The retinoid X receptor agonist, 9-cis UAB30, inhibits cutaneous T-cell lymphoma proliferation through the SKP2-p27kip1 axis

Chou, Chu-Fang; Hsieh, Yu‐Hsuan; Grubbs, Clinton J.; Atigadda, Venkatram R.; Mobley, James A.; Dummer, Reinhard; Muccio, Donald D.; Eto, Isao; Elmets, Craig A.; Garvey, W. Timothy; Chang, Ping‐Ying

doi:10.1016/j.jdermsci.2018.03.006

Cited by 17 publications

(17 citation statements)

References 56 publications

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“…Bexarotene is a third-generation retinoid X receptor (RXR)-selective retinoid that has been approved for use in the treatment of both early and advanced CTCL (7–9). Although bexarotene has been used for decades in the treatment of CTCL, and several preclinical studies have suggested anti-CTCL mechanisms are involved in the efficacy of this drug (10–12), little is known about the exact mechanisms underlying its anti-tumor effects in CTCL patients in vivo (7–9, 11, 12). Since bexarotene is useful for both early and advanced CTCL, bexarotene is applied in the real world to ultraviolet-tolerant early CTCL patients as a first-line therapy.…”

Section: Introductionmentioning

confidence: 99%

Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma

et al. 2019

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Bexarotene is a third-generation retinoid X receptor-selective retinoid that has been approved for use in the treatment of both early and advanced cutaneous T-cell lymphoma (CTCL). Although bexarotene has been used for decades in the treatment of CTCL, little is known about the mechanisms underlying its anti-tumor effects in CTCL patients. This study therefore focused on the immunomodulatory effects of bexarotene in vivo using an EL4 mouse T-cell lymphoma model, followed by investigation in CTCL patients treated with bexarotene. Intraperitoneal injection of bexarotene significantly decreased expressions of CCL22, CXCL5, CXCL10, and p19 in the tumor microenvironment. Based on those results, we then evaluated serum levels of CCL22, CXCL5, and CXCL10 in 25 patients with CTCL, revealing that CCL22 was significantly increased in advanced CTCL compared with early CTCL. Next, we evaluated serum levels of CCL22, CXCL5, and CXCL10 in CTCL patients treated with bexarotene. Serum levels of CCL22 were significantly decreased in 80% of CTCL patients who responded to bexarotene therapy. In addition, immunofluorescence staining revealed CD163+ M2 macrophages as the main source of CCL22. Moreover, bexarotene decreased the production of CCL22 by M2 macrophages generated from monocytes in vitro. Our findings suggest that the clinical benefits of bexarotene are partially attributable to suppressive effects on the production of CCL22 by M2-polarized tumor-associated macrophages.

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Section: Introductionmentioning

confidence: 99%

Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma

et al. 2019

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“…Retinoids, and particularly RA, have been shown to affect cell-cycle progression in a variety of cancer cell lines [ [40] , [41] , [42] , [43] ] including neuroblastoma [ [44] , [45] , [46] ]. UAB30 has also been shown to induce G0/G1 cell-cycle arrest in rhabdomyosarcoma [ 47 ], hepatoblastoma [ 48 ], and neuroblastoma [ 13 , 14 ] cell lines. In this study, we showed that treatment of COA3 with RA and both PDXs with UAB30 caused a dose-dependent block in the G1/S transition triggering a decreased S phase and an increased percentage of cells in the G1 phase, a critical stage for cell differentiation and maturation.…”

Section: Discussionmentioning

confidence: 99%

“…RA has numerous undesirable side effects, including hepatotoxicity, mucocutaneous disorders, and hypertriglyceridemia, that may limit the dosing amount and duration of treatment [ 10 , 11 ]. 9- cis -UAB30 (8-(3′,4′-dihydro-1′(2′H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, UAB30) is a novel retinoid X receptor (RXR) agonist that has demonstrated similar efficacy but a minimal toxicity profile when compared to RA [ 12 , 13 ]. Our laboratory has previously shown the effectiveness of UAB30 in long-term passage neuroblastoma cell lines in decreasing proliferation, viability, and motility in vitro , as well as tumor growth in vivo [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

9-cis-UAB30, a novel rexinoid agonist, decreases tumorigenicity and cancer cell stemness of human neuroblastoma patient-derived xenografts

