- •9-cis UA30 (UAB30) induces apoptosis and suppresses proliferation in CTCL cells.
- •Inhibition of G1 cell-cycle checkpoint by UAB30 involves the SKP2-p27kip1 axis.
- •UAB30, a RXR-selective agonist, may also have RXR-independent function.
- •UAB30 can be as effective as bexarotene in treating CTCL.
- •This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Bexarotene (Targretin®) is currently the only FDA approved retinoid X receptor (RXR) –selective agonist for the treatment of cutaneous T-cell lymphomas (CTCLs). The main side effects of bexarotene are hypothyroidism and elevation of serum triglycerides (TGs). The novel RXR ligand, 9-cis UAB30 (UAB30) does not elevate serum TGs or induce hypothyroidism in normal subjects.
To assess preclinical efficacy and mechanism of action of UAB30 in the treatment of CTCLs and compare its action with bexarotene.
With patient-derived CTCL cell lines, we evaluated UAB30 function in regulating growth, apoptosis, cell cycle check points, and cell cycle-related markers.
Compared to bexarotene, UAB30 had lower half maximal inhibitory concentration (IC50) values and was more effective in inhibiting the G1 cell cycle checkpoint. Both rexinoids increased the stability of the cell cycle inhibitor, p27kip1 protein, in part, through targeting components involved in the ubiquitination–proteasome system: 1) decreasing SKP2, a F-box protein that binds and targets p27kip1 for degradation by 26S proteasome and 2) suppressing 20S proteasome activity (cell line-dependent) through downregulation of PSMA7, a component of the 20S proteolytic complex in 26S proteasome.
UAB30 and bexarotene induce both early cell apoptosis and suppress cell proliferation. Inhibition of the G1 to S cell cycle transition by rexinoids is mediated, in part, through downregulation of SKP2 and/or 20S proteasome activity, leading to increased p27kip1 protein stability. Because UAB30 has minimal effect in elevating serum TGs and inducing hypothyroidism, it is potentially a better alternative to bexarotene for the treatment of CTCLs.
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- Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722
- Mycosis fungoides and Sezary syndrome.Lancet. 2008; 371: 945-957
- Incidence of cutaneous T-cell lymphoma in the United States, 1973–2002.Arch. Dermatol. 2007; 143: 854-859
- Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases.Blood. 2009; 113: 5064-5073
- Worldwide Study, Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results.J. Clin. Oncol. 2001; 19: 2456-2471
- Bexarotene ligand pharmaceuticals.Curr. Opin. Investig. Drugs. 2000; 1: 514-523
- Central hypothyroidism associated with retinoid X receptor-selective ligands.N. Engl. J. Med. 1999; 340: 1075-1079
- Plasma triglyceride as a risk factor for cardiovascular disease.Can. J. Cardiol. 1998; 14: 14B-17B
- Triglycerides and risk for coronary heart disease.JAMA. 2007; 298: 336-338
- Conformationally defined retinoic acid analogues. 4. Potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias.J. Med. Chem. 1998; 41: 1679-1687
- Efficacy of new retinoids in the prevention of mammary cancers and correlations with short-term biomarkers.Carcinogenesis. 2006; 27: 1232-1239
- Assessment of oral toxicity and safety of 9-cis-UAB30, a potential chemopreventive agent, in rat and dog studies.Drug Chem. Toxicol. 2011; 34: 300-310
- A pilot, first-in-human, pharmacokinetic study of 9cUAB30 in healthy volunteers.Cancer Prev. Res. (Phila). 2010; 3: 1565-1570
- Effects on gene expression in rat liver after administration of RXR agonists: UAB30, 4-Methyl-UAB30, and targretin (Bexarotene).Mol. Pharmacol. 2013; 83: 698-708
- Global molecular changes in rat livers treated with RXR agonists: a comparison using transcriptomics and proteomics.Pharmacol. Res. Perspect. 2014; 2: 1-16
- 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).J. Med. Chem. 2003; 46: 3766-3769
- 9cUAB30, an RXR specific retinoid, and/or tamoxifen in the prevention of methylnitrosourea-induced mammary cancers.Cancer Lett. 2003; 201: 17-24
- The low-toxicity 9-cis UAB30 novel retinoid down-regulates the DNA methyltransferases and has anti-telomerase activity in human breast cancer cells.Int. J. Oncol. 2007; 30: 641-650
- Preclinical evaluation of a novel RXR agonist for the treatment of neuroblastoma.Mol. Cancer Ther. 2015; 14: 1559-1569
- Preclinical evaluation of UAB30 in pediatric renal and hepatic malignancies.Mol. Cancer Ther. 2016; 15: 911-921
- Establishment of two continuous T-cell strains from a single plaque of a patient with mycosis fungoides.In Vitro Cell. Dev. Biol. 1992; 28A: 161-167
