413
Views
1
CrossRef citations to date
0
Altmetric
Review

Emerging roles of bexarotene in the prevention, treatment and anti-drug resistance of cancers

, , , , , & show all
Pages 487-499 | Received 15 Dec 2017, Accepted 05 Mar 2018, Published online: 20 Mar 2018

  • Shulman AI, Larson C, Mangelsdorf DJ, et al. Structural determinants of allosteric ligand activation in RXR heterodimers. Cell. 2004 Feb 06;116(3):417–429. PubMed PMID: 15016376.
  • Brtko J, Dvorak Z. Triorganotin compounds–ligands for “rexinoid” inducible transcription factors: biological effects. Toxicol Lett. 2015 Apr 02;234(1):50–58. PubMed PMID: 25683035. DOI:10.1016/j.toxlet.2015.02.009
  • Wagner CE, Jurutka PW, Marshall PA, et al. Retinoid X receptor selective agonists and their synthetic methods. Curr Top Med Chem. 2017;17(6):742–767. PubMed PMID: 27320333.
  • Ruhl R, Krzyzosiak A, Niewiadomska-Cimicka A, et al. 9-cis-13,14-dihydroretinoic acid is an endogenous retinoid acting as RXR ligand in mice. PLoS Genet. 2015 Jun;11(6):e1005213. PubMed PMID: 26030625; PubMed Central PMCID: PMC4451509. DOI:10.1371/journal.pgen.1005213
  • de Lera AR, Krezel W, Ruhl R. An endogenous mammalian retinoid X receptor ligand, at last! Chem Med Chem. 2016 May 19;11(10):1027–1037. PubMed PMID: 27151148. DOI:10.1002/cmdc.201600105
  • Yamada S, Kakuta H. Retinoid X receptor ligands: a patent review (2007-2013). Expert Opin Ther Pat. 2014 Apr;24(4):443–452. PubMed PMID: 24456080. DOI:10.1517/13543776.2014.880692
  • Kotani H, Tanabe H, Mizukami H, et al. Identification of a naturally occurring rexinoid, honokiol, that activates the retinoid X receptor. J Nat Prod. 2010 Aug 27;73(8):1332–1336. PubMed PMID: 20695472. DOI:10.1021/np100120c
  • Vedell PT, Lu Y, Grubbs CJ, et al. Effects on gene expression in rat liver after administration of RXR agonists: UAB30, 4-methyl-UAB30, and Targretin (Bexarotene). Mol Pharmacol. 2013 Mar;83(3):698–708. PubMed PMID: 23292798; PubMed Central PMCID: PMC3583492. DOI:10.1124/mol.112.082404
  • Duvic M, Hymes K, Heald P, et al. 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 May 01;19(9):2456–2471. PubMed PMID: 11331325. DOI:10.1200/JCO.2001.19.9.2456
  • Prince HM, McCormack C, Ryan G, et al. Bexarotene capsules and gel for previously treated patients with cutaneous T-cell lymphoma: results of the Australian patients treated on phase II trials. Australas J Dermatol. 2001 May;42(2):91–97. PubMed PMID: 11309029.
