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Experimental Therapeutics |
and Mediated by Inhibition of Translation Initiation1
Laboratory for Membrane Transport, Harvard Medical School, Boston, Massachusetts 02115 [S. S. P., H. A., L. M. G., J. A. H.]; Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115 [H. A., J. A. H.]; and Department of Physiology and Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622 [R. M. M.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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ligands, known for their ability to induce adipocyte differentiation and increase insulin sensitivity, also exhibits anticancer properties. Currently, TZDs are being tested in clinical trials for treatment of human cancers expressing high levels of PPAR because it is assumed that activation of PPAR mediates their anticancer activity. Using PPAR-/- and PPAR+/+ mouse embryonic stem cells, we report here that inhibition of cell proliferation and tumor growth by TZDs is independent of PPAR. Our studies demonstrate that these compounds block G1-S transition by inhibiting translation initiation. Inhibition of translation initiation is the consequence of partial depletion of intracellular calcium stores and the resulting activation of protein kinase R that phosphorylates the 
subunit of eukaryotic initiation factor 2 (eIF2), thus rendering eIF2 inactive. PPAR-independent inhibition of translation initiation most likely accounts for the anticancer properties of thiazolidinediones. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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3
plays a crucial role in adipocyte differentiation (1
, 2)
, and the TZD class of PPAR ligands induces differentiation of PPAR expressing preadipocytes (3)
and primary human liposarcoma cells (4)
. TZDs also inhibit the growth of several cancer cell lines including lung (5)
, breast (6)
, colon (7)
, prostate (8)
, and hematopoietic (9)
cells in vitro and in animal models of cancer (6
, 7)
. In addition, loss-of-function mutations of PPAR have been found in some human colon and thyroid carcinomas (10
, 11)
. As a consequence, PPAR has become a molecular target for anticancer drug development, and TZDs have been proposed for differentiation-mediated therapy of human cancers that express high levels of PPAR such as liposarcoma (12)
, breast (13)
, and colon (14)
cancer.
Cell cycle withdrawal induced by TZDs is assumed to be mediated by PPAR activation (15
, 16)
as a necessary step toward terminal differentiation (17)
. Although the ability of TZDs to induce PPAR-mediated cell differentiation has been demonstrated clearly, neither a role for PPAR in cell cycle regulation nor the mechanism by which TZDs inhibit cell growth has been established conclusively. Indeed, the sensitivity of cancer cell lines to the growth-inhibitory effect of TZDs does not seem to correlate with the levels of PPAR as exemplified by TZD-resistant but high PPAR-expressing 21 MT human breast cancer cells (13)
. We have analyzed the molecular mechanism underlying TZD-induced cell cycle arrest using PPAR-/- and PPAR+/+ mouse ES cells as well as cell lines expressing different levels of PPAR. We report here that TZDs inhibit proliferation of PPAR-/- and PPAR+/+ ES cells to the same extent. We also show that TZDs induce cell cycle arrest in G1 by a PPAR-independent mechanism that involves partial depletion of intracellular Ca2+ stores, activation of PKR, and phosphorylation of the subunit of eIF2, resulting in inhibition of translation initiation. Because TZDs have already shown anticancer efficacy in humans, our findings have important implications for human disease because they validate inhibition of translation initiation as a target for cancer therapy and also place TZDs among inhibitors of translation initiation, which are an emerging class of mechanism-specific anticancer drugs.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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-/- and PPAR+/+ mouse ES cells used in this study were derived from cells reported by Milstone et al. (18)
. PPAR-/- cells are insensitive and PPAR+/+ are sensitive to induction of differentiation under appropriate conditions (2)
. These cells were routinely cultured in DMEM supplemented with 15% heat inactivated FBS (Hyclone, Logan, UT), 0.1 mM ß-mercaptoethanol, 2.0 mM L-glutamine, 20 mM glucose, 25 mM HEPES, and 1000 units/ml of ESGRO (Chemicon International, Temecula, CA; Ref. 19
). For the experiments performed within 1–2 h of TZD treatment, FBS concentration was reduced to 1%, and for longer duration experiments FBS concentration was reduced to 5%. NIH 3T3 and 3T3 L1 cells were cultured in DMEM/10% heat-inactivated calf serum (Life Technologies, Inc., Gaithersburg, MD). For all of the experiments performed within 1–2 h of TZD treatment, the medium was replaced by DMEM supplemented with bFGF (5 ng/ml) and 0.1% calf serum. Human cancer cell lines were grown in RPMI 1640 with 5% FBS (Gemini Bio Products, Calabasas, CA). NIH 3T3 cells were transfected with 10 µg of the plasmids carrying the mouse pBabe-PPAR2. Dominant-negative PKR (PKR-K296) and eIF-251A expressing cells are described elsewhere (20
, 21)
.
Cell Growth Assay.
Adherent human solid tumor cells were plated in 96-well plates and maintained for 5 days in the presence of 6.25–100 µM TRO (gift from Dr. Allison Goldfine, Joslin Diabetes Center, MA) or CGT (Biomol, Plymouth Meeting, PA), and cell proliferation was measured by the SRB assay as described (22)
. Briefly, cells were fixed in 10% cold trichloroacetic acid at 4°C for 1 h, extensively washed with double-distilled H2O and air-dried. Plates were then incubated with 0.4% SRB in 1% acetic acid for 1 h, washed with 1% acetic acid to remove the unbound dye, and air-dried. The bound dye was solubilized by addition of 10 mM Tris (pH 10), and the absorbance was determined in a Titertek Multiscan plate reader at 490 nM. The data calculations were carried out as described (22)
.