Marayati

Bownes

Stafman

et al. 2021

Translational Oncology

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Retinoic acid (RA) therapy has been utilized as maintenance therapy for high-risk neuroblastoma, but over half of patients treated with RA relapse. Neuroblastoma stem cell-like cancer cells (SCLCCs) are a subpopulation of cells characterized by the expression of the cell surface marker CD133 and are hypothesized to contribute to drug resistance and disease relapse. A novel rexinoid compound, 9- cis -UAB30 (UAB30), was developed having the same anti-tumor effects as RA but a more favorable toxicity profile. In the current study, we investigated the efficacy of UAB30 in neuroblastoma patient-derived xenografts (PDX). Two PDXs, COA3 and COA6, were utilized and alterations in the malignant phenotype were assessed following treatment with RA or UAB30. UAB30 significantly decreased proliferation, viability, and motility of both PDXs. UAB30 induced cell-cycle arrest as demonstrated by the significant increase in percentage of cells in G1 (COA6: 33.7 ± 0.7 vs. 43.3 ± 0.7%, control vs. UAB30) and decrease in percentage of cells in S phase (COA6: 44.7 ± 1.2 vs. 38.6 ± 1%, control vs. UAB30). UAB30 led to differentiation of PDX cells, as evidenced by the increase in neurite outgrowth and mRNA abundance of differentiation markers. CD133 expression was decreased by 40% in COA6 cells after UAB30. The ability to form tumorspheres and mRNA abundance of known stemness markers were also significantly decreased following treatment with UAB30, further indicating decreased cancer cell stemness. These results provide evidence that UAB30 decreased tumorigenicity and cancer cell stemness in neuroblastoma PDXs, warranting further exploration as therapy for high-risk neuroblastoma.

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“…Bexarotene is the only U.S. Food and Drug Administration (FDA) approved agonist for RXR, and it is used clinically for the treatment of cutaneous T-cell lymphomas (CTCLs). 32 Bexarotene has been shown to be an effective chemopreventive agent preclinically and clinically, including those for lung cancer. 11,12,33 In our previous study, we found that aerosolized bexarotene with DMSO/ethanol as solvent significantly decreased lung tumorigenesis in a B(a)P-induced mouse lung adenoma model.…”

Section: Nano Lettersmentioning

confidence: 99%

Optimized Bexarotene Aerosol Formulation Inhibits Major Subtypes of Lung Cancer in Mice

et al. 2019

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Bexarotene has shown inhibition of lung and mammary gland tumorigenesis in preclinical models and in clinical trials. The main side effects of orally administered bexarotene are hypertriglyceridemia and hypercholesterolemia. We previously demonstrated that aerosolized bexarotene administered by nasal inhalation has potent chemopreventive activity in a lung adenoma preclinical model without causing hypertriglyceridemia. To facilitate its future clinical translation, we modified the formula of the aerosolized bexarotene with a clinically relevant solvent system. This optimized aerosolized bexarotene formulation was tested against lung squamous cell carcinoma mouse model and lung adenocarcinoma mouse model and showed significant chemopreventive effect. This new formula did not cause visible signs of toxicity and did not increase plasma triglycerides or cholesterol. This aerosolized bexarotene was evenly distributed to the mouse lung parenchyma, and it modulated the microenvironment in vivo by increasing the tumor-infiltrating T cell population. RNA sequencing of the lung cancer cell lines demonstrated that multiple pathways are altered by bexarotene. For the first time, these studies demonstrate a new, clinically relevant aerosolized bexarotene formulation that exhibits preventive efficacy against the major subtypes of lung cancer. This approach could be a major advancement in lung cancer prevention for high risk populations, including former and present smokers.

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The retinoid X receptor agonist, 9-cis UAB30, inhibits cutaneous T-cell lymphoma proliferation through the SKP2-p27kip1 axis

Cited by 17 publications

References 56 publications

Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma

Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma

9-cis-UAB30, a novel rexinoid agonist, decreases tumorigenicity and cancer cell stemness of human neuroblastoma patient-derived xenografts

Optimized Bexarotene Aerosol Formulation Inhibits Major Subtypes of Lung Cancer in Mice

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