  • Duvic M, Kim YH, Zinzani PL, et al. Results from a phase I/II open-label, dose-finding study of pralatrexate and oral bexarotene in patients with relapsed/refractory cutaneous T-cell lymphoma. Clin Cancer Res. 2017 Feb 06;23:3552–3556. PubMed PMID: 28167509. DOI:10.1158/1078-0432.CCR-16-2064
  • Talpur R, Thompson A, Gangar P, et al. Pralatrexate alone or in combination with bexarotene: long-term tolerability in relapsed/refractory mycosis fungoides. Clin Lymphoma Myeloma Leuk. 2014 Aug;14(4):297–304. PubMed PMID: 24589156. DOI:10.1016/j.clml.2014.01.010
  • Dummer R, Beyer M, Hymes K, et al. Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition. Leuk Lymphoma. 2012 Aug;53(8):1501–1508. PubMed PMID: 22239668. DOI:10.3109/10428194.2012.656625
  • Illidge T, Chan C, Counsell N, et al. Phase II study of gemcitabine and bexarotene (GEMBEX) in the treatment of cutaneous T-cell lymphoma. Br J Cancer. 2013 Nov 12;109(10):2566–2573. PubMed PMID: 24136145; PubMed Central PMCID: PMC3833210. DOI:10.1038/bjc.2013.616
  • Straus DJ, Duvic M, Horwitz SM, et al. Final results of phase II trial of doxorubicin HCl liposome injection followed by bexarotene in advanced cutaneous T-cell lymphoma. Ann Oncol. 2014 Jan;25(1):206–210. PubMed PMID: 24285015. DOI:10.1093/annonc/mdt480
  • Sepmeyer JA, Greer JP, Koyama T, et al. Open-label pilot study of combination therapy with rosiglitazone and bexarotene in the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol. 2007 Apr;56(4):584–587. PubMed PMID: 17184879. DOI:10.1016/j.jaad.2006.10.033
  • Whittaker S, Ortiz P, Dummer R, et al. Efficacy and safety of bexarotene combined with psoralen-ultraviolet A (PUVA) compared with PUVA treatment alone in stage IB-IIA mycosis fungoides: final results from the EORTC Cutaneous Lymphoma Task Force phase III randomized clinical trial (NCT00056056). Br J Dermatol. 2012 Sep;167(3):678–687. PubMed PMID: 22924950. DOI:10.1111/j.1365-2133.2012.11156.x
  • Straus DJ, Duvic M, Kuzel T, et al. Results of a phase II trial of oral bexarotene (Targretin) combined with interferon alfa-2b (Intron-A) for patients with cutaneous T-cell lymphoma. Cancer. 2007 May 01;109(9):1799–1803. PubMed PMID: 17366595. DOI:10.1002/cncr.22596
  • Demierre MF, Ferzli P, Miller D. Measuring HRQOL in patients with cutaneous T-cell lymphoma undergoing therapy with oral bexarotene and extracorporeal photopheresis. Arch Dermatol. 2007 May;143(5):659–661. PubMed PMID: 17515522. DOI:10.1001/archderm.143.5.659
  • Blumenschein GR Jr., Khuri FR, von Pawel J, et al. Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT II. J Clin Oncol. 2008 Apr 10;26(11):1879–1885. PubMed PMID: 18398153. DOI:10.1200/JCO.2007.12.2689
  • Tyagi P, Belani CP, Jain VK. Bexarotene in combination with chemotherapy fails to prolong survival in patients with advanced non–small- cell lung cancer: results from the SPIRIT I and II trials. Clin Lung Cancer. 2005;7(1):17–19.
  • Luo W, Schork NJ, Marschke KB, et al. Identification of polymorphisms associated with hypertriglyceridemia and prolonged survival induced by bexarotene in treating non-small cell lung cancer. Anticancer Res. 2011 Jun;31(6):2303–2311. PubMed PMID: 21737656.
