma cell line using the compound, BADGE, which as\nnoted has been classified as both an agonist and antagonist. This initial study\ndid not examine effects on proliferation, but showed that apoptotic effects, such\nas increases in annexin-V binding and reductions in DNA content as assessed by propidium\niodide staining, required 50–100 μM concentrations of BADGE, which\nwould tend to increase off-target effects. Subsequently, Seargent et al. [23] showed that a\nhigher affinity, selective PPARγ antagonist, GW9662, had direct antiproliferative\neffects on three breast cancer cell lines of differing phenotypes (ER+, ER−,\nand p53-null). This antagonist compound was somewhat more potent in its effects\nthan an agonist (rosiglitazone). In this report, the role of PPARγ in mediating growth inhibition was addressed,\nbut not fully elucidated. All three cell lines expressed it and the predicted,\ncanonical PPARγ-related transactivation effects were\ndemonstrated, with the agonist inducing transactivation and the antagonist suppressing\nit, thus excluding PPARγ-mediated transactivation as the mechanism of\nthis effect. There are data, however, that\nsuggest that antagonist-type compounds may also act via other PPARγ-dependent pathways. Lea et al. reported similar results using\na range of agonist and antagonist compounds on both murine and human cell lines\n[24]. Schaefer et al. showed\nthat the antiproliferative effect of the PPARγ antagonist, T0070907, on\nhepatocellular carcinoma cell lines was attenuated by knockdown of PPARγ by siRNA [25]. \nThese data are consistent with a PPARγ-mediated transrepression mechanism, which has\nbeen demonstrated with respect to anti-inflammatory effects of PPARγ ligands mediated by the NF-κB signaling pathway. Pascual et al. showed similar\neffects of a pure agonist (rosiglitazone) and a mixed agonist/antagonist (GW0072)\non the repression of a NF-κB-regulated gene, iNOS, suggesting that pure antagonists may also be capable of\nmediating this effect [26].There are also data that PPARγ ligands (both agonist and antagonist) exert PPARγ-independent effects suggesting other cellular\ntargets of these compounds. This was demonstrated clearly by Palakurthi\net al., who demonstrated in\nvitro and in vivo growth\ninhibition of two agonist compounds, troglitazone and ciglitazone, in\nexperiments utilizing PPARγ\n−/− and PPARγ\n+/+ embryonic stem cell lines (ES),\nboth of which exhibited very similar sensitivity to these compounds [19]. This\neffect was shown to be mediated in part by the inhibition of the initiation of\nprotein translation, since these TZD compounds increased the phosphorylation\nand consequent inactivation of elongation-initiation factor 2 (eIF2) both in\ncells that expressed and were null for PPARγ. The\neffect of antagonist compounds on this pathway has not been reported. As noted, BADGE had similar proapoptotic\neffects in a colon cancer line expressing PPARγ and a T-lymphoma line that showed no\ndetectable expression of it (by immunoblotting and RT-PCR) of this target [22].\nBut, given the variable classification of this compound as both an antagonist\nand agonist, the mechanism underlying this effect and its attribution are unclear.3. OTHER EFFECTS OF PPARγ ANTAGONIST COMPOUNDSPPARγ antagonist compounds have also\nbeen shown to affect cell shape, adhesion, and invasiveness of cancer cell\nlines. Masuda et al. evaluated\nthe effects of the PPARγ antagonists, BADGE, GW9662 and\nT0070907, on four squamous carcinoma cell lines derived from tumors of the oral\ncavity. Antiproliferative effects were\nshown for the three antagonists, but not for the agonist, pioglitazone [27]. Effects of these agents on adhesion and\nanoikis were also evaluated. Antagonists\nwere found to inhibit adhesion and induce cell death related to loss of\nadhesion (known as anoikis) under normal tissue culture conditions on untreated\nplastic dishes. T0070907 induced similar inhibition of adhesion to\nfibronectin-coated plates, and this was significantly reversed