Conformationally Defined Retinoic Acid Analogues. 5. Large-Scale Synthesis and Mammary Cancer Chemopreventive Activity for (2E,4E,6Z,8E)-8- (3‘,4‘-Dihydro-1‘(2‘H)-naphthalen-1‘-ylidene)-3,7-dimethyl-2,4,6-octatrienoic Acid (9cUAB30)

Atigadda, Venkatram R.; Vines, Kimberly K.; Grubbs, Clinton J.; Hill, Donald L.; Beenken, Samuel L.; Bland, Kirby I.; Brouillette, Wayne J.; Muccio, Donald D.

doi:10.1021/jm030095q

Cited by 37 publications

(49 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mouse monoclonal anti-RXR and anti-nestin was obtained from Abcam (clones MOK13–17 and 10C, respectively, Cambridge, MA). UAB30 was synthesized as described [10]. 13- cis -retinoic acid (13- cis -RA) was from Sigma (R3255, Sigma-Aldrich, St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma

Waters

Stewart

Atigadda

et al. 2015

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Neuroblastoma remains a common cause of pediatric cancer deaths, especially for children who present with advanced stage or recurrent disease. Currently, retinoic acid therapy is used as maintenance treatment to induce differentiation and reduce tumor recurrence following induction therapy for neuroblastoma, but unavoidable side effects are seen. A novel retinoid, UAB30, has been shown to generate negligible toxicities. In the current study, we hypothesized that UAB30 would have a significant impact on multiple neuroblastoma cell lines in vitro and in vivo. Cellular survival, cell cycle analysis, migration, and invasion were studied using alamarBlue® assays, FACS, and Transwell® assays, respectively, in multiple cell lines following treatment with UAB30. In addition, an in vivo murine model of human neuroblastoma was utilized to study the effects of UAB30 upon tumor xenograft growth and animal survival. We successfully demonstrated decreased cellular survival, invasion and migration, cell cycle arrest and increased apoptosis after treatment with UAB30. Furthermore, inhibition of tumor growth and increased survival was observed in a murine neuroblastoma xenograft model. The results of these in vitro and in vivo studies suggest a potential therapeutic role for the low toxicity synthetic retinoid X receptor selective agonist, UAB30, in neuroblastoma treatment.

show abstract

Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma

Waters

Stewart

Atigadda

et al. 2015

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…In brief, agonists were administered in Teklad mash diet (4%) to female Sprague-Dawley rats obtained from Harlan Sprague-Dawley, Inc. (Madison, WI). The dietary supplements [TRG (150 ppm in diet), 4-Me-UAB30 (200 ppm in diet), and UAB30 (200 ppm in diet)] were obtained from Eisai, Inc. (TRG) or was synthesized at the University of Alabama at Birmingham (4-Me-UAB30, UAB30) (Atigadda et al, 2003). In brief, rats were obtained at 28 days of age and housed in polycarbonate cages (five per cage) in a room lighted 12 hours per day and maintained at 22°C 6 2°C.…”

Section: Methodsmentioning

confidence: 99%

“…However, the elevation of triglycerides levels by 9-cis-RA, TRG, and various retinoids has been known for many years and is a major concern in the use of these agents, particularly in a cancer-prevention setting (Grubbs et al, 2006;Kolesar et al, 2010). We previously designed selective RXR agonists based on 9-cis-RA that are effective agents with lower toxicity and with varying ability to inhibit mammary cancer formation (Muccio et al, 1998;Atigadda et al, 2003;.Grubbs et al, 2006). One of these analogs (UAB30) did not increase serum triglycerides in rodents (Grubbs et al, 2006) and humans (Kolesar et al, 2010) but was nevertheless effective in preventing mammary cancers in rats.…”

Section: Introductionmentioning

confidence: 99%

Effects on Gene Expression in Rat Liver after Administration of RXR Agonists: UAB30, 4-Methyl-UAB30, and Targretin (Bexarotene)

