Complete clinical remission of tumor-stage mycosis fungoides after acute extensive skin necroses, granulomatous reaction, and fever under treatment with bexarotene, vorinostat, and high-dose fenofibrate

Steinhoff, Matthias; Beyer, Marc; Roewert-Huber, Joachim; Lukowsky, Ansgar; Assaf, Chalid; Sterry, Wolfram

doi:10.1016/j.jaad.2007.07.012

Cited by 21 publications

(17 citation statements)

References 12 publications

(11 reference statements)

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“…In CTCL patients, retinoid X receptor (RXR)-selective retinoids (rexinoids) have proven effective for the treatment of refractory disease (31). Recently, the first CTCL patient treated with a combination of HDACI and a rexinoid has been reported, and this patient showed massive tumor necrosis of lymphoma lesions and no new lesions after discontinuation of treatment (32). The mechanism of the remarkable antitumor action of rexinoid and HDACI therapy in this patient has not been clarified.…”

Section: Discussionmentioning

confidence: 94%

A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors

Epping

Wang

Plumb

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the pathways that are targeted by cancer drugs is instrumental for their rational use in a clinical setting. Inhibitors of histone deacetylases (HDACI) selectively inhibit proliferation of malignant cells and are used for the treatment of cancer, but their cancer selectivity is understood poorly. We conducted a functional genetic screen to address the mechanism(s) of action of HDACI. We report here that ectopic expression of two genes that act on retinoic acid (RA) signaling can cause resistance to growth arrest and apoptosis induced by HDACI of different chemical classes: the retinoic acid receptor ␣ (RAR␣) and preferentially expressed antigen of melanoma (PRAME), a repressor of RA signaling. Treatment of cells with HDACI induced RA signaling, which was inhibited by RAR␣ or PRAME expression. Conversely, RAR-deficient cells and PRAME-knockdown cells show enhanced sensitivity to HDACI in vitro and in mouse xenograft models. Finally, a combination of RA and HDACI acted synergistically to activate RA signaling and inhibit tumor growth. These experiments identify the RA pathway as a rate-limiting target of HDACI and suggest strategies to enhance the therapeutic efficacy of HDACI.biomarker ͉ chromatin modification ͉ drug resistance ͉ epigenetics ͉ nuclear hormone receptor E pigenetic DNA and histone modifications are appreciated as major determinants in the control of gene activity, and they are extensively deregulated in cancer. Histone acetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs), which catalyze the addition and removal of acetyl groups to histones, respectively, and to a growing list of nonhistone substrates (1). The activities of HATs and HDACs are altered in several human cancers, and modulation of these classes of enzymes provides a potentially attractive therapeutic modality (2, 3). Several classes of HDAC inhibitors (HDACI) have been identified that block enzyme activity, resulting in global histone hyperacetylation. A wide array of literature on HDACI exists, describing their various effects, including G 1 and G 2 /M cell cycle arrests, apoptosis, and differentiation, and several HDACI have entered clinical trials (2-4). Gene expression profiling studies revealed that HDACI treatment induces alterations in transcription of Ͻ5% to Ϸ20% of expressed genes (5, 6) and have not elucidated a consistent picture of the pathway(s) or target(s) that are modulated by HDACI and, consequently, have not provided a comprehensive explanation for their anticancer effects.To identify cellular targets of HDACI action in transformed cells, we used the approach of large-scale functional genetic screening. In this screen we asked which genes or pathways could confer cellular resistance to HDACI. The present work provides evidence that the retinoic acid receptor (RAR) pathway is targeted by HDACI and that the cytotoxic effects of HDACI in solid tumor cells are, at least in part, through derepression of retinoic acid (RA) signaling. ResultsGe...

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Section: Discussionmentioning

confidence: 94%

A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors

Epping

Wang

Plumb

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…The half-life of fenofibrate has been reported to be 20 h in individuals with normal renal functions, and the level of fenofibrate required to achieve IC 50 for MCL is within the therapeutic range that is used to treat hyperlipidemia. [43][44][45][46] In light of the excellent safety, tolerability and affordability of fenofibrate, there is merit in investigating the possibility of extending the clinical use of fenofibrate, either as a sole agent or in combination with conventional chemotherapy, in the treatment of MCL.…”