by coincubation\nof cells with this antagonist and the agonist, pioglitazone, suggesting a PPARγ-dependent effect. Since adhesion\nand detachment are related to cytoskeletal structure and function, this was\nassessed by fluorescent staining of F-actin. \nUsing confocal microscopy, T0070907 was shown to cause dose-dependent\ndisruption of F-actin, associated with rounding of the cells. Additional\nexperiments showed inhibition of FAK and MEK-ERK signaling pathways, as well as\ndecreased expression of integrin α5 and CD151, both of which are adhesion\nproteins that have been implicated in cancer cell invasion and metastasis. Schaefer\net al. showed similar effects\nof PPARγ antagonists on hepatocellular\ncarcinoma cell lines including inhibition of adhesion, induction of anoikis, and\ninhibition of phosphorylation and activation of FAK [25]. These effects were shown to be dependent on\nthe degree of PPARγ inhibition, and could be mediated\nby the antagonist or knockdown of PPARγ via specific, cognate siRNA.\nT0070907 was also shown to have substantially greater growth inhibitory effects\non the HepG2 line compared with the agonist drugs, troglitazone, and\nrosiglitazone. Takahashi et al. demonstrated anti-invasive and\ngrowth inhibitory effects of the antagonists, GW9662 and\nT0070907, on\nesophageal cancer cell lines. The anti-invasive effects were observed at levels\nsubstantially lower than those required for growth inhibition [28]. In summary, all of these studies addressing\nanticancer effects of PPARγ antagonist compounds have show\neffects on cell growth, adhesion, and invasion in multiple epithelial cancer\nmodels.Some of these effects\nare PPARγ-dependent, but the potential role of other\ntargets is suggested by the similar effects of BADGE on a PPARγ+ colon cancer line and a PPARγ-negative T-lymphoma line. Also, the\nsubstantially different concentrations of PPARγ antagonists needed to induce anti-invasive\neffects versus growth inhibition in esophageal cancer lines suggest different\nmechanisms 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\ncolorectal cancer cell lines and in an in\nvivo tumor xenograft derived from one of the lines was shown in a more\nrecent report by Schaefer et al.\n[29]. A decrease in tubulin levels was observed\nthat was independent of PPARγ, PPARδ,\nand proteasome function. This downregulation of tubulins α and β may explain\nthe antimigratory, anti-invasive, and antimetastatic effects that were\nobserved. Thus, in summary, PPARγ antagonist compounds with varying chemical\nstructures (though GW9662 and T0070907 are similar) have several significant\nanticancer effects in vitro and\nin vivo in epithelial cancer\nmodel systems including breast, colon, aerodigestive squamous cell, and\nhepatocellular.4. EFFECTS OF PPARγ ANTAGONISTS IN\nHEMATOPOIETIC CANCER MODEL SYSTEMSStudies were conducted\nin our lab to assess the effects of PPARγ antagonists on hematopoietic cell lines. Initial screening showed that several\nmyeloma (MM) cell lines had the greatest sensitivity to the antiproliferative\neffects of the antagonists, GW9662 and T0070907. Thus multiple MM lines were\ntested, including one that is IL-6-dependent, for sensitivity to these\ncompounds as well as to the agonist, pioglitazone. MM lines as well as\nnon-Hodgkin lymphoma (NHL) lines showed significantly greater sensitivity to\nthe growth inhibitory effects of the two antagonist drugs compared with the\nagonist [30]. As a group, the MM lines were more sensitive than the other\ngroups of cancer cell lines to the antiproliferative effects of the\nantagonists, particularly T0070907. Other goals were to directly compare the\nsensitivity of previously tested epithelial cancer types (breast and colon) to\nhematopoietic lines (MM and NHL) as well as to evaluate a chemoresistant\nepithelial cancer type (renal cell). These experiments showed that in all the\nepithelial and hematopoietic cell lines tested, the antagonists were\nsignificantly more potent in their growth inhibitory effects