- Detection of mycoplasma infection of cell cultures by DNA fluorochrome staining.in: Tully J.G. Razin E. Methods in Mycoplasmology. Academic Press, New York1983: 155-208
- Current Protocols in Cytometry.J. Wiley & Sons, NY1997
- Osteopontin mediates tumorigenic transformation of a preneoplastic murine cell line by suppressing anoikis: an Arg-Gly-Asp-dependent-focal adhesion kinase-caspase-8 axis.Mol. Carcinog. 2015; 54: 379-392
- Osteopontin facilitates ultraviolet B-induced squamous cell carcinoma development.J. Dermatol. Sci. 2014; 75: 121-132
- Loss of p27 expression through RAS-->BRAF--> MAP kinase-dependent pathway in human thyroid carcinomas.Cell Cycle. 2007; 6: 2817-2825
- High Skp2 expression characterizes high-risk neuroblastomas independent of MYCN status.Clin. Cancer Res. 2007; 13: 4695-4703
- Suppression of colonic polyposis by homeoprotein CDX2 through its nontranscriptional function that stabilizes p27Kip1.Cancer Res. 2011; 71: 593-602
- Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer.Breast Cancer Res. 2004; 6: 13-21
- Cyclin E-CDK2 is a regulator of p27Kip1.Genes Dev. 1997; 11: 1464-1478
- p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells.Nat. Cell Biol. 1999; 1: 207-214
- SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27.Nat. Cell Biol. 1999; 1: 193-199
- COP1 enhances ubiquitin-mediated degradation of p27Kip1 to promote cancer cell growth.Oncotarget. 2015; 6: 19721-19734
- SUMOylation regulates p27Kip1 stability and localization in response to TGFbeta.J. Mol. Cell Biol. 2016; 8: 17-30
- p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27.Curr. Biol. 1999; 9: 661-664
- Deregulated degradation of the cdk inhibitor p27 and malignant transformation.Semin. Cancer Biol. 2003; 13: 41-47
- p27 Destruction: cks1 pulls the trigger.Nat. Cell Biol. 2001; 3: E95-E98
- Recent advances in the structural biology of the 26 s proteasome.Int. J. Biochem. Cellbiol. 2016; 79: 437-442
- Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer.Nat. Rev. Cancer. 2008; 8: 438-449
- A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice.Cell. 1996; 85: 733-744
- Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control.Cell. 1995; 82: 675-684
- Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication.EMBO J. 2000; 19: 2069-2081
- Role of the F-box protein Skp2 in lymphomagenesis.Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 2515-2520
- Retinoic acid downregulates Rae1 leading to APC(Cdh1) activation and neuroblastoma SH-SY5Y differentiation.Oncogene. 2008; 27: 3339-3344
- Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins.Oncogene. 2005; 24: 2483-2494
- Retinoic acid decreases targeting of p27 for degradation via an N-myc-dependent decrease in p27 phosphorylation and an N-myc-independent decrease in Skp2.Cell Death Differ. 2003; 10: 230-239
- Retinoic acid-mediated growth arrest requires ubiquitylation and degradation of the F-box protein Skp2.J. Biol. Chem. 2001; 276: 45945-45951
- All-trans retinoic acid inhibits mesangial cell proliferation by up-regulating p21Waf1/Cip1 and p27Kip1 and down-regulating Skp2.J. Nephrol. 2012; 25: 1031-1040
- Vasoactive intestinal peptide decreases MYCN expression and synergizes with retinoic acid in a human MYCN-amplified neuroblastoma cell line.Int. J. Oncol. 2008; 33: 1081-1089
- Retinoic acid induces p27Kip1 nuclear accumulation by modulating its phosphorylation.Cancer Res. 2006; 66: 4240-4248
- Upstream molecular signaling pathways of p27(Kip1) expression: effects of 4-hydroxytamoxifen, dexamethasone, and retinoic acids.Cancer Cell Int. 2010; 10: 3
- Retinoids inhibit proliferation of human coronary smooth muscle cells by modulating cell cycle regulators.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 746-751
- Suppression of human pancreatic cancer cell proliferation by AGN194204, an RXR-selective retinoid.Carcinogenesis. 2004; 25: 1377-1385
- Mammalian proteasome subtypes: their diversity in structure and function.Arch. Biochem. Biophys. 2016; 591: 132-140
- Prevention of KLF4-mediated tumor initiation and malignant transformation by UAB30 rexinoid.Cancer. Biol. Ther. 2009; 8: 289-298
- The novel retinoid, 9cUAB30, inhibits telomerase and induces apoptosis in HL60Cells.Transl. Oncol. 2008; 1: 148-152
- The impact of novel retinoids in combination with platinum chemotherapy on ovarian cancer stem cells.Gynecol. Oncol. 2012; 125: 226-230
- Src is a novel potential off-target of RXR agonists, 9-cis-UAB30 and Targretin, in human breast cancer cells.Mol. Carcinog. 2015; 54: 1596-1604
Published online: March 15, 2018
Accepted: March 8, 2018
Received in revised form: February 15, 2018
Received: July 18, 2017
© 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.