PPAR-alpha is a therapeutic target for chronic lymphocytic leukemia

Spaner, David; Lee, E; Shi, Yonghong; Wen, Feng; Li, Y; Tung, Stephanie; McCaw, Lindsay; Wong, Karrie; Gary-Gouy, Hélène; Dalloul, Ali; Ceddia, Rolando B.; Gorzcynski, R

doi:10.1038/leu.2012.329

Cited by 70 publications

(85 citation statements)

References 35 publications

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“…PPARα was previously shown to mediate protection of CLL cells from harsh microenvironmental conditions, including the presence of cytotoxic agents (23,30). This result suggests that PPARα plays a role in CLL cell viability.…”

Section: Pparα Antagonist Is Cytotoxic To Cll Cells Even In the Presesupporting

confidence: 58%

“…Spaner et al (23) showed that PPARα expression was highly associated with advanced-stage disease. Thus, PPAR expression could be used to select the patient population that would benefit from treatment.…”

Section: Resultsmentioning

confidence: 99%

“…PPARα is overexpressed in CLL cells and helps to protect them from harsh microenvironmental conditions. MK886, a small molecule that is reported to have PPARα antagonist properties, exhibits anti-CLL activity in vitro and in vivo (23,30 (Figures 2, 3), but was less cytotoxic to B cells isolated from healthy volunteers ( Supplementary Figure S1). Because accessory cells can rescue CLL cells from spontaneous and drug-induced apoptosis (43)(44)(45), as well as protect CLL cells from fludarabineinduced apoptosis in vitro (31), it is essential to evaluate potential therapeutics in CLL accessory cell cocultures.…”

Section: Discussionmentioning

confidence: 99%

“…NXT962 has a similar chemical structure, but does not significantly inhibit PPARα in the luciferase reporter assay (IC 50 = 15 μmol/L). A recent study demonstrated that CLL cells show increased expression levels of PPARα relative to B cells from healthy donors (23). As a transcriptional regulator, PPARα controls the expression of a number of genes, including those involved in β-oxidation (27,28).…”

Section: Nxt629 Inhibits Transcription Of Pparα Target Genesmentioning

confidence: 99%

“…It was recently shown that compared with normal B cells, CLL cells overexpress PPARα, rendering them dependent on β-oxidation for energy (23). This metabolic strategy helps account for some of the pathogenic characteristics of CLL, including immunosuppression and drug resistance.…”

Section: Introductionmentioning

confidence: 99%

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A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo

Messmer

Lorrain

Stebbins

et al. 2015

Mol Med

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Tumor-specific metabolic changes can reveal new therapeutic targets. Our findings implicate a supporting role for fatty acid metabolism in chronic lymphocytic leukemia (CLL) cell survival. Peroxisome proliferator-activated receptor (PPAR)-α, a major transcriptional regulator of fatty acid oxidation, was recently shown to be upregulated in CLL. To evaluate PPARα as a potential therapeutic target, we developed a highly selective, potent small molecule antagonist of PPARα, NXT629. NXT629 inhibited agonistinduced transcription of PPARα-regulated genes, demonstrating target engagement in CLL cells. Furthermore, NXT629 induced apoptosis of CLL cells even in the presence of a protective microenvironment. To mimic the proliferative lymphoid compartment of CLL, we examined the activity of NXT629 on CLL cells that were stimulated to proliferate in vitro. NXT629 reduced the number of leukemia cells undergoing cell division. In addition, in two xenograft mouse models of CLL (one a model for nondividing and one for dividing CLL), NXT629 reduced the number of viable CLL cells in vivo. Overall, these results suggest that fatty acid metabolism promotes survival and proliferation of primary CLL cells and that inhibiting PPARα gene regulation could be a new therapeutic approach to treating CLL.

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Section: Pparα Antagonist Is Cytotoxic To Cll Cells Even In the Presesupporting

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Nxt629 Inhibits Transcription Of Pparα Target Genesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo

Messmer

Lorrain

Stebbins

et al. 2015

Mol Med

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m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia

Wu,

Zuo,

Zhang

et al. 2023

Advanced Science

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Chronic lymphocytic leukemia (CLL) is a hematological malignancy with high metabolic heterogeneity. N6‐methyladenosine (m6A) modification plays an important role in metabolism through regulating circular RNAs (circRNAs). However, the underlying mechanism is not yet fully understood in CLL. Herein, an m6A scoring system and an m6A‐related circRNA prognostic signature are established, and circTET2 as a potential prognostic biomarker for CLL is identified. The level of m6A modification is found to affect the transport of circTET2 out of the nucleus. By interacting with the RNA‐binding protein (RBP) heterogeneous nuclear ribonucleoprotein C (HNRNPC), circTET2 regulates the stability of CPT1A and participates in the lipid metabolism and proliferation of CLL cells through mTORC1 signaling pathway. The mTOR inhibitor dactolisib and FAO inhibitor perhexiline exert a synergistic effect on CLL cells. In addition, the biogenesis of circTET2 can be affected by the splicing process and the RBPs RBMX and YTHDC1. CP028, a splicing inhibitor, modulates the expression of circTET2 and shows pronounced inhibitory effects. In summary, circTET2 plays an important role in the modulation of lipid metabolism and cell proliferation in CLL. This study demonstrates the clinical value of circTET2 as a prognostic indicator as well as provides novel insights in targeting treatment for CLL.

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Blocking the Peroxisome Proliferator‐Activated Receptor (PPAR): An Overview

et al. 2013

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Peroxisome proliferator-activated receptors (PPARs) have been studied extensively over the last few decades and have been assessed as molecular targets for the development of drugs against metabolic disorders. A rapid increase in understanding of the physiology and pharmacology of these receptors has occurred, together with the identification of novel chemical structures that are able to activate the various PPAR subtypes. More recent evidence suggests that moderate activation of these receptors could be favorable in pathological situations due to a decrease in the side effects brought about by PPAR agonists. PPAR partial agonists and antagonists are interesting tools that are currently used to better elucidate the biological processes modulated by this family of nuclear receptors. Herein we present an overview of the various molecular structures that are able to block each of the PPAR subtypes, with a focus on promising therapeutic applications.

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PPAR-alpha is a therapeutic target for chronic lymphocytic leukemia

Cited by 70 publications

References 35 publications

A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo

A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo

m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia

Blocking the Peroxisome Proliferator‐Activated Receptor (PPAR): An Overview

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