The microtubule-targeting agents (MTAs) are a very successful class of cancer drugs with therapeutic benefits in both hematopoietic and solid tumors.  However, resistance to these drugs is a significant problem.  Current MTAs bind to microtubules, and/or to their constituent tubulin heterodimers, and affect microtubule polymerization and dynamics.  The PPAR<span class="inline" id="M2"  /> inhibitor T0070907 can reduce tubulin levels in colorectal cancer cell lines and suppress tumor growth in a murine xenograft model.  T0070907 does not alter microtubule polymerization in vitro, and does not appear to work by triggering modulation of tubulin RNA levels subsequent to decreased polymerization.  This observation suggests the possible development of antimicrotubule drugs that work by a novel mechanism, and implies the presence of cancer therapeutic targets that have not yet been exploited.  This review summarizes what is known about PPAR<span class="inline" id="M3"  /> inhibitors and cancer cell death, with emphasis on the tubulin phenotype and PPAR-dependence, and identifies potential mechanisms of action.

Katherine L. Schaefer

PPAR<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z"/></g></svg> Inhibitors as Novel Tubulin-Targeting Agents

Peroxisome proliferator-activated receptor gamma (PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M1" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
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			</text>

		</g>
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</svg>) is a multifunctional transcription factor with important regulatory roles in inflammation, cellular growth, differentiation, and apoptosis. PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M2" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
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				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
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</svg> is expressed in a variety of immune cells as well as in numerous leukemias and lymphomas. Here, we review recent studies that provide new insights into the mechanisms by which PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M3" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
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		</g>
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</svg> ligands influence hematological malignant cell growth, differentiation, and survival. Understanding the diverse properties of PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M4" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
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				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
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		</g>
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</svg> ligands is crucial for the development of new therapeutic approaches for hematological malignancies.

Tatiana M. Garcia-Bates

Geniece M. Lehmann

Patricia J. Simpson-Haidaris

Steven H. Bernstein

Patricia J. Sime

Richard P. Phipps

Role of Peroxisome Proliferator-Activated Receptor Gamma and Its Ligands in the Treatment of Hematological Malignancies

Thiazolidinediones (TZDs) are selective agonists of the peroxisome proliferator-activated receptor (PPAR) gamma, a transcription factor belonging to the superfamily of nuclear hormone receptors. Although activation of PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M2" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> by TZDs has been best characterized by its ability to regulate expression of genes associated with lipid metabolism, PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M3" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> agonists have other physiological effects including modulating pro- and anti-inflammatory gene expression and inducing apoptosis in several cell types including glioma cells and cell lines. Immunotherapeutic approaches to reducing brain tumors are focused on means to reduce the immunosuppressive responses of tumors which dampen the ability of cytotoxic T-lymphocytes to kill tumors. Initial studies from our lab show that combination of an immunotherapeutic strategy with TZD treatment provides synergistic benefit in animals with implanted tumors. The potential of this combined approach for treatment of brain tumors is reviewed in this report.

Terry Lichtor

Alessandra Spagnolo

Roberta P. Glick

Douglas L. Feinstein

PPAR-<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5&#xA;t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z" /></g></svg> Thiazolidinedione Agonists and Immunotherapy in the Treatment of Brain Tumors

Peroxisome proliferator-activated receptors (PPARs) have lately attracted much attention as therapeutic targets. Previously, PPAR ligands were associated with the treatment of diabetes, hyperlipidemia and cardiovascular diseases, as they modulate the expression of genes regulating glucose and lipid metabolism. Recently, PPAR ligands have been also considered as potential anticancer agents, with relatively low systemic toxicity. The emerging evidence for antiproliferative, proapoptotic, antiinflammatory and potential antimetastatic properties of PPAR<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M2" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg> ligands prompted us to discuss possible roles of PPAR<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M3" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg> in tumor suppression. PPAR<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M4" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg> activation can target cancer cells energy balance by blocking fatty acid synthesis and by promoting fatty acid <svg     style="vertical-align:-3.56265pt;width:10px;" id="M5" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><path id="x1D6FD" d="M558 587q0 -32 -14 -61t-40 -53.5t-48.5 -41t-54.5 -36.5q144 -51 144 -174q0 -55 -43.5 -108t-104.5 -87q-77 -42 -131 -42q-31 0 -54 20t-31 47l11 18q48 -29 108 -29q79 0 119.5 43t40.5 109t-44.5 107.5t-119.5 50.5l22 47q34 1 65 21q96 61 96 157q0 42 -24 67.5&#xA;t-62 25.5q-24 0 -43.5 -9t-35 -29.5t-27 -44t-22.5 -63t-19.5 -75.5t-18.5 -91q-57 -294 -68 -380q-26 -190 -35 -200q-26 -31 -97 -37l-4 26q19 9 48 170l77 413q23 121 52.5 187.5t83.5 114.5q70 62 148 62q51 0 88.5 -34t37.5 -91z" /></g>

