PPAR Research

Review Article

Anticancer Role of PPARγ Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

Table 3

Effects of PPAR

γ

agonists on endothelial cell function and angiogenesis.


Ref.	Goal of Study	Results	Pro- or antiangiogenic	Direct or Indirect Effects

[192]	To determine whether PPAR $γ$ ligands induce EC proliferation or influence cytokine-induced proliferation in vitro.	PPAR $γ$ ligands troglitazone and pioglitazone negligibly affected basal EC proliferation in vitro; troglitazone and pioglitazone significantly inhibited FGF-2-induced EC growth.	• Antiangiogenic activity as shown by inhibiting FGF-2-induced EC proliferation	Not reported

[22]	To determine effects of PPAR $γ$ ligands on in vitro and in vivo angiogenesis and EC proliferation.	15d-PGJ₂, BRL49653, or ciglitazone, dose-dependently suppresses HUVEC differentiation into tube-like structures and cell proliferation; 15d-PGJ₂ downregulated VEGFR1, VEGFR2 and uPA and increased PAI-1 mRNA expression in vitro; 15d-PGJ₂ inhibited angiogenesis in vivo.	• Antiangiogenic activity	Not reported
			• Anti-cell proliferation and anti-cell differentiation activity

[193]	To determine whether human ECs express PPAR $γ$ and if PPAR $γ$ regulates PAI-1 expression in EC.	ECs expressed functionally active PPAR $γ$ ; PPAR $γ$ ligands (15d-PGJ₂) and oxidized linoleic acid regulated PAI-1 expression in ECs.	• Antiangiogenic activity by inhibiting fibrinolysis (fibrin induces angiogenesis)	Not reported

[194]	To determine the antiangiogenic effects of PPAR $γ$ agonists on CNV in vitro and on experimental laser photocoagulation-induced CNV in vivo.	PPAR $γ$ ligands troglitazone and rosiglitazone inhibited VEGF-induced migration and proliferation of human RPE cells and bovine CECs and tube formation of CEC in a dose-response manner; troglitazone inhibited CNV in rat and monkey eyes.	• Antiangiogenic activity in the eye	Not reported
			• Anti-cell proliferation activity

[195]	To determine whether PPAR $γ$ ligands inhibit cancer cell growth and cancer-associated angiogenesis.	PPAR $γ$ expressed in tumor EC; rosiglitazone suppressed primary tumor growth and metastasis; rosiglitazone inhibited bovine capillary EC but not tumor cell proliferation; rosiglitazone decreased VEGF production by tumor cells in vitro; rosiglitazone suppressed angiogenesis in vivo and in a variety of primary tumors.	• Antiangiogenic activity	Direct and indirect
			• Anti-EC but not tumor cell proliferation activity

[196]	To determine whether PPAR $γ$ ligands regulate PPAR $γ$ and CD36 gene expression in microvascular and large vessel EC in vitro and modulate TSP-1 peptide ABT510 antiangiogenic activity in tumor-associated endothelium in vivo (mouse tumor models).	15d-PGJ₂, troglitazone, and rosiglitazone induced PPAR $γ$ and CD36 gene expression in EC in vitro and inhibited angiogenic endothelial functions in vitro and neovascularization in vivo in an additive manner; ABT510 and PPAR $γ$ ligands enhancedsynergistically the antiangiogenic and antitumor effects of TSP-1 peptide ABT510.	• Antiangiogenic activity	Direct for in vitro activities
			• Anti-proliferation activity in EC
			• Anti-invasion activity of EC
			• Cooperative inhibition of EC angiogenic functions
			• Synergistic inhibition of tumor angiogenesis
[197]	To determine whether PPAR $γ$ agonists modulate bone marrow-derived bipotential APCs to promote endothelial lineage differentiation and re-endothelialization after vascular intervention.	Rosiglitazone promoted differentiation of bone marrow-derived APCs toward the endothelial lineage and attenuated restenosis after angioplasty in C57/BL6 mice; rosiglitazone inhibited APC differentiation toward smooth muscle cell lineage.	• Proangiogenic activity	Not reported
			• Anti-inflammatory
			• Promoted lineage-specific differentiation

[198]	To determine the efficacy of pioglitazone to inhibit corneal neovascularization.	PPAR $γ$ ligand pioglitazone decreased MVD in a VEGF-induced neovascularization in a rat cornea model.	• Antiangiogenic activity in the eye	Not reported

[24]	To determine whether PPAR $γ$ ligands can inhibit angiogenesis in A549 lung cancer cell xenograft in vivo and which signaling pathway is involved in vitro.	PPAR $γ$ ligands troglitazone and pioglitazone significantly inhibited A549 primary tumor growth in SCID mice, likely due to inhibition of cancer-associated angiogenesis; in vitro studies on A549 cells suggested PPAR $γ$ ligands inhibit chemokine expression and inhibit NF-κB activity, the transcription factor necessary for chemokine expression.	• Antiangiogenic activity	Direct and indirect
			• Inhibited NF-κB transcription factor activity

[199]	To determine effects of PPAR $γ$ ligands on VEGF expression by human endometrial cells.	PPAR $γ$ ligands rosiglitazone and 15d-PGJ₂ repressed VEGF gene expression through a PPRE in the VEGF promoter.	• Antiangiogenic activity	Not reported
			• Identified PPRE in VEGF promoter