compared with the\nagonist drug.The IC50 values for the panel of 16 cell lines\ntested in these studies are shown in Table 1. For each of the cell lines in the panel, significant\ndifferences in the IC50 values of the antagonist\ncompounds and the agonist drug, pioglitazone, were observed (P values ranging from <.04 to\n<.001, with 12 of 16 lines at <.001). While the MM lines showed the\ngreatest sensitivity to the antagonists, similar degrees of sensitivity to the\nantagonists were also seen in the subset of breast cancer lines, which included\ntwo lines that are estrogen receptor-negative. Though not quite as sensitive as\na subset, significant differences between the antagonists and the agonist were\nalso observed in the renal cell lines, which are among the most chemoresistant\nepithelial lines. The differential sensitivities within and across cell lines\ndid not appear to be related to the levels of PPARγ expression. Also, neither the agonist nor the\nantagonist induced significant upregulation of PPARγ as has been reported in some studies with PPARγ ligands. Consistent with prior reports, combinations\nof the agonist and with each of the antagonists did not result in attenuation\nof growth inhibitory effects. In fact, schedule-dependent increases in growth\ninhibition were observed, particularly when the antagonists were added to cells\n24 hours prior to the agonist. Aspects of the mechanisms of cytotoxicity of the\nantagonists and agonists were also compared. It was shown that both classes of PPARγ ligand-induced apoptotic effects, but this\neffect was found to be caspase-independent for the agonist, pioglitazone [30].Another question that\nwas addressed was the impact of IL-6 on the responses of the MM lines to PPARγ antagonists, since this is a cytokine that\nplays a central role in the pathogenesis and progression of MM, as well as\nother cancer types. For these studies, 4 of the 5 MM lines that were utilized\nwere IL-6-independent in order to follow up on a previous\nreport of Wang et al. that\nanalyzed the responses of three MM lines to the PPARγ agonists, 15-d-PGJ2 and\ntroglitazone. This report showed that growth\ninhibition and certain downstream signaling events were PPARγ-dependent, and also\nthat two IL-6-dependent MM lines expressed PPARγ while an IL-6-independent line did not [31].\nAlso, GW9662 was reported to block the effects of the agonists, and had no antiproliferative activity on its own. We utilized five\ndifferent MM lines, of which four are IL-6 independent (CAG, KMS12-BM, KMS12-PE,\nand OPM-6) as well as a fifth that is dependent on an IL-6 autocrine loop\n(U266B1). In contrast to the prior report cited above, of the lines analyzed,\nCAG expressed PPARγ, while the autocrine IL-6-dependent line,\nU266B1, did not express PPARγ by immunoblotting. Also, three of the four of IL-6-independent MM lines were more sensitive to the growth\ninhibitory effects of both of the two PPARγ antagonist compounds compared with the\nIL-6-dependent line, U266B1 (see Table 1).In MM cell lines, which\nare more often IL-6 dependent compared with other B cell lines, the strict dependence\non exogenous IL-6 is indicative of ongoing requirement for this signaling\npathway, which in pathophysiologic states, such as MM, usually depends on production\nof this cytokine by stromal cells. In\nMM, clinically more aggressive or treatment-resistant disease is associated\nwith production of IL-6 by the myeloma cell themselves as opposed to the bone\nmarrow stroma [32]. MM lines show a spectrum of IL-6 dependence, with some\nbeing dependent on exogenous IL-6, others being dependent on its autocrine\nproduction, and yet others being IL-6-independent for their growth. Even those\nMM lines that are not strictly dependent on IL-6 for their growth (exogenous or\nautocrine) can still be affected by the addition of exogenous IL-6 [33] (also\nshown in one of the lines tested, OPM-6, [34]). Addition of IL-6 to such MM\nlines has been shown to induce either incremental stimulation of proliferation