		
	
</svg>-oxidation. In the state of limited nutrient availability, frequently presents in the tumor microenvironment, PPAR<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M6" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg> cooperates with AMP-dependent protein kinase in: (i) repressing oncogenic Akt activity, (ii) inhibiting cell proliferation, and (iii) forcing glycolysis-dependent cancer cells into &#x201C;metabolic catastrophe.&#x201D; Other potential anticancer effects of PPAR<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M7" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g>

		
	
</svg> include suppression of inflammation, and upregulation of uncoupling proteins (UCPs), which attenuates mitochondrial reactive oxygen species production and cell proliferation. In conclusion, there are strong premises that the low-toxic and well-tolerated PPAR ligands should be considered as new therapeutic agents to fight disseminating cancer, which represents the major challenge for modern medicine and basic research.

Maja Grabacka

Krzysztof Reiss

Anticancer Properties of PPAR<svg style="vertical-align:-0.1638pt" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FC" d="M545 106q-67 -118 -134 -118q-24 0 -40 37.5t-30 129.5h-2q-47 -72 -103 -119.5t-108 -47.5q-47 0 -76 45.5t-29 119.5q0 113 85 204t174 91q47 0 70 -33.5t43 -119.5h3q32 47 80 140l55 13l10 -9q-47 -80 -138 -201q17 -99 27.5 -136t22.5 -37q23 0 69 61zM333 204&#xA;q-14 98 -31 149.5t-50 51.5q-49 0 -94 -70t-45 -164q0 -55 15.5 -86t40.5 -31q70 0 164 150z" /></g></svg>-Effects on Cellular Metabolism and Inflammation

Peroxisome proliferator-activated receptor-<svg     style="vertical-align:-3.56265pt;width:10px;" id="M3" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>/<svg     style="vertical-align:-0.1638pt;width:8.9125004px;" id="M4" height="12.4375" version="1.1" viewBox="0 0 8.9125004 12.4375" width="8.9125004"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FF"/></g>

		
	
</svg> (PPAR<svg     style="vertical-align:-3.56265pt;width:10px;" id="M5" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>/<svg     style="vertical-align:-0.1638pt;width:8.9125004px;" id="M6" height="12.4375" version="1.1" viewBox="0 0 8.9125004 12.4375" width="8.9125004"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FF"/></g>

		
	
</svg>) is a transcription factor that is activated by endogenous fatty acid ligands and by synthetic agonists. Its role in the regulation of skeletal muscle fatty acid catabolism, glucose homeostasis, and cellular differentiation has been established in multiple studies. On the contrary, a role for PPAR<svg     style="vertical-align:-3.56265pt;width:10px;" id="M7" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>/<svg     style="vertical-align:-0.1638pt;width:8.9125004px;" id="M8" height="12.4375" version="1.1" viewBox="0 0 8.9125004 12.4375" width="8.9125004"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FF"/></g>

		
	
</svg> in tumorigenesis is less clear because there are contradictory reports in the literature. However, the majority of these studies have not examined the role of PPAR<svg     style="vertical-align:-3.56265pt;width:10px;" id="M9" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>/<svg     style="vertical-align:-0.1638pt;width:8.9125004px;" id="M10" height="12.4375" version="1.1" viewBox="0 0 8.9125004 12.4375" width="8.9125004"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FF"/></g>

		
	
</svg> in the tumor stroma. Recent evidence suggests that stromal PPAR<svg     style="vertical-align:-3.56265pt;width:10px;" id="M11" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>/<svg     style="vertical-align:-0.1638pt;width:8.9125004px;" id="M12" height="12.4375" version="1.1" viewBox="0 0 8.9125004 12.4375" width="8.9125004"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FF"/></g>

		
	
</svg> regulates tumor endothelial cell proliferation and promotes differentiation leading to the properly orchestrated events required for tumor blood vessel formation. This review briefly summarizes the significance of these studies that may provide clues to help explain the reported discrepancies in the literature regarding the role of PPAR<svg     style="vertical-align:-3.56265pt;width:10px;" id="M13" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>/<svg     style="vertical-align:-0.1638pt;width:8.9125004px;" id="M14" height="12.4375" version="1.1" viewBox="0 0 8.9125004 12.4375" width="8.9125004"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FF"/></g>

		
	
</svg> in tumorigenesis.