Vedell

Lü

Grubbs

et al. 2013

Molecular Pharmacology

Self Cite

View full text Add to dashboard Cite

Examination of three retinoid X receptor (RXR) agonists [Targretin (TRG), UAB30, and 4-methyl-UAB30 (4-Me-UAB30)] showed that all inhibited mammary cancer in rodents and two (TRG and 4-Me-UAB30) strikingly increased serum triglyceride levels. Agents were administered in diets to female Sprague-Dawley rats. Liver RNA was isolated and microarrayed on the Affymetrix GeneChip Rat Exon 1.0 ST array. Statistical tests identified genes that exhibited differential expression and fell into groups, or modules, with differential expression among agonists. Genes in specific modules were changed by one, two, or all three agonists. An interactome analysis assessed the effects on genes that heterodimerize with known nuclear receptors. For proliferator-activated receptor a/RXR-activated genes, the strongest response was TRG . 4-Me-UAB30 . UAB30. Many liver X receptor/RXRrelated genes (e.g., Scd-1 and Srebf1, which are associated with increased triglycerides) were highly expressed in TRG and 4-Me-UAB30-but not UAB30-treated livers. Minimal expression changes were associated with retinoic acid receptor or vitamin D receptor heterodimers by any of the agonists. UAB30 unexpectedly and uniquely activated genes associated with the aryl hydrocarbon hydroxylase (Ah) receptor (Cyp1a1, Cyp1a2, Cyp1b1, and Nqo1). Based on the Ah receptor activation, UAB30 was tested for its ability to prevent dimethylbenzanthracene (DMBA)-induced mammary cancers, presumably by inhibiting DMBA activation, and was highly effective. Gene expression changes were determined by reverse transcriptasepolymerase chain reaction in rat livers treated with Targretin for 2.3, 7, and 21 days. These showed similar gene expression changes at all three time points, arguing some steady-state effect. Different patterns of gene expression among the agonists provided insight into molecular differences and allowed one to predict certain physiologic consequences of agonist treatment.

show abstract

“…Mouse monoclonal anti-RXR was from Abcam (clone MOK13-17, Cambridge, MA), rabbit anti-Src from Santa Cruz Biotechnology (Santa Cruz, CA), and anti-phospho FAK (Y397) from Invitrogen (Invitrogen Life Technologies, Carlsbad, CA). 9- cis -UAB30 (UAB30) was synthesized as described [18]. …”

Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies

Waters

Stewart

Atigadda

et al. 2016

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Rare tumors of solid organs remain some of the most difficult pediatric cancers to cure. These difficult tumors include rare pediatric renal malignancies such as malignant rhabdoid kidney tumors (MRKT) and non-osseous renal Ewing sarcoma, and hepatoblastoma, a pediatric liver tumor that arises from immature liver cells. There are data in adult renal and hepatic malignancies demonstrating the efficacy of retinoid therapy. The investigation of retinoic acid therapy in cancer is not a new strategy, but the widespread adoption of this therapy has been hindered by toxicities. Our laboratory has been investigating a novel synthetic rexinoid, UAB30, which exhibits a more favorable side effect profile. In this current study, we hypothesized that UAB30 would diminish the growth of tumor cells from both rare renal and liver tumors in vitro and in vivo. We successfully demonstrated decreased cellular proliferation, invasion and migration, cell cycle arrest and increased apoptosis after treatment with UAB30. Additionally, in in vivo murine models of human hepatoblastoma or rare human renal tumors, there were significantly decreased tumor xenograft growth and increased animal survival after UAB30 treatment. UAB30 should further be investigated as a developing therapeutic in these rare and difficult to treat, pediatric solid organ tumors.

show abstract

Conformationally Defined Retinoic Acid Analogues. 5. Large-Scale Synthesis and Mammary Cancer Chemopreventive Activity for (2E,4E,6Z,8E)-8- (3‘,4‘-Dihydro-1‘(2‘H)-naphthalen-1‘-ylidene)-3,7-dimethyl-2,4,6-octatrienoic Acid (9cUAB30)

Cited by 37 publications

References 13 publications

Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma

Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma

Effects on Gene Expression in Rat Liver after Administration of RXR Agonists: UAB30, 4-Methyl-UAB30, and Targretin (Bexarotene)

Preclinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies

Contact Info

Product

Resources

About