or\ninduction of resistance to various agents such as dexamethasone, standard chemotherapy\ndrugs such as melphalan and other agents. Thus the interaction of IL-6 and PPARγ antagonist compounds were examined in two MM\nlines (KMS12-PE and OPM-6). MTT assays were performed in the\npresence and absence of exogenous IL-6 (5 ng/mL). For both of these MM lines,\naddition of IL-6 did not induce resistance, but instead appeared to increase\nthe sensitivity of these lines to T0070907, with a similar trend observed with\nGW9662 [30].5. DOSE-RESPONSE EFFECTS OF PPARγ ANTAGONIST COMPOUNDS AND\nINTERACTION WITH OTHER AGENTSThe PPARγ antagonist\ncompounds, GW9662 and T0070907, differ in their antiproliferative dose-response\neffects compared with the agonist as well as other agents. Not only are the corresponding IC50 values for the\nantagonists significantly lower than the agonist, pioglitazone, but a greater\ndegree of growth inhibition (85–97% versus 50–80%) was observed\nwith the former compounds. Also, of note was that the maximal effects of these\nagents were seen at concentrations that were only 2- to 3-fold greater than the\nIC50 across the entire panel of cell lines tested that included cell\nlines with relative and very high levels of chemoresistance (colon and renal\ncell, resp.). The dose-response curves were much steeper with the antagonist\ncompounds compared to the agonist, pioglitazone, and also much steeper than\nwhat is observed with most other agents, including standard chemotherapy drugs\nand other agents (see Figure 2). This dose-response relationship suggests\neither a positive cooperative effect, potentially via increased, cooperative recruitment\nof corepresssors, thereby increasing transrepression. The alternate possibility\nis that different targets are being engaged with gradually increasing\nconcentrations, which together exhibit additive or supra-additive interactions.Since MM lines as a group were the most sensitive of\nthe cell lines we tested, interaction with other novel agents for therapy of MM\nwere evaluated. One such agent is anti-CD74 monoclonal antibody (mAb). CD74 was\nshown to be strongly expressed by the malignant plasma cells in the vast\nmajority of clinical MM specimens as well as the majority of MM lines [35]. It\nwas also shown that this mAb in unlabeled (cold) form exhibited in vitro growth inhibitory effects on both NHL and MM lines [36]. The\nanti-CD74 mAb used in these studies, LL1, also showed significant therapeutic\neffects in two preclinical murine NHL xenograft models. In preliminary in vitro studies, the humanized anti-CD74 mAb was combined with T0070907 in\ntwo MM lines. These studies also evaluated a sixth MM line (KMS11), which is\nIL-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\nlines, with an (unpublished observations, J Burton). Another IL-6-independent\nMM line that was used in initial studies, KMS12-PE, was also used to evaluate\ninteractions between T0070907 and the hLL1 mAb. While KMS11 line showed moderate\nsensitivity to hLL1 (maximum growth inhibition of 50–70%), the KMS12-PE line\nwas resistant to single-agent hLL1 (<10% inhibition). However, in\ncombination with T0070907, there was a sizable shift to the left of the\ndose-response curve, as is shown in one representative experiment in Figure 2.\nCurrent data indicate that the IC50 value decreases by from a mean\nvalue of ~4.1 μM for T0070907 alone versus ~3.0 μM with T0070907 in combination\nwith hLL1, suggestive of a supra-additive effect (25–30% observed versus <8%\nexpected based effect of hLL1 alone). This is a promising initial preclinical\nlead given that hLL1 is now being evaluated in several phase I/II clinical\ntrials in B-cell cancers such as NHL and MM, and appears to be safe and well\ntolerated.6. OVERVIEWOF MECHANISMS OF ACTION OF PPARγ AGONIST AND ANTAGONIST COMPOUNDSThe studies reviewed above have shown\nthat the effects of PPARγ ligands are mediated by various mechanisms.