Rolf Müller

Martin Kömhoff

Jeffrey M. Peters

Sabine Müller-Brüsselbach

A Role for PPAR<svg style="vertical-align:-3.56265pt" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,12.162)"><path id="x1D6FD" d="M558 587q0 -32 -14 -61t-40 -53.5t-48.5 -41t-54.5 -36.5q144 -51 144 -174q0 -55 -43.5 -108t-104.5 -87q-77 -42 -131 -42q-31 0 -54 20t-31 47l11 18q48 -29 108 -29q79 0 119.5 43t40.5 109t-44.5 107.5t-119.5 50.5l22 47q34 1 65 21q96 61 96 157q0 42 -24 67.5t-62 25.5q-24 0 -43.5 -9t-35 -29.5t-27 -44t-22.5 -63t-19.5 -75.5t-18.5 -91q-57 -294 -68 -380q-26 -190 -35 -200q-26 -31 -97 -37l-4 26q19 9 48 170l77 413q23 121 52.5 187.5t83.5 114.5q70 62 148 62q51 0 88.5 -34t37.5 -91z"/></g></svg>/<svg style="vertical-align:-0.1638pt" height="12.4375" version="1.1" viewBox="0 0 8.9125004 12.4375" width="8.9125004" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,12.162)"><path id="x1D6FF" d="M494 514l-10 -15q-56 76 -106.5 117t-110.5 41q-45 0 -45 -30q0 -28 109 -152q59 -68 86 -118.5t27 -107.5q0 -62 -29.5 -119.5t-86.5 -96.5q-64 -45 -138 -45q-76 0 -121.5 53t-45.5 136q0 74 40.5 135t98.5 95q43 26 87 42q-40 59 -57.5 92t-17.5 62q0 46 39 77.5t90 31.5q54 0 97.5 -35.5t65 -78.5t28.5 -84zM359 234q0 84 -90 191q-47 -17 -74 -47q-81 -89 -81 -200q0 -71 32.5 -109.5t72.5 -38.5q47 0 80 33t46.5 77.5t13.5 93.5z"/></g></svg> in Tumor Stroma and Tumorigenesis

Peroxisome proliferators-activated receptors (PPARs) that are members of the nuclear receptor superfamily have three different isoforms: PPAR<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M1" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FC" d="M545 106q-67 -118 -134 -118q-24 0 -40 37.5t-30 129.5h-2q-47 -72 -103 -119.5t-108 -47.5q-47 0 -76 45.5t-29 119.5q0 113 85 204t174 91q47 0 70 -33.5t43 -119.5h3q32 47 80 140l55 13l10 -9q-47 -80 -138 -201q17 -99 27.5 -136t22.5 -37q23 0 69 61zM333 204&#xA;q-14 98 -31 149.5t-50 51.5q-49 0 -94 -70t-45 -164q0 -55 15.5 -86t40.5 -31q70 0 164 150z" /></g>

		
	
</svg>, PPAR<svg     style="vertical-align:-0.1638pt;width:8.9125004px;" id="M2" height="12.4375" version="1.1" viewBox="0 0 8.9125004 12.4375" width="8.9125004"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><path id="x1D6FF" d="M494 514l-10 -15q-56 76 -106.5 117t-110.5 41q-45 0 -45 -30q0 -28 109 -152q59 -68 86 -118.5t27 -107.5q0 -62 -29.5 -119.5t-86.5 -96.5q-64 -45 -138 -45q-76 0 -121.5 53t-45.5 136q0 74 40.5 135t98.5 95q43 26 87 42q-40 59 -57.5 92t-17.5 62q0 46 39 77.5&#xA;t90 31.5q54 0 97.5 -35.5t65 -78.5t28.5 -84zM359 234q0 84 -90 191q-47 -17 -74 -47q-81 -89 -81 -200q0 -71 32.5 -109.5t72.5 -38.5q47 0 80 33t46.5 77.5t13.5 93.5z" /></g>

		
	
</svg>, and PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M3" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5&#xA;t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z" /></g>

		
	
</svg>. PPARs are ligand-activated transcription factors, and they are implicated in tumor progression, differentiation, and apoptosis. Activation of PPAR isoforms lead to both anticarcinogenesis and anti-inflammatory effect. It has so far identified many PPAR ligands including chemical composition and natural occurring. PPAR ligands are reported to activate PPAR signaling and exert cancer prevention and treatment in vitro and/or in vivo studies. Although the effects depend on the isoforms and the types of ligands, biological modulatory activities of PPARs in carcinogenesis and disease progression are attracted for control or combat cancer development. This short review summarizes currently available data on the role of PPAR ligands in carcinogenesis.