DNA Synthesis.
DNA synthesis was determined in 3T3 cells either transfected or not, by measuring incorporation of [3H]thymidine as described (23)
.
Cell Cycle Analysis.
Exponentially growing PPAR-/- and PPAR+/+ ES cells were treated with TZDs in ES medium with 5% FBS for 3 days. The cells were fixed with ethanol and stained with propidium iodide for cell cycle analysis by flow cytometry. Nocodazole-treated cells were used to verify the G2-M peak.
Expression of Cell Cycle Regulatory Proteins.
PPAR-/- and PPAR+/+ ES cells were treated with TZDs for 24 h in ES medium with 2% FBS. Expression of cell cycle regulatory proteins was determined by Western blotting with specific antibodies (Santa Cruz Biotechnology, Santa Cruz, CA).
Polysome Profile Analysis
Exponentially growing PPAR-/- and PPAR+/+ ES cells were exposed to either TRO or CGT (25 µM) for 2 h, followed by treatment with cycloheximide (25 µg/ml) for 5 min. The cells were washed, collected in ice-cold PBS/cycloheximide, and lysed. Samples of equal absorbance at 260 nm were subjected to sucrose (13–60%) density gradient centrifugation (24)
. The gradients were eluted from the bottom while monitoring absorbance at 254 nm.
Phosphorylation of eIF2.
eIF2 phosphorylation in exponentially growing ES cells was determined by Western blot analysis using a phospho-specific eIF2 antibody [Rabbit Pan Anti-eIF2 (pS51); Biosource International, Hopkinton, MA]. For ES cells, TZDs were used at 25 µM and for all other cells at 12.5 µM concentration.
Ca2+ Measurements.
Exponentially growing cells were loaded with 5 µM Fura-2 AM (Molecular Probes, Eugene, OR) in Krebs-Ringer medium buffered with 25 mM HEPES (pH 7.4 at 37°C) for 25 min. Cells were then transferred to a stirred, thermostated cuvette in a dual-wavelength spectrofluorometer system (Photon Technology International, Inc., South Brunswick, NJ). Fluorescence emission was analyzed at 505 nm, with simultaneous excitation at 340 and 380 nm, as described (25)
.
PPAR-/- and PPAR+/+ Tumors.
DB2-J male mice, 4 weeks of age, were obtained from The Jackson Laboratory. Twenty-four mice received injections s.c. of 4 x 106 PPAR-/-, and 24 mice received injections of PPAR+/+ mouse ES cells in 0.1 ml PBS/animal. After 2 weeks, the mice bearing distinctly visible tumors were randomly distributed into treatment and vehicle groups. The animals were given either 500 mg/kg/day TRO (Sanyko Parke Davis, Parsippany, NJ) by gavage in gum-arabicum or gum-arabicum (vehicle group) alone 5 days/week. The tumor dimensions were measured weekly using calipers, and tumor volume was calculated using the following formula: tumor volume = 4/3 x 3.14 x (L/2 x W/2 x W/2), where L is the length and W is the width of the tumor. One mouse in the vehicle group died of bleeding from the tumor site. The data were analyzed by Student’s t test. All animals were sacrificed after 4 weeks of treatment.
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RESULTS AND DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Levels. in inhibition of cell proliferation by TZDs, PPAR-/- and PPAR+/+ ES cells (2
, 18)
were treated with different doses of TRO or CGT for 5 days, and cell growth was monitored by the SRB assay. In both cell lines, TRO and CGT similarly inhibited cell proliferation in a concentration-dependent manner, with IC50s of 
20 µM (Fig. 1, a and b)
. The IC50s are consistent with the growth-inhibitory (6
, 7
, 14
, 26)
and anti-inflammatory (27)
effects of these drugs reported by others. Consistently, we have also observed that in human colon cancer cell lines expressing different levels of PPAR, there is no correlation between the sensitivity of cells toward the growth-inhibitory action of TZDs and their PPAR expression level (data not shown). These data are consistent with the report indicating that 21 MT human breast cancer cells are relatively resistant to TZDs, although they express a high level of PPAR (13)
.
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, undergo TZD-induced adipocyte differentiation, whereas NIH 3T3 cells, which do not express detectable PPAR, are resistant to the adipogenic effect of TZDs (1)
. To further determine whether the cell growth-inhibitory effect of TZDs is attributable to their ability to activate PPAR, we challenged NIH 3T3 and 3T3 L1 cells with TZDs and measured DNA synthesis by [3H]thymidine incorporation. The results show that both TZDs inhibit DNA synthesis in NIH 3T3 and 3T3 L1 cells in a dose-dependent manner. The potency of CGT (IC50, 7.5 µM) is comparable in both cell lines. TRO seems to be more potent in NIH 3T3 cells (IC50, 3.5 µM) that express no detectable PPAR compared with 3T3 L1 cells (IC50, 7.5 µM), which express a high level of PPAR and show ligand-mediated stimulation of PPAR activity (Fig. 1, c and d)
. These results indicate that inhibition of DNA synthesis by TZDs bears no correlation with the levels of PPAR expression. Taken together, these results indicate that inhibition of cell growth by TZDs is not the consequence of PPAR-mediated differentiation signaling.