  • Ramlau R, Zatloukal P, Jassem J, et al. Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. J Clin Oncol. 2008 Apr 10;26(11):1886–1892. PubMed PMID: 18398154. DOI:10.1200/JCO.2007.12.2614
  • Dragnev KH, Ma T, Cyrus J, et al. Bexarotene plus erlotinib suppress lung carcinogenesis independent of KRAS mutations in two clinical trials and transgenic models. Cancer Prev Res. 2011 Jun;4(6):818–828. PubMed PMID: 21636548; PubMed Central PMCID: PMC3108499. DOI:10.1158/1940-6207.CAPR-10-0376
  • Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011 Jun;1(1):44–53. PubMed PMID: 22586319; PubMed Central PMCID: PMC4211116. DOI:10.1158/2159-8274.CD-10-0010
  • Tam AL, Kim ES, Lee JJ, et al. Feasibility of image-guided transthoracic core-needle biopsy in the BATTLE lung trial. J Thorac Oncol. 2013 Apr;8(4):436–442. PubMed PMID: 23442309; PubMed Central PMCID: PMC3879952. DOI:10.1097/JTO.0b013e318287c91e
  • Padda SK, Chhatwani L, Zhou L, et al. Phase I and pharmacokinetic study of bexarotene in combination with gefitinib in the third-line treatment of non-small-cell lung cancer: brief report. Anticancer Drugs. 2013 Aug;24(7):731–735. PubMed PMID: 23552470. DOI:10.1097/CAD.0b013e32836100d7
  • Dragnev KH, Petty WJ, Shah S, et al. Bexarotene and erlotinib for aerodigestive tract cancer. J Clin Oncol. 2005 Dec 1;23(34):8757–8764. PubMed PMID: 16314636. DOI:10.1200/JCO.2005.01.9521
  • Welch JS, Niu H, Uy GL, et al. A phase I dose escalation study of oral bexarotene in combination with intravenous decitabine in patients with AML. Am J Hematol. 2014 Aug;89(8):E103–E108. PubMed PMID: 24723466; PubMed Central PMCID: PMC4108244. DOI:10.1002/ajh.23735
  • Tsai DE, Luger SM, Andreadis C, et al. A phase I study of bexarotene, a retinoic X receptor agonist, in non-M3 acute myeloid leukemia. Clin Cancer Res. 2008 Sep 01;14(17):5619–5625. PubMed PMID: 18765556. DOI:10.1158/1078-0432.CCR-07-5185
  • Esteva FJ, Glaspy J, Baidas S, et al. Multicenter phase II study of oral bexarotene for patients with metastatic breast cancer. J Clin Oncol. 2003 Mar 15;21(6):999–1006. PubMed PMID: 12637463. DOI:10.1200/JCO.2003.05.068
  • Klopper J, Kane M, Jimeno A, et al. A phase II trial of bexarotene for advanced differentiated thyroid cancer. Thyroid. 2015 May;25(5):563–564. PubMed PMID: 25778496; PubMed Central PMCID: PMC4426316. DOI:10.1089/thy.2014.0399
  • Cummings JL, Zhong K, Kinney JW, et al. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease. Alzheimers Res Ther. 2016 Jan 29;8:4. PubMed PMID: 26822146; PubMed Central PMCID: PMC4731943. DOI:10.1186/s13195-016-0173-2
  • Lerner V, Miodownik C, Gibel A, et al. The retinoid X receptor agonist bexarotene relieves positive symptoms of schizophrenia: a 6-week, randomized, double-blind, placebo-controlled multicenter trial. J Clin Psych. 2013 Dec;74(12):1224–1232. PubMed PMID: 24434091. DOI:10.4088/JCP.12m08160
  • Lerner V, Miodownik C, Gibel A, et al. Bexarotene as add-on to antipsychotic treatment in schizophrenia patients: a pilot open-label trial. Clin Neuropharmacol. 2008 Jan-Feb;31(1):25–33. PubMed PMID: 18303488. DOI:10.1097/WNF.0b013e31806450da
  • Talpur R, Vu J, Bassett R, et al. Phase I/II randomized bilateral half-head comparison of topical bexarotene 1% gel for alopecia areata. J Am Acad Dermatol. 2009 Oct;61(4):592 e1–e9. PubMed PMID: 19682769. DOI:10.1016/j.jaad.2009.02.037
  • Magliocco MA, Pandya K, Dombrovskiy V, et al. A randomized, double-blind, vehicle-controlled, bilateral comparison trial of bexarotene gel 1% versus vehicle gel in combination with narrowband UVB phototherapy for moderate to severe psoriasis vulgaris. J Am Acad Dermatol. 2006 Jan;54(1):115–118. PubMed PMID: 16384765. DOI:10.1016/j.jaad.2005.09.012
  • Breneman D, Sheth P, Berger V, et al. Phase II clinical trial of bexarotene gel 1% in psoriasis. J Drugs Dermatol. 2007 May;6(5):501–506. PubMed PMID: 17679184.