Yumiko Yasui

Mihye Kim

Takuji Tanaka

PPAR Ligands for Cancer Chemoprevention

The past 30 years have only seen slight improvement in melanoma therapy. Despite a wide variety of therapeutic options, current survival for patients with metastatic disease is only 6&#x2013;8 months. Part of the reason for this treatment failure is the broad chemoresistance of melanoma, which is due to an altered survival capacity and an inactivation of apoptotic pathways. Several targetable pathways, responsible for this survival/apoptosis resistance in melanoma, have been described and current research has focused on mechanism inactivating these pathways. As PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M2" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5&#xA;t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z" /></g>

		
	
</svg> was shown to be constitutively active in several tumour entities and PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M3" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg> agonists extent strong anticancer effects, the role of PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M4" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg> as a possible target for specific anticancer strategy was investigated in numerous studies. However, only a few studies have focused on the effects of PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M5" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg> agonists in melanoma, showing conflicting results. The use of PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M6" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg> agonists in melanoma therapy has to be 
carefully weighted against considerable, 
undesirable side effects, as their mode of action is not fully 
understood and even pro-proliferative effects have 
been described. In the current review, we discuss the role of 
PPARs, in particular PPAR<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M7" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg> in melanoma and their potential role as a molecular target for melanoma therapy.

Christian Freudlsperger

Udo Schumacher

Siegmar Reinert

J&#xfc;rgen Hoffmann

The Critical Role of PPAR<svg style="vertical-align:-2.7573pt" height="11.4125" version="1.1" viewBox="0 0 8.4499998 11.4125" width="8.4499998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.912)"><path id="x1D738" d="M377 450h126l-264 -401q0 -75 -21 -153q-12 -44 -36 -71t-56 -27q-27 0 -42 18.5t-15 42.5q0 34 30 89q9 16 32 50q21 31 29 46q13 91 13 208q0 45 -11 94q-11 47 -34 47q-38 0 -61 -81h-23q40 150 121 150q46 0 65 -34.5t19 -99.5q0 -54 -7 -125z"/></g></svg> in Human Malignant Melanoma

Peroxisome proliferator-activated receptor-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M2" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
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				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> (PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M3" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg>) has currently been considered as molecular target for the treatment of human metabolic disorders. Experimental data from in vitro cultures, animal models, and clinical trials have shown that PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M4" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> ligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Tumor angiogenesis constitutes a multifaceted process implicated in complex downstream signaling pathways that triggers tumor growth, invasion, and metastasis. In this aspect, accumulating in vitro and in vivo studies have provided extensive evidence that PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M5" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> ligands can function as modulators of the angiogenic signaling cascade. In the current review, the crucial role of PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M6" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> ligands and the underlying mechanisms participating in tumor angiogenesis are summarized. Targeting PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M7" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> may prove to be a potential therapeutic strategy in combined treatments with conventional chemotherapy; however, special attention should be taken as there is also substantial evidence to support that PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M8" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg> ligands can enhance angiogenic phenotype in tumoral cells.

Costas Giaginis

Anna Tsantili-Kakoulidou

Stamatios Theocharis

Peroxisome Proliferator-Activated Receptor-<svg style="vertical-align:-2.7573pt" height="11.4125" version="1.1" viewBox="0 0 8.4499998 11.4125" width="8.4499998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.912)"><path id="x1D738" d="M377 450h126l-264 -401q0 -75 -21 -153q-12 -44 -36 -71t-56 -27q-27 0 -42 18.5t-15 42.5q0 34 30 89q9 16 32 50q21 31 29 46q13 91 13 208q0 45 -11 94q-11 47 -34 47q-38 0 -61 -81h-23q40 150 121 150q46 0 65 -34.5t19 -99.5q0 -54 -7 -125z" /></g></svg> Ligands: Potential Pharmacological Agents for Targeting the Angiogenesis Signaling Cascade in Cancer

About this journal

<p><em>PPAR Research</em> publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.</p>


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<p>Chief Editor, Dr Xiao-Jie Lu, is dedicated to basic and translational research on liver diseases. His research at Nanjing Medical University, China, focuses&nbsp;on exploring these diseases' underlying mechanisms that may be translatable to novel diagnostic biomarkers or therapeutic targets.</p>


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PPAR Research publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.

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PPAR Research | Hindawi

PPAR Research

<p>This Issue is now open for submissions.</p>
<p>Papers are published upon acceptance, regardless of the Special Issue publication date.</p>


PPAR Research

PPARs: A Double-Edged Sword in Cancer Therapy?

PPARs: A Double-Edged Sword in Cancer Therapy?

Articles

PPAR Inhibitors as Novel Tubulin-Targeting Agents

Role of Peroxisome Proliferator-Activated Receptor Gamma and Its Ligands in the Treatment of Hematological Malignancies

PPAR- Thiazolidinedione Agonists and Immunotherapy in the Treatment of Brain Tumors

Anticancer Properties of PPAR-Effects on Cellular Metabolism and Inflammation

A Role for PPAR/ in Tumor Stroma and Tumorigenesis

PPAR Ligands for Cancer Chemoprevention

The Critical Role of PPAR in Human Malignant Melanoma

Peroxisome Proliferator-Activated Receptor- Ligands: Potential Pharmacological Agents for Targeting the Angiogenesis Signaling Cascade in Cancer