\nSome studies show or suggest canonical PPARγ-mediated effects (i.e., via transactivation),\nas exemplified by early in vitro studies with agonist compounds that\nshowed fat accumulation, a major PPARγ-mediated effect, in both breast cancer and\nliposarcoma cell lines [10, 12]. This was\nalso demonstrated in liposarcoma patients in whom increased fat content within\ntumors was demonstrated by serial CT scanning before and after treatment with\nan 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\nlines expressing PPARγ and that these effects were reversed by\ncotreatment with an antagonist compound [31]. In contrast, completely PPARγ-independent effects were demonstrated for both\nagonist and antagonist compounds in reports from Palakurthi et\nal. [19] and Schaefer et al. [29]. This was clearly shown for the agonist\ncompounds, troglitazone and ciglitazone, which showed similar antiproliferative\neffects in PPARγ-wild type and PPARγ-null (knockout) embryonic stem cell lines,\nboth in vitro and in vivo [19]. PPARγ-independent growth inhibitory and\nantimetastatic effects of several antagonist compounds were shown in both in vitro and in vivo studies using three\ncolon carcinoma cell lines. These effects were associated with reductions in\ntubulin levels and were also shown to be independent of PPARδ and proteasome function. The PPARγ-independent effect of agonist compounds was\nshown to be associated with inhibitory effects on the protein translation\npathway. The mechanism of PPARγ-independent effects of antagonist compounds on\ntubulin levels has not been elucidated.The\nmechanism of PPARγ-mediated transrepression may explain some of\nthe effects of antagonist compounds. This was suggested by the attenuation of\nthe effects of antagonist compounds by PPARγ knockdown by siRNA in hepatocellular carcinoma\ncell lines [25]. Also, the observation that combinations of PPARγ agonist and antagonist compounds result in\nadditive antiproliferative effects in various cancer cell lines [24, 30] is\nconsistent with this mechanism. This mechanism is plausible, as it has been\nshown to inhibit the NF-κB signaling pathway, which is central to inflammation and to the proliferation \nand survival of multiple cancer types including hepatocellular and\ncolon carcinomas as well as multiple myeloma. The potential role of this and\nother mechanisms remain to be determined.7. SUMMARY OF PRECLINICAL STUDIES OF PPARγ ANTAGONIST COMPOUNDS AND THEIR\nCLINICAL POTENTIALThe studies reviewed above have shown that PPARγ antagonists have in vitro and preclinical in vivo anticancer effects that are as\nbroad and potent as agonist compounds. These effects have been demonstrated in\na wide range of epithelial cancer cell lines as well as hematopoietic cancer\ncell lines. Exploration of the\nunderlying mechanisms of action for antagonist compounds has shown either involvement\nof PPARγ or a PPARγ-independent effect. One study suggested the\ninvolvement of the canonical transactivation mechanism in that antagonist\neffects were antagonized by coincubation with an agonist compound, pioglitazone\n[27]. In another study, where knockdown of PPARγ affected responses to antagonist compounds,\nthe effect was not consistent with the canonical transactivation mechanism, but\nmay be consistent with a transrepressive mechanism [25]. Another study showed\nthat anticancer effects were associated with reductions in tubulin levels (a\nvalidated 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\nPPARγ agonists, there have been relatively few with\nantagonist compounds. Also agonists have been tested clinically. Some studies with\nantagonists have been conducted in noncancer models at low doses (≤1 mg/kg),\nwhich were not toxic and biologically active [37, 38]. A chemically distinct,\nbut selective PPARγ antagonist, SR-202, has been synthesized and evaluated\nin preclinical models (Figure 1). It was given at a dose of 400 mg/kg for\nperiods of up to 10 weeks with favorable metabolic effects such protection\nagainst diet-induced hyperinsulinemia and reduction in hyperinsulinemia and\nhyperglycemia in genetically predisposed (ob/ob) mice [39]. In pilot studies,\nwe have administered moderate doses of GW9662 (15 mg/kg) and T0070907 (7.5\nmg/kg) daily for 3 weeks by the intraperitoneal route to immunodeficient mice.