[200]	Because endothelial precursor cell (EPC) function is impaired in type 2 diabetic patients and EC dysfunction can be ameliorated by treatment with TZDs, this study asked whether TZDs affect the number and function of EPCs.	Rosiglitazone improved number and migratory activity of EPCs from type 2 diabetic patients; rosiglitazone increased the CD133+ subpopulation of CD34+ cells (stem cells); rosiglitazone increased circulating levels of VEGF; effects may be due to increased bioavailability of NO by Akt-dependent phosphorylation of eNOS—a pathway that is activated by VEGF or the insulin signaling cascade.	• Proangiogenic activity	Not reported
			• Akt survival pathway activated
			• Elevated CD133+/CD34+ stem cells towards EC lineage (VE-cadherin+ and CD31+)

[201]	To determine whether TZDs increase the number of bone marrow-derived EPCs in mice and the signaling pathways activated.	Treatment of mice with pioglitazone upregulated bone marrow and circulating EPCs; pioglitazone prevented apoptosis of human and mouse EPCs in a PI3K-dependent manner in vitro.	• Proangiogenic activity	Not reported; indirect activation of PI3K-Akt not activated by pioglitazone
			• PI3K activated
			• Anti-apoptotic

[27]	To study the effect of PPAR $γ$ agonists on VEGF- and FGF-2-induced angiogenesis and EC migration.	Pioglitazone and rosiglitazone inhibited the proangiogenic effects of FGF-2 and VEGF in the chick chorioallantoic membrane model angiogenesis; pioglitazone and rosiglitazone inhibited VEGF- and FGF-2-induced EC migration.	• Antiangiogenic in vivo	not reported
			• Inhibited EC migration

[28]	To determine whether activation of PPARα and PPAR $γ$ stimulates angiogenesis.	PPAR $α$ agonist WY14643 and PPAR $γ$ agonist GW1929 induced EC tube formation in EC/interstitial cell cocultures by increasing VEGF production; WY14643 and GW1929 induced angiogenesis in murine corneal angiogenesis model and Akt activated in vitro.	• Proangiogenic activity	Direct for both PPAR $α$ and PPAR $γ$
			• Induced VEGF production
			• Prosurvival
[30]	To investigate the impact of diabetes on ischemia-induced collateral vessel growth, and tested the hypothesis that PPAR $γ$ agonists augment collateral flow to ischemic tissue.	Pioglitazone ameliorated endothelial dysfunction and enhanced blood flow recovery after tissue ischemia in diabetic mice; pioglitazone restored VEGF levels that were reduced by ischemic injury; Activation of eNOS essential for pioglitazone to promote angiogenesis in ischemic tissue.	• Proangiogenic activity	Not reported
			• Induced VEGF production

[202]	To determine effects of rosiglitazone on gastric cancer cell cycle, proliferation, migration, and invasion; endothelial capillary tube formation (an in vitro measure of angiogenesis).	Rosiglitazone inhibited gastric cancer cell growth, caused G1 cell cycle arrest and induced apoptosis in a dose-dependent and PPAR $γ$ -dependent manner; rosiglitazone inhibited gastric cancer cell migration, invasion, and expression of MMP-2 in a dose-dependent manner in a PPAR $γ$ -independent manner; rosiglitazone reduced VEGF-induced “angiogenesis” of HUVEC in a dose- and PPAR $γ$ -dependent manner.	• Antiangiogenic activity	Not reported
			• Antitumor cell proliferation activity
			• Anti-invasion
			• Proapoptotic

[32]	To determine the effects of PPAR $γ$ ligands on pancreatic cancer-associated angiogenesis, VEGF expression, and tumor growth in vitro and in vivo.	Rosiglitazone inhibited pancreatic carcinoma growth both in vitro and in vivo; rosiglitazone suppressed xenograft tumor angiogenesis by downregulating VEGF expression; 15d-PGJ₂, 9-cis-RA, and their combination inhibited VEGF mRNA expression in PANC-1 cells in a dose- and time-dependent manner; MVD was decreased in rosiglitazone-treated mice.	• Antiangiogenic activity	Not reported
			• Antitumor cell proliferation activity

[203]	To determine whether adipose tissue angiogenesis was stimulated by rosiglitazone using an assay to study angiogenic sprout formation ex vivo.	Obesity and TZD treatment in vivo induced angiogenic sprout formation from adipose tissue fragments, but not from aorta rings; rosiglitazone induced expression of VEGF-A, VEGF-B, and ANGPTL4; ANGPTL4 stimulated EC growth and capillary tube formation; ANGPTL4 alleviated the growth inhibitory actions of rosiglitazone on ECs in the presence or absence of VEGF likely causing a net expansion of the capillary network in adipose tissue in response to PPAR $γ$ activators.	• Proangiogenic activity in adipose tissue	Indirect likely via a PPAR $γ$ -stimulated adipocyte-specific factor ANGPLT4 capable of overcoming direct antiangiogenic effect of rosiglitazone on ECs
			• Induced VEGF production
			• Induced ANGPLT4 expression