To explore the stage of the cell cycle that is blocked by TZDs, we added 25 µM TRO to quiescent NIH 3T3 cells at different times after bFGF stimulation and monitored DNA synthesis by pulse labeling the cells with [3H]thymidine 12 h after stimulation with bFGF. To determine the time of the G1-S transition, quiescent cells were pulsed with [3H]thymidine for 2 h at different times after bFGF stimulation and harvested immediately to measure incorporation of [3H]thymidine into the DNA. Quiescent NIH 3T3 cells stimulated with bFGF entered S-phase 12 h after mitogenic stimulation (Fig. 2a
, top). TRO inhibited DNA synthesis when it was added until late G1 but not at later times (Fig. 2a
, bottom). These data suggest that TZDs inhibit cell growth by blocking cell cycle progression before G1-S transition but not at S-phase. To further confirm these results, we performed fluorescence-activated cell sorter analysis of exponentially growing PPAR+/+ and PPAR-/- ES cells exposed to TZDs. ES cells display a cell cycle profile that is very similar to early embryonic cycles, i.e., a short G1 phase and shortened overall duplication time. As a result, in exponentially growing cultures most cells are in S-phase because this is the longest phase of cell cycle (28)
. Consistently, treatment of ES cells with nocodazole, an inhibitor of G2-M transition, for as little as 4 h causes accumulation of cells in G2-M (Fig. 2b)
. Both TRO and CGT blocked ES cells in G1, with similar potency in both PPAR+/+ and PPAR-/- cells (Fig. 2b)
, as well as in NIH 3T3 and 3T3 L1 cells (data not shown). These results indicate that TZDs cause G1 arrest independently of PPAR.
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and thus inhibits translation initiation (20
, 29)
. A recent report that TRO inhibits the capacitative influx of Ca2+ in porcine endothelial cells (30)
prompted us to speculate that an effect on intracellular Ca2+ homeostasis could mediate TZD-induced cell cycle arrest in G1.
To investigate the effect of TZDs on the filling state of internal Ca2+ stores, PPAR-/- and PPAR+/+ ES cells were loaded with Fura-2 AM and then challenged with TZDs (25)
. TZDs rapidly increased cytosolic Ca2+ by release from intracellular stores in a dose-dependent manner (Fig. 3, a and b)
. Subsequent addition of TG, a specific inhibitor of the SER-Ca2+ATPase, did not cause further Ca2+ release (data not shown), indicating that TZDs cause depletion of TG-sensitive calcium stores. Ca2+ store depletion activates SOCs that increase capacitative Ca2+ influx from the external medium and refill the Ca2+ stores.
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-/- or PPAR+/+ ES cells. The plateau phase of increased cytosolic Ca2+ seen after the addition of TG in Ca2+-containing medium represents capacitative Ca2+ influx (Fig. 3, c and d)
. Addition of either TRO or CGT during this plateau phase initially triggered an additional spike of cytosolic Ca2+, most likely from a TG-independent pool, and then returned cytosolic Ca2+ toward its basal levels (Fig. 3, c and d)
. The similar effect seen in both cell types indicates that TZDs inhibit capacitative Ca2+ influx independently of PPAR. Consistently, TZDs induced Ca2+ release from intracellular stores and inhibited SOC-mediated Ca2+ influx in a similar fashion in cells with varying levels of PPAR expression. TZDs caused depletion of internal Ca2+ stores in: (a) NIH 3T3 cells and 3T3 L1 cells; (b) 3T3 L1 cells before differentiation when PPAR levels are low and after differentiation when PPAR levels are induced (31)
; (c) human colon cancer cell lines that express different levels of PPAR; and (d) in murine PPAR or empty vector-transfected NIH 3T3 cells (data not shown). We have reported previously that both release of intracellular Ca2+ and inhibition of SOCs are required to induce sustained partial depletion of intracellular Ca2+ stores, sustained inhibition of protein synthesis, and down-regulation of cell cycle regulatory proteins (20)
. These results demonstrate that TZDs have a Ca2+ store-depleting effect that is totally independent of PPAR, which may account for the antiproliferative effects of these compounds.
TZDs Inhibit Translation Initiation by eIF2 Phosphorylation.
To determine whether depletion of internal Ca2+ stores by TZDs also inhibits translation initiation, we analyzed the ribosomal profile of TZD or vehicle-treated cells by sucrose density gradient centrifugation. Exponentially growing PPAR-/- and PPAR+/+ ES cells as well as NIH 3T3 and 3T3 L1 cells were challenged with TZDs for 2 h, and cell lysates were subjected to sucrose density gradient centrifugation. In both PPAR-/- and PPAR+/+ ES cells, TZDs identically shifted the ribosomal profile from heavy to lighter polysomes (Fig. 4, a and b)
, as is characteristic of inhibition of translation initiation (32)
. Identical results were obtained when we studied the effects of TZDs on polysome profiles of NIH 3T3 and 3T3 L1 cells and of human colon cancer cells that express different levels of PPAR (data not shown). These results conclusively demonstrate that TZDs inhibit translation initiation, regardless of the PPAR status of the cells.
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inhibits this exchange reaction by increasing the affinity of eIF2 for eIF2B, locking these two translation initiation factors into stable but unproductive complexes, and thus inhibiting translation initiation.