Section: Minomentioning

confidence: 99%

Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFα/NF-κB signaling axis

2010

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Mantle cell lymphoma (MCL) is a type of aggressive B-cell non-Hodgkin's lymphoma characterized by frequent resistance to conventional chemotherapy. In this study we provided evidence that fenofibrate, which is widely known as an agonist for peroxisome proliferator-activated receptor-a (PPARa), can induce effective apoptosis in treating MCL cells. Addition of fenofibrate to MCL cell lines significantly decreased the number of viable cells by 50% at approximately 20 lM at 72 h. This decrease in cell growth was due to apoptosis, as evidenced by the cleavage of caspase 3 and poly(ADP-ribose) polymerase. The fenofibrate-mediated effects were not significantly affected by GW6471, a specific PPARa antagonist. Using an apoptosis pathway-specific oligonucleotide array, we found that fenofibrate significantly downregulated several pro-survival genes, including tumor necrosis factor-a (TNFa). Importantly, addition of recombinant TNF-a conferred partial protection against fenofibrate-induced apoptosis. Fenofibrate also decreased the nuclear translocation of nuclear factor (NF)-jB-p65 and significantly inhibited the DNA binding of NF-jB in a dose-dependent manner. To conclude, fenofibrate shows efficacy against MCL, and the mechanism can be attributed to its inhibitory effects on the TNF-a/NF-jB signaling axis. In view of the documented safety of fenofibrate in humans, it may provide a valuable therapeutic option for MCL patients.

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“…The CYP2C epoxygenases metabolize AA to 5,8,11,and 14,, and these metabolites have been characterized as pro-angiogenic lipids in vitro (20 -22) and in vivo (23). The demonstration that the anti-tumorigenic effects of PPAR␣ ligand activation were associated with reductions in the endothelial expression of the murine Cyp2c44 epoxygenase and in the levels of plasma and endothelial EETs (6), suggested pro-angiogenic and pro-tumorigenic roles for this epoxygenase, and pointed to this enzyme as a target of the anti-tumorigenic effects resulting from PPAR␣ activation (6).…”

mentioning

confidence: 99%

The Anti-tumorigenic Properties of Peroxisomal Proliferator-activated Receptor α Are Arachidonic Acid Epoxygenase-mediated

Pozzi

Popescu

Yang

et al. 2010

Journal of Biological Chemistry

104

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Despite advances in diagnosis and treatment, cancer continues to pose major clinical challenges and is the focus of efforts to develop therapies that combine effectiveness with low toxicity. Among these, angiogenesis is a current target of attempts aimed to reduce tumor vascularization and growth (1, 2), because it holds a promise for more effective and better tolerated approaches for cancer treatment. The peroxisomal proliferator-activated nuclear receptors (PPARs), 2 i.e. PPAR␣, PPAR␥, and PPAR␦, control the transcription of genes mostly involved in the regulation of lipid metabolism and energy homeostasis. Although several roles for the PPAR␦ and -␥ isotypes in the pathophysiology of cancer have been proposed (3-5), recent animal studies have identified PPAR␣ ligands as effective inhibitors of tumor angiogenesis and growth (6 -8).The potential significance of these findings has been emphasized by epidemiological data (9 -12), and by studies in human cancer cell lines (13-16), suggesting that PPAR␣ ligands such as Fenofibrate and Bezafibrate may have beneficial effects in the prognosis of human cancer. A unique feature of these PPAR␣ ligands is that, through their long history of clinical use as hypolipidemic drugs, they have been shown to be well tolerated and to have limited side effects and/or toxicity, indicating that they could serve as targets for the development of novel, safer, and with low toxicity anti-cancer treatments.The PPAR␣-mediated transcriptional regulation of members of the CYP2C gene subfamily of cytochrome P450s is well established (17, 18), as is the role of these enzymes in the metabolism and bio-activation of arachidonic acid (AA) (19). The CYP2C epoxygenases metabolize AA to 5,8,11,and 14,, and these metabolites have been characterized as pro-angiogenic lipids in vitro (20 -22) and in vivo (23). The demonstration that the anti-tumorigenic effects of PPAR␣ ligand activation were associated with reductions in the endothelial expression of the murine Cyp2c44 epoxygenase and in the levels of plasma and endothelial EETs (6), suggested pro-angiogenic and pro-tumorigenic roles for this epoxygenase, and pointed to this enzyme as a target of the anti-tumorigenic effects resulting from PPAR␣ activation (6). The murine Cyp2c44 epoxygenase generates 11,12-and 14,15-EET as its major products (24), is expressed in endothelial cells (6), and is under PPAR␣ transcriptional control (6). Similarly, human CYP2C8 and CYP2C9, catalytic homologues of murine Cyp2c44 (25), have been identified as endothelial epoxygenases (21,22), and their participation in

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Complete clinical remission of tumor-stage mycosis fungoides after acute extensive skin necroses, granulomatous reaction, and fever under treatment with bexarotene, vorinostat, and high-dose fenofibrate

Cited by 21 publications

References 12 publications

A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors

A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors

Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFα/NF-κB signaling axis

The Anti-tumorigenic Properties of Peroxisomal Proliferator-activated Receptor α Are Arachidonic Acid Epoxygenase-mediated

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