\nThese doses and schedules were well tolerated and resulted in no signs of\ntoxicity (unpublished observations). \nThese data indicate that the doses of these antagonists that may be\nsufficient for anticancer therapy are well tolerated, paving the way for\nfurther development of these agents for treatment of cancer.\n\nREFERENCES:\n1. Juge-AubryCPerninAFavezTDNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5′-flanking regionThe Journal of Biological Chemistry19972724025252252599312141\n2. DiRenzoJSöderströmMKurokawaRPeroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressorsMolecular and Cellular Biology1997174216621769121466\n3. McInerneyEMRoseDWFlynnSEDeterminants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activationGenes & Development19981221335733689808623\n4. YuanC-XItoMFondellJDFuZ-YRoederRGThe TRAP220 component of a thyroid hormone receptor-associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashionProceedings of the National Academy of Sciences of the United States of America19989514793979449653119\n5. KoderaYTakeyamaKMurayamaASuzawaMMasuhiroYKatoSLigand type-specific interactions of peroxisome proliferator-activated receptor γ with transcriptional coactivatorsThe Journal of Biological Chemistry200027543332013320410944516\n6. WermanAHollenbergASolanesGBjørbækCVidal-PuigAJFlierJSLigand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor γ (PPARγ). Differential activity of PPARγ1 and -2 isoforms and influence of insulinThe Journal of Biological Chemistry19972723220230202359242701\n7. LehmannJMMooreLBSmith-OliverTAWilkisonWOWillsonTMKliewerSAAn antidiabetic thiazolidinedione is a high affinity ligand for peroxisome \nproliferator-activated receptor γ (PPARγ)The Journal of Biological Chemistry19952702212953129567768881\n8. ZhuYAlvaresKHuangQRaoMSReddyJKCloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liverThe Journal of Biological Chemistry19932683626817268208262913\n9. ChenFLawSWO'MalleyBWIdentification of two mPPAR related receptors and evidence for the existence of five subfamily membersBiochemical and Biophysical Research Communications199319626716778240342\n10. TontonozPSingerSFormanBMTerminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor γ and the retinoid X receptorProceedings of the National Academy of Sciences of the United States of America19979412372418990192\n11. DuBoisRNGuptaRBrockmanJReddyBSKrakowSLLazarMAThe nuclear eicosanoid receptor, PPARγ, is aberrantly expressed in colonic cancersCarcinogenesis199819149539472692\n12. MuellerESarrafPTontonozPTerminal differentiation of human breast cancer through PPARγ\nMolecular Cell1998134654709660931\n13. KubotaTKoshizukaKWilliamsonEALigand for peroxisome proliferator-activated receptor γ (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivoCancer Research19985815334433529699665\n14. IkezoeTMillerCWKawanoSMutational analysis of the peroxisome proliferator-activated receptor γ in human malignanciesCancer Research200161135307531011431375\n15. DemetriGDFletcherCDMMuellerEInduction of solid tumor differentiation by the peroxisome proliferator-activated receptor-γ ligand troglitazone in patients with liposarcomaProceedings of the National Academy of Sciences of the United States of America19999673951395610097144\n16. MuellerESmithMSarrafPEffects of ligand activation of peroxisome proliferator-activated receptor γ in human prostate cancerProceedings of the National Academy of Sciences of the United States of America20009720109901099510984506\n17. HanSWGreeneMEPittsJWadaRKSidellNNovel expression and function of peroxisome proliferator-activated receptor gamma (PPARγ) in human neuroblastoma cellsClinical Cancer Research2001719810411205925\n18. SuhNWangYHondaTA novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activityCancer