To test whether TZDs inhibit translation initiation by phosphorylating eIF2, we measured phosphorylation of eIF2 by Western blot analysis using an antibody that specifically recognizes eIF2 when its serine 51 residue is phosphorylated (37)
. Treatment of PPAR-/- or PPAR+/+ ES cells with TZDs induced a comparable phosphorylation of eIF2 that is evident within 30 min after drug addition (Fig. 4, c and d)
. Similar results were obtained by measuring the direct incorporation of 32P into eIF2 in NIH 3T3 and 3T3 L1 cells and in the human colon cancer cells (data not shown).
Mutation of serine 51 residue of eIF2 to alanine (eIF2-51A) renders the initiation factor nonphosphorylatable and therefore constitutively active (20
, 38)
. Consistently, NIH 3T3 cells stably transfected with eIF2-51A were totally resistant to the phosphorylation of eIF2 (Fig. 5)
and to the DNA synthesis inhibitory effects of both TZDs (TROIC50, 10 ± 0.2 µM; CGTIC50, 15 ± 0.4 µM) as compared with vector control cells (TROIC50, 3.8 ± 0.2 µM; CGTIC50, 5 ± 0.4 µM). These data indicate that phosphorylation of eIF2 and inhibition of eIF2 activity mediate inhibition of translation initiation by TZDs.
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is phosphorylated on serine 51 residue by PKR (37)
. NIH 3T3 cells expressing a dominant-negative mutant of PKR (PKR-K296; Refs. 20
, 39
) were also significantly resistant to the phosphorylation of eIF2 (Fig. 5)
and to the DNA synthesis inhibitory effects of both TZDs (TROIC50, 10 ± 0.5 µM; CGTIC50, 17 ± 0.4 µM) as compared with vector control cells (TROIC50, 3.8 ± 0.2 µM; CGTIC50, 5 ± 0.4 µM). Taken together, these results demonstrate that TZDs inhibit translation initiation and cell proliferation by PKR (or related kinase)-mediated phosphorylation of eIF2.
TZDs Abrogate Expression of G1 Cyclins.
G1 cyclins bind to and activate cdks that drive the cell cycle through the G1 phase and govern G1-S transition (40, 41, 42)
. To understand the mechanism of G1 arrest induced by TZDs, we analyzed their effect on the expression of G1 regulatory proteins including G1 cyclins, cdks, and cdk inhibitors in exponentially growing PPAR-/- and PPAR+/+ ES cells. The results show that in both PPAR-/- and PPAR+/+ ES cells, TRO significantly down-regulates cyclin D1 and cyclin E in a dose-dependent manner and has a minimal effect on p21cip1, cyclin B, and cyclin A. In contrast, the expression of other cell cycle regulatory proteins, such as cdk4 and cdk2, and of housekeeping proteins, such as ß-actin, was not affected (Fig. 6)
. Identical results were obtained with CGT (data not shown). Consistent with their inhibitory effect on translation initiation, TZDs inhibit synthesis of G1 cyclins without affecting the level of their respective mRNAs (data not shown). These data indicate that TZDs do not interfere with mitogenic signaling upstream from cyclin D1 transcription. Whether down-regulation of cyclin D1 is necessary and/or sufficient for cell cycle-inhibitory effects of TZDs and whether other cell cycle regulatory proteins are also abrogated by these compounds remain to be determined.
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., we injected DB2-J male mice with PPAR-/- and PPAR+/+ mouse ES cells and treated tumor-bearing mice with either TRO or vehicle alone. Treatment with TRO almost totally suppressed the growth of tumors established by injection of both PPAR-/- and PPAR+/+ mouse ES cells (Fig. 7)
. These results conclusively demonstrate that the antitumor activity of TZDs is independent of PPAR and may be mediated through its effects on inhibition of translation initiation.
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receptor, it is widely believed that all anticancer properties of these drugs are part of the PPAR-mediated differentiation response and involve activation of the PPAR nuclear receptor. In this report, we identify a novel PPAR-independent mechanism for the antiproliferative activity of the TZDs. Indeed, Ca2+ release from ER stores and closing of SOCs in the plasma membrane, PKR-mediated phosphorylation of eIF2 and inhibition of translation initiation, abrogation of synthesis and expression of cell cycle regulatory proteins, and the consequent cell cycle arrest in G1 occur identically in both PPAR+/+ and PPAR-/- ES cells. Furthermore, all these phenomena were observed in cells expressing different levels of PPAR, either naturally or after transfection with PPAR. Most importantly, TZDs inhibit the growth of tumors formed by injection of both PPAR+/+ and PPAR-/- ES cells to the same extent. These data demonstrate clearly that the antitumor effects of TZDs are independent of PPAR.
