A phase 1 study of tazarotene in adults with advanced cancer

Jones, Philip H.; Burnett, R D; Fainaru, I; Nadolny, Patrick; Walker, Patricia S.; Yu, Zhi‐Ling; Tang-Liu, Diane; Ganesan, Trivadi S.; Talbot, Denis; Harris, Adrian L.; Rustin, G. J. S.

doi:10.1038/sj.bjc.6601169

Cited by 10 publications

(6 citation statements)

References 18 publications

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“…1 E and F ). It is noteworthy that, whereas RA treatment lowered serum triglyceride levels in mice, it has been reported that administration of the agent to human patients leads to hypertriglyceridemia ( 43 – 46 ). The differential response may reflect species specificities.…”

Section: Discussionmentioning

confidence: 99%

“…The differential response may reflect species specificities. However, as biochemical abnormalities in human patients appear only at high RA doses ( 45 , 46 ), it is possible that hypertriglyceridemia may be avoided if RA is used at subtoxic doses. The efficacy of a low-dose RA treatment in overcoming obesity and insulin resistance in humans remains to be examined.…”

Section: Discussionmentioning

confidence: 99%

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Retinoic Acid Upregulates Preadipocyte Genes to Block Adipogenesis and Suppress Diet-Induced Obesity

et al. 2012

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Retinoic acid (RA) protects mice from diet-induced obesity. The activity is mediated in part through activation of the nuclear receptors RA receptors (RARs) and peroxisome proliferator–activated receptor β/δ and their associated binding proteins cellular RA binding protein type II (CRABP-II) and fatty acid binding protein type 5 in adipocytes and skeletal muscle, leading to enhanced lipid oxidation and energy dissipation. It was also reported that RA inhibits differentiation of cultured preadipocytes. However, whether the hormone suppresses adipogenesis in vivo and how the activity is propagated remained unknown. In this study, we show that RA inhibits adipocyte differentiation by activating the CRABP-II/RARγ path in preadipose cells, thereby upregulating the expression of the adipogenesis inhibitors Pref-1, Sox9, and Kruppel-like factor 2 (KLF2). In turn, KLF2 induces the expression of CRABP-II and RARγ, further potentiating inhibition of adipocyte differentiation by RA. The data also indicate that RA suppresses adipogenesis in vivo and that the activity significantly contributes to the ability of the hormone to counteract diet-induced obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Upregulates Preadipocyte Genes to Block Adipogenesis and Suppress Diet-Induced Obesity

et al. 2012

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“…As mentioned above, metabolic effects of retinoids are well described in a number of in vitro and in vivo models and have also been reported in humans [146]. Indeed, patients under retinoid therapy display increased transaminases, hypertriglyceridemia, and hyper LDL-cholesterolemia [147,148]. However, the impact on lipid metabolism is highly variable among patients and call for a stringent follow-up before after initiation of treatment.…”

Section: Pharmacological Alteration Of Metabolism By Retinoids and Prmentioning

confidence: 91%

Retinoids and nuclear retinoid receptors in white and brown adipose tissues: physiopathologic aspects

Flajollet

Staels²,

Lefèbvre³

2013

Hormone Molecular Biology and Clinical Investigation

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Vitamin A, ingested either as retinol or β-carotene from animal- or plant-derived foods respectively, is a nutrient essential for many biological functions such as embryonic development, vision, immune response, tissue remodeling, and metabolism. Its main active metabolite is all trans-retinoic acid (atRA), which regulates gene expression through the activation of α, β, and γ isotypes of the nuclear atRA receptor (RAR). More recently, retinol derivatives were also shown to control the RAR activity, enlightening the interplay between vitamin A metabolism and RAR-mediated transcriptional control. The white and brown adipose tissues regulate the energy homeostasis by providing dynamic fatty acid storing and oxidizing capacities to the organism, in connection with the other fatty acid-consuming tissues. This concerted interorgan response to fatty acid fluxes is orchestrated, in part, by the endocrine activity of the adipose tissue depots. The adipose tissues are also sites for synthesizing and storing vitamin A derivatives, which will act as hormonal cues or intracellularly to regulate essential aspects of adipocyte biology. As agents that prevent adipocyte differentiation hence, expected to decrease fat mass, and inducers of uncoupling protein expression, thus, favoring energy expenditure, retinoids have prompted many investigations to decipher their roles in adipose tissue pathophysiology, which are summarized in this review.

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“…15 Oral Tazarotene does not appear to be associated with adverse events that are typical of oral retinoids, including hypertriglyceridemia and hypercholesterolemia. 48 Thus, repurposing of Tazarotene could be explored for treatment of pathological conditions where circulatory insufficiency is a significant factor for instance in delayed wound healing. …”

Section: Discussionmentioning

confidence: 99%

The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing

et al. 2016

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Therapeutic angiogenesis is a major goal of regenerative medicine, but no clinically approved small molecule exists that enhances new blood vessel formation. Here we show, using a phenotype-driven high-content imaging screen of an annotated chemical library of 1,280 bioactive small molecules, that the retinoid agonist Tazarotene, enhances in vitro angiogenesis, promoting branching morphogenesis, and tubule remodeling. The proangiogenic phenotype is mediated by retinoic acid receptor but not retinoic X receptor activation, and is characterized by secretion of the proangiogenic factors hepatocyte growth factor, vascular endothelial growth factor, plasminogen activator, urokinase and placental growth factor, and reduced secretion of the antiangiogenic factor pentraxin-3 from adjacent fibroblasts. In vivo, Tazarotene enhanced the growth of mature and functional microvessels in Matrigel implants and wound healing models, and increased blood flow. Notably, in ear punch wound healing model, Tazarotene promoted tissue repair characterized by rapid ear punch closure with normal-appearing skin containing new hair follicles, and maturing collagen fibers. Our study suggests that Tazarotene, an FDA-approved small molecule, could be potentially exploited for therapeutic applications in neovascularization and wound healing.

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A phase 1 study of tazarotene in adults with advanced cancer

Cited by 10 publications

References 18 publications

Retinoic Acid Upregulates Preadipocyte Genes to Block Adipogenesis and Suppress Diet-Induced Obesity

Retinoic Acid Upregulates Preadipocyte Genes to Block Adipogenesis and Suppress Diet-Induced Obesity

Retinoids and nuclear retinoid receptors in white and brown adipose tissues: physiopathologic aspects

The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing

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