Research19995923363419927043\n19. PalakurthiSSAktasHGrubissichLMMortensenRMHalperinJAAnticancer effects of thiazolidinediones are independent of peroxisome proliferator-activated receptor γ and mediated by inhibition of translation initiationCancer Research200161166213621811507074\n20. WrightHMClishCBMikamiTA synthetic antagonist for the peroxisome proliferator-activated receptor γ inhibits adipocyte differentiationThe Journal of Biological Chemistry200027531873187710636887\n21. Bishop-BaileyDHlaTWarnerTDBisphenol A diglycidyl ether (BADGE) is a PPARγ agonist in an ECV304 cell lineBritish Journal of Pharmacology2000131465165411030710\n22. FehlbergSTrautweinSGökeAGökeRBisphenol A diglycidyl ether induces apoptosis in tumour cells independently of peroxisome proliferator-activated receptor-γ, in caspase-dependent and -independent mannersBiochemical Journal2002362357357811879183\n23. SeargentJMYatesEAGillJHGW9662, a potent antagonist of PPARγ, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARγ agonist rosiglitazone, independently of PPARγ activationBritish Journal of Pharmacology2004143893393715533890\n24. LeaMASuraMDesbordesCInhibition of cell proliferation by potential peroxisome proliferator-activated receptor (PPAR) gamma agonists and antagonistsAnticancer Research2004245A2765277115517883\n25. SchaeferKLWadaKTakahashiHPeroxisome proliferator-activated receptor γ inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular \ncarcinoma cellsCancer Research20056562251225915781638\n26. PascualGFongALOgawaSA SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ\nNature2005437705975976316127449\n27. MasudaTWadaKNakajimaACritical role of peroxisome proliferator-activated receptor γ on anoikis \nand invasion of squamous cell carcinomaClinical Cancer Research200511114012402115930335\n28. TakahashiHFujitaKFujisawaTInhibition of peroxisome proliferator-activated receptor gamma activity in esophageal carcinoma cells results in a drastic decrease of invasive propertiesCancer Science200697985486016805824\n29. SchaeferKLTakahashiHMoralesVMPPARγ inhibitors reduce tubulin protein levels by a PPARγ, PPARδ and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cellsInternational Journal of Cancer2007120370271317096328\n30. BurtonJDCastilloMEGoldenbergDMBlumenthalRDPeroxisome proliferator-activated receptor-γ antagonists exhibit potent antiproliferative effects versus many hematopoietic and epithelial cancer \ncell linesAnti-Cancer Drugs200718552553417414621\n31. WangLHYangXYZhangXTranscriptional inactivation of STAT3 by PPARγ suppresses IL-6-responsive multiple myeloma cellsImmunity200420220521814975242\n32. FrassanitoMACusmaiAIodiceGDammaccoFAutocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosisBlood200197248348911154226\n33. BhartiACDonatoNAggarwalBBCurcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cellsThe Journal of Immunology200317173863387114500688\n34. OgawaMNishiuraTOritaniKCytokines prevent dexamethasone-induced apoptosis via the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in a new multiple myeloma cell lineCancer Research200060154262426910945640\n35. BurtonJDElySReddyPKCD74 is expressed by multiple myeloma and is a promising target for therapyClinical Cancer Research200410196606661115475450\n36. SteinRQuZCardilloTMAntiproliferative activity of a humanized anti-CD74 monoclonal antibody, hLL1, on B-cell malignanciesBlood2004104123705371115297317\n37. CollinMMurchOThiemermannCPeroxisome proliferator-activated receptor-γ antagonists GW9662 and T0070907 reduce the protective effects of lipopolysaccharide preconditioning against organ failure caused by endotoxemiaCritical Care Medicine20063441131113816484917\n38. LiuDZengB-XZhangS-HRosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, reduces acute lung injury in endotoxemic ratsCritical Care Medicine200533102309231616215386\n39. RieussetJTouriFMichalikLA new selective peroxisome proliferator-activated receptor γ antagonist with antiobesity and antidiabetic activityMolecular Endocrinology200216112628264412403851" |