Most differentiation-inducing agents, such as sodium butyrate and retinoids (43)
, induce cell cycle arrest in G1, suggesting that G1 arrest is frequently a prerequisite for cell differentiation. In view of our new findings, it is tempting to postulate that the TZDs have a dual pharmacological effect on the target cells. On one hand they inhibit translation initiation via partial depletion of intracellular Ca2+ stores, activation of PKR, and phosphorylation of eIF2, thus inhibiting cell proliferation. These are rapid epigenetic effects that occur within the first 30 min of drug addition and are totally PPAR independent. On the other hand, in preadipocytes, liposarcoma, and perhaps some other susceptible cells, TZDs activate PPAR and the transcription of an array of PPAR-responsive genes that lead to their differentiation. Interestingly, EPA, another inhibitor of translation initiation via partial ER calcium depletion (21)
, is also a PPAR ligand (44)
. It is conceivable that the ligand-binding pocket of the PPAR molecule may share some common features with one of the receptors responsible for Ca2+ release and SOC closing. The other compounds such as clotrimazole that also inhibit translation initiation by ER calcium depletion do not induce differentiation of 3T3 L1 cells (data not shown), indicating that Ca2+-mediated inhibition of translation initiation and G1 arrest are not sufficient to cause cell differentiation. Whether Ca2+ release-mediated cell cycle arrest in G1 and inhibition of translation initiation are required for the PPAR-mediated induction of differentiation by TZDs and EPA is not known.
This work defines the TZDs as novel inhibitors of translation initiation. The crucial role of translation initiation in cell growth regulation and oncogenesis makes this cellular process an attractive target for cancer treatment (20
, 21)
. The anticancer activity of the TZDs therefore should be explored in clinical trials independently of the levels and/or genetic status of PPAR in cancers.
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ACKNOWLEDGMENTS |
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plasmids and Dr. A. Goldfine for helpful discussions and for kindly providing TRO. |
FOOTNOTES |
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1 This work was supported in part by NIH Grants CA 78411 and NCDDG 1 U19 CA 87427-01. 
2 To whom requests for reprints should be addressed, at Laboratory for Membrane Transport, Harvard Medical School, 240 Longwood Avenue, C1–607, Boston, MA 02115. Phone: (617) 432-2394; Fax: (617) 432-0933; E-mail: jose_halperin{at}hms.harvard.edu
3 The abbreviations used are: PPAR, peroxisome proliferator activated receptor; TZD, thiazolidinedione; eIF2, eukaryotic initiation factor 2; ES, embryonic stem; PKR, double-stranded RNA-dependent protein kinase; FBS, fetal bovine serum; bFGF, basic fibroblast growth factor; SRB, sulforhodamine B; TRO, troglitazone; CGT, ciglitazone; EPA, eicosapentaenoic acid; ER, endoplasmic reticulum; TG, thapsigargin; SOC, store-operated Ca2+ channel; cdk, cyclin-dependent kinase.
Received 3/14/01. Accepted 7/ 5/01.
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C.-C. Yang, Y.-C. Wang, S. Wei, L.-F. Lin, C.-S. Chen, C.-C. Lee, C.-C. Lin, and C.-S. Chen Peroxisome Proliferator-Activated Receptor {gamma}-Independent Suppression of Androgen Receptor Expression by Troglitazone Mechanism and Pharmacologic Exploitation Cancer Res., April 1, 2007; 67(7): 3229 - 3238. [Abstract] [Full Text] [PDF]
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P. Kempna, G. Hofer, P. E. Mullis, and C. E. Fluck Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2 Mol. Pharmacol., March 1, 2007; 71(3): 787 - 798. [Abstract] [Full Text] [PDF]
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 D.-H. Cho, Y. J. Choi, S. A. Jo, J. Ryou, J. Y. Kim, J. Chung, and I. Jo Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition Am J Physiol Cell Physiol, August 1, 2006; 291(2): C317 - C326. [Abstract] [Full Text] [PDF]
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J. J. Schlezinger, J. K. Emberley, and D. H. Sherr Activation of Multiple Mitogen-Activated Protein Kinases in Pro/Pre-B Cells by GW7845, a Peroxisome Proliferator-Activated Receptor {gamma} Agonist, and Their Contribution to GW7845-Induced Apoptosis Toxicol. Sci., August 1, 2006; 92(2): 433 - 444. [Abstract] [Full Text] [PDF]
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 K. Ota, K. Ito, T. Suzuki, S. Saito, M. Tamura, S.-i. Hayashi, K. Okamura, H. Sasano, and N. Yaegashi Peroxisome Proliferator-Activated Receptor {gamma} and Growth Inhibition by Its Ligands in Uterine Endometrial Carcinoma. Clin. Cancer Res., July 15, 2006; 12(14): 4200 - 4208. [Abstract] [Full Text] [PDF]
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 J-R Weng, C-Y Chen, J J Pinzone, M D Ringel, and C-S Chen Beyond peroxisome proliferator-activated receptor {gamma} signaling: the multi-facets of the antitumor effect of thiazolidinediones. Endocr. Relat. Cancer, June 1, 2006; 13(2): 401 - 413. [Abstract] [Full Text] [PDF]
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 J. Lopez-Soriano, C. Chiellini, M. Maffei, P. A. Grimaldi, and J. M. Argiles Roles of Skeletal Muscle and Peroxisome Proliferator-Activated Receptors in the Development and Treatment of Obesity Endocr. Rev., May 1, 2006; 27(3): 318 - 329. [Abstract] [Full Text] [PDF]
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C.-C. Yang, C.-Y. Ku, S. Wei, C.-W. Shiau, C.-S. Chen, J. J. Pinzone, M. D. Ringel, and C.-S. Chen Peroxisome Proliferator-Activated Receptor {gamma}-Independent Repression of Prostate-Specific Antigen Expression by Thiazolidinediones in Prostate Cancer Cells Mol. Pharmacol., May 1, 2006; 69(5): 1564 - 1570. [Abstract] [Full Text] [PDF]
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M. A. Peraza, A. D. Burdick, H. E. Marin, F. J. Gonzalez, and J. M. Peters The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR) Toxicol. Sci., April 1, 2006; 90(2): 269 - 295. [Abstract] [Full Text] [PDF]
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Y. Akasaki, G. Liu, H. H. Matundan, H. Ng, X. Yuan, Z. Zeng, K. L. Black, and J. S. Yu A Peroxisome Proliferator-activated Receptor-{gamma} Agonist, Troglitazone, Facilitates Caspase-8 and -9 Activities by Increasing the Enzymatic Activity of Protein-tyrosine Phosphatase-1B on Human Glioma Cells J. Biol. Chem., March 10, 2006; 281(10): 6165 - 6174. [Abstract] [Full Text] [PDF]
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 A. B. Goldfine, S. Crunkhorn, M. Costello, H. Gami, E. J. Landaker, M. Niinobe, K. Yoshikawa, D. Lo, A. Warren, J. Jimenez-Chillaron, et al. Necdin and E2F4 Are Modulated by Rosiglitazone Therapy in Diabetic Human Adipose and Muscle Tissue Diabetes, March 1, 2006; 55(3): 640 - 650. [Abstract] [Full Text] [PDF]
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G. He, Y. M. Sung, J. DiGiovanni, and S. M. Fischer Thiazolidinediones Inhibit Insulin-Like Growth Factor-I-Induced Activation of p70S6 Kinase and Suppress Insulin-Like Growth Factor-I Tumor-Promoting Activity Cancer Res., February 1, 2006; 66(3): 1873 - 1878. [Abstract] [Full Text] [PDF]
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M. Konopleva, W. Zhang, Y.-X. Shi, T. McQueen, T. Tsao, M. Abdelrahim, M. F. Munsell, M. Johansen, D. Yu, T. Madden, et al. Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells. Mol. Cancer Ther., February 1, 2006; 5(2): 317 - 328. [Abstract] [Full Text] [PDF]
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S. Chintharlapalli, S. Papineni, S. J. Baek, S. Liu, and S. Safe 1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes Are Peroxisome Proliferator-Activated Receptor {gamma} Agonists but Decrease HCT-116 Colon Cancer Cell Survival through Receptor-Independent Activation of Early Growth Response-1 and Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Mol. Pharmacol., December 1, 2005; 68(6): 1782 - 1792. [Abstract] [Full Text] [PDF]
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O. S. Gardner, B. J. Dewar, and L. M. Graves Activation of Mitogen-Activated Protein Kinases by Peroxisome Proliferator-Activated Receptor Ligands: An Example of Nongenomic Signaling Mol. Pharmacol., October 1, 2005; 68(4): 933 - 941. [Abstract] [Full Text] [PDF]
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 S. Z. Duan, C. Y. Ivashchenko, M. W. Russell, D. S. Milstone, and R. M. Mortensen Cardiomyocyte-Specific Knockout and Agonist of Peroxisome Proliferator-Activated Receptor-{gamma} Both Induce Cardiac Hypertrophy in Mice Circ. Res., August 19, 2005; 97(4): 372 - 379. [Abstract] [Full Text] [PDF]
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 M. B. Oleksiewicz, I. Thorup, H. S. Nielsen, H. V. Andersen, A. C. Hegelund, L. Iversen, T. S. Guldberg, P. R. Brinck, I. Sjogren, U. K. Thinggaard, et al. Generalized Cellular Hypertrophy is Induced by a Dual-Acting PPAR Agonist in Rat Urinary Bladder Urothelium In Vivo Toxicol Pathol, August 1, 2005; 33(5): 552 - 560. [Abstract] [Full Text] [PDF]
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 M. J. Betz, I. Shapiro, M. Fassnacht, S. Hahner, M. Reincke, F. Beuschlein, and for the German Austrian Adrenal Network Peroxisome Proliferator-Activated Receptor-{gamma} Agonists Suppress Adrenocortical Tumor Cell Proliferation and Induce Differentiation J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 3886 - 3896. [Abstract] [Full Text] [PDF]
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E. Frohlich, F. Machicao, and R. Wahl Action of thiazolidinediones on differentiation, proliferation and apoptosis of normal and transformed thyrocytes in culture Endocr. Relat. Cancer, June 1, 2005; 12(2): 291 - 303. [Abstract] [Full Text] [PDF]
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J. Lu, K. Imamura, S. Nomura, K.-i. Mafune, A. Nakajima, T. Kadowaki, N. Kubota, Y. Terauchi, G. Ishii, A. Ochiai, et al. Chemopreventive Effect of Peroxisome Proliferator-Activated Receptor {gamma} on Gastric Carcinogenesis in Mice Cancer Res., June 1, 2005; 65(11): 4769 - 4774. [Abstract] [Full Text] [PDF]
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Y. Yin, R. G. Russell, L. E. Dettin, R. Bai, Z.-L. Wei, A. P. Kozikowski, L. Kopleovich, and R. I. Glazer Peroxisome Proliferator-Activated Receptor {delta} and {gamma} Agonists Differentially Alter Tumor Differentiation and Progression during Mammary Carcinogenesis Cancer Res., May 1, 2005; 65(9): 3950 - 3957. [Abstract] [Full Text] [PDF]
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O. S. Gardner, C.-W. Shiau, C.-S. Chen, and L. M. Graves Peroxisome Proliferator-activated Receptor {gamma}-independent Activation of p38 MAPK by Thiazolidinediones Involves Calcium/Calmodulin-dependent Protein Kinase II and Protein Kinase R: CORRELATION WITH ENDOPLASMIC RETICULUM STRESS J. Biol. Chem., March 18, 2005; 280(11): 10109 - 10118. [Abstract] [Full Text] [PDF]
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P. Ferruzzi, E. Ceni, M. Tarocchi, C. Grappone, S. Milani, A. Galli, G. Fiorelli, M. Serio, and M. Mannelli Thiazolidinediones Inhibit Growth and Invasiveness of the Human Adrenocortical Cancer Cell Line H295R J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1332 - 1339. [Abstract] [Full Text] [PDF]
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C.-W. Shiau, C.-C. Yang, S. K. Kulp, K.-F. Chen, C.-S. Chen, J.-W. Huang, and C.-S. Chen Thiazolidenediones Mediate Apoptosis in Prostate Cancer Cells in Part through Inhibition of Bcl-xL/Bcl-2 Functions Independently of PPAR{gamma} Cancer Res., February 15, 2005; 65(4): 1561 - 1569. [Abstract] [Full Text] [PDF]
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R. Maniratanachote, K. Minami, M. Katoh, M. Nakajima, and T. Yokoi Chaperone Proteins Involved in Troglitazone-Induced Toxicity in Human Hepatoma Cell Lines Toxicol. Sci., February 1, 2005; 83(2): 293 - 302. [Abstract] [Full Text] [PDF]
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M. Konopleva, T. Tsao, Z. Estrov, R.-m. Lee, R.-Y. Wang, C. E. Jackson, T. McQueen, G. Monaco, M. Munsell, J. Belmont, et al. The Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid Induces Caspase-Dependent and -Independent Apoptosis in Acute Myelogenous Leukemia Cancer Res., November 1, 2004; 64(21): 7927 - 7935. [Abstract] [Full Text] [PDF]
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 A Galli, E Ceni, D W Crabb, T Mello, R Salzano, C Grappone, S Milani, E Surrenti, C Surrenti, and A Casini Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPAR{gamma} independent mechanisms Gut, November 1, 2004; 53(11): 1688 - 1697. [Abstract] [Full Text] [PDF]
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F. Turturro, E. Friday, R. Fowler, D. Surie, and T. Welbourne Troglitazone Acts on Cellular pH and DNA Synthesis through a Peroxisome Proliferator-Activated Receptor {gamma}-Independent Mechanism in Breast Cancer-Derived Cell Lines Clin. Cancer Res., October 15, 2004; 10(20): 7022 - 7030. [Abstract] [Full Text] [PDF]
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M. Konopleva, E. Elstner, T. J. McQueen, T. Tsao, A. Sudarikov, W. Hu, W. D. Schober, R.-Y. Wang, D. Chism, S. M. Kornblau, et al. Peroxisome proliferator-activated receptor {gamma} and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias Mol. Cancer Ther., October 1, 2004; 3(10): 1249 - 1262. [Abstract] [Full Text] [PDF]
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 E. Saez, J. Rosenfeld, A. Livolsi, P. Olson, E. Lombardo, M. Nelson, E. Banayo, R. D. Cardiff, J. C. Izpisua-Belmonte, and R. M. Evans PPAR{gamma} signaling exacerbates mammary gland tumor development Genes & Dev., March 1, 2004; 18(5): 528 - 540. [Abstract] [Full Text] [PDF]
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C. Qin, D. Morrow, J. Stewart, K. Spencer, W. Porter, R. Smith III, T. Phillips, M. Abdelrahim, I. Samudio, and S. Safe A new class of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists that inhibit growth of breast cancer cells: 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes Mol. Cancer Ther., March 1, 2004; 3(3): 247 - 260. [Abstract] [Full Text]
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T. Kumagai, T. Ikezoe, D. Gui, J. O'Kelly, X.-J. Tong, F. J. Cohen, J. W. Said, and H. P. Koeffler RWJ-241947 (MCC-555), A Unique Peroxisome Proliferator-Activated Receptor-{gamma} Ligand with Antitumor Activity against Human Prostate Cancer in Vitro and in Beige/Nude/ X-Linked Immunodeficient Mice and Enhancement of Apoptosis in Myeloma Cells Induced by Arsenic Trioxide Clin. Cancer Res., February 15, 2004; 10(4): 1508 - 1520. [Abstract] [Full Text] [PDF]
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J. R. Worley, M. D. Baugh, D. A. Hughes, D. R. Edwards, A. Hogan, M. J. Sampson, and J. Gavrilovic Metalloproteinase Expression in PMA-stimulated THP-1 Cells: EFFECTS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-{gamma} (PPAR{gamma}) AGONISTS AND 9-CIS-RETINOIC ACID J. Biol. Chem., December 19, 2003; 278(51): 51340 - 51346. [Abstract] [Full Text] [PDF]
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O. S. Gardner, B. J. Dewar, H. S. Earp, J. M. Samet, and L. M. Graves Dependence of Peroxisome Proliferator-activated Receptor Ligand-induced Mitogen-activated Protein Kinase Signaling on Epidermal Growth Factor Receptor Transactivation J. Biol. Chem., November 21, 2003; 278(47): 46261 - 46269. [Abstract] [Full Text] [PDF]
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 F. Liang, F. Wang, S. Zhang, and D. G. Gardner Peroxisome Proliferator Activated Receptor (PPAR){alpha} Agonists Inhibit Hypertrophy of Neonatal Rat Cardiac Myocytes Endocrinology, September 1, 2003; 144(9): 4187 - 4194. [Abstract] [Full Text] [PDF]
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D. Bruemmer, F. Yin, J. Liu, J. P. Berger, T. Sakai, F. Blaschke, E. Fleck, A. J. Van Herle, B. M. Forman, and R. E. Law Regulation of the Growth Arrest and DNA Damage-Inducible Gene 45 (GADD45) by Peroxisome Proliferator-Activated Receptor {gamma} in Vascular Smooth Muscle Cells Circ. Res., August 22, 2003; 93 (4): e38 - e47. [Abstract] [Full Text] [PDF]
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 S. Laurora, S. Pizzimenti, F. Briatore, A. Fraioli, M. Maggio, P. Reffo, C. Ferretti, M. U. Dianzani, and G. Barrera Peroxisome Proliferator-Activated Receptor Ligands Affect Growth-Related Gene Expression in Human Leukemic Cells J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 932 - 942. [Abstract] [Full Text] [PDF]
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 D. Bruemmer, F. Yin, J. Liu, J. P. Berger, T. Kiyono, J. Chen, E. Fleck, A. J. Van Herle, B. M. Forman, and R. E. Law Peroxisome Proliferator-Activated Receptor {gamma} Inhibits Expression of Minichromosome Maintenance Proteins in Vascular Smooth Muscle Cells Mol. Endocrinol., June 1, 2003; 17(6): 1005 - 1018. [Abstract] [Full Text] [PDF]
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 S. T. de Dios, D. Bruemmer, R. J. Dilley, M. E. Ivey, G. L.R. Jennings, R. E. Law, and P. J. Little Inhibitory Activity of Clinical Thiazolidinedione Peroxisome Proliferator Activating Receptor-{gamma} Ligands Toward Internal Mammary Artery, Radial Artery, and Saphenous Vein Smooth Muscle Cell Proliferation Circulation, May 27, 2003; 107(20): 2548 - 2550. [Abstract] [Full Text] [PDF]
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S. J. Baek, L. C. Wilson, L. C. Hsi, and T. E. Eling Troglitazone, a Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) Ligand, Selectively Induces the Early Growth Response-1 Gene Independently of PPARgamma . A NOVEL MECHANISM FOR ITS ANTI-TUMORIGENIC ACTIVITY J. Biol. Chem., February 14, 2003; 278(8): 5845 - 5853. [Abstract] [Full Text] [PDF]
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H. P. Koeffler Peroxisome Proliferator-activated Receptor {gamma} and Cancers Clin. Cancer Res., January 1, 2003; 9(1): 1 - 9. [Abstract] [Full Text] [PDF]
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 E. Cernuda-Morollon, F. Rodriguez-Pascual, P. Klatt, S. Lamas, and D. Perez-Sala PPAR Agonists Amplify iNOS Expression While Inhibiting NF-{kappa}B: Implications for Mesangial Cell Activation by Cytokines J. Am. Soc. Nephrol., September 1, 2002; 13(9): 2223 - 2231. [Abstract] [Full Text] [PDF]
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Y. Kim, N. Suh, M. Sporn, and J. C. Reed An Inducible Pathway for Degradation of FLIP Protein Sensitizes Tumor Cells to TRAIL-induced Apoptosis J. Biol. Chem., June 14, 2002; 277(25): 22320 - 22329. [Abstract] [Full Text] [PDF]
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N. Marx, B. Kehrle, K. Kohlhammer, M. Grub, W. Koenig, V. Hombach, P. Libby, and J. Plutzky PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis Circ. Res., April 5, 2002; 90(6): 703 - 710. [Abstract] [Full Text] [PDF]
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 J. Auwerx Nuclear Receptors: I. PPARgamma in the gastrointestinal tract: gain or pain? Am J Physiol Gastrointest Liver Physiol, April 1, 2002; 282(4): G581 - G585. [Abstract] [Full Text] [PDF]
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 R. Cunard, M. Ricote, D. DiCampli, D. C. Archer, D. A. Kahn, C. K. Glass, and C. J. Kelly Regulation of Cytokine Expression by Ligands of Peroxisome Proliferator Activated Receptors J. Immunol., March 15, 2002; 168(6): 2795 - 2802. [Abstract] [Full Text] [PDF]
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N. Marx, B. Kehrle, K. Kohlhammer, M. Grub, W. Koenig, V. Hombach, P. Libby, and J. Plutzky PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis Circ. Res., April 5, 2002; 90(6): 703 - 710. [Abstract] [Full Text] [PDF]
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) ES cells were treated with the indicated concentration of either TRO (a) or CGT (b) for 5 days, and percentage of growth of the cells was measured. c and d, DNA synthesis in the absence or presence of TRO (c) or CGT (d) was measured in quiescent NIH 3T3 (
) that were almost totally suppressed by the administration of TRO (p.o., 500 mg/kg/day;