  • Available from: https://www.clinicaltrialsregister.eu/ctr-search/search
  • Trautinger F, Eder J, Assaf C, et al. European organisation for research and treatment of cancer consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome - update 2017. Eur J Cancer. 2017 Mar 30;77:57–74. PubMed PMID: 28365528. DOI:10.1016/j.ejca.2017.02.027
  • Duvic M, Hymes K, Heald P, et al. 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 May;19(9):2456–2471. PubMed PMID: WOS:000168484000012.
  • Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of oral bexarotene (targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol. 2001 May;137(5):581–593. PubMed PMID: WOS:000168812400005.
  • Breneman D, Duvic M, Kuzel T, et al. Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol. 2002 Mar;138(3):325–332. PubMed PMID: WOS:000174367300005. DOI:10.1001/archderm.138.3.325
  • Heald P, Mehlmauer M, Martin AG, et al. Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial. J Am Acad Dermatol. 2003 Nov;49(5):801–815. PubMed PMID: WOS:000186238000002. DOI:10.1067/s0190-96922(3)01475-0
  • Tsirigotis P, Pappa V, Papageorgiou S, et al. Extracorporeal photopheresis in combination with bexarotene in the treatment of mycosis fungoides and Sezary syndrome. Br J Dermatol. 2007 Jun;156(6):1379–1381. PubMed PMID: 17459033. DOI:10.1111/j.1365-2133.2007.07901.x
  • Zhang CL, Hazarika P, Ni X, et al. Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. Clin Cancer Res. 2002 May;8(5):1234–1240. PubMed PMID: WOS:000175547700040.
  • Budgin JB, Richardson SK, Newton SB, et al. Biological effects of bexarotene in cutaneous T-cell lymphoma. Arch Dermatol. 2005 Mar;141(3):315–321. PubMed PMID: WOS:000227502300004. DOI:10.1001/archderm.141.3.315
  • Nieto-Rementería N, Pérez-Yarza G, Boyano MD, et al. Bexarotene activates the p53/p73 pathway in human cutaneous T-cell lymphoma. Br J Dermatol. 2009;160(3):519–526.
  • Ferenczi K, Fuhlbrigge RC, Pinkus JL, et al. Increased CCR4 expression in cutaneous T cell lymphoma. J Invest Dermatol. 2002 Dec;119(6):1405–1410. PubMed PMID: WOS:000179803200029. DOI:10.1046/j.1523-1747.2002.19610.x
  • Richardson SK, Newton SB, Bach TL, et al. Bexarotene blunts malignant T-cell chemotaxis in sezary syndrome: reduction of chemokine receptor 4-positive lymphocytes and decreased chemotaxis to thymus and activation-regulated chemokine. Am J Hematol. 2007 Sep;82(9):792–797. PubMed PMID: WOS:000249293300005. DOI:10.1002/ajh.20952
  • Ballanger F, Nguyen JM, Khammari A, et al. Evolution of clinical and molecular responses to bexarotene treatment in cutaneous T-cell lymphoma. Dermatology. 2010;220(4):370–375. PubMed PMID: 20484880. DOI:10.1159/000305354
  • Ranki A, Vakeva L, Sipila L, et al. Molecular markers associated with clinical response to bexarotene therapy in Cutaneous T-cell Lymphoma. Acta Derm Venereol. 2011;91(5):568–573. PubMed PMID: WOS:000294887800014. DOI:10.2340/00015555-1114
  • Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 Mar 1;136(5):E359–E386. PubMed PMID: 25220842. DOI:10.1002/ijc.29210
  • Wang Y, Wen W, Yi Y, et al. Preventive effects of bexarotene and budesonide in a genetically engineered mouse model of small cell lung cancer. Cancer Prev Res. 2009 Dec;2(12):1059–1064. PubMed PMID: 19934342. DOI:10.1158/1940-6207.CAPR-09-0221
  • Casto BC, Pereira MA. Prevention of mouse lung tumors by combinations of chemopreventive agents using concurrent and sequential administration. Anticancer Res. 2011 Oct;31(10):3279–3284. PubMed PMID: 21965737.
  • Pereira MA, Kramer PM, Nines R, et al. Prevention of mouse lung tumors by targretin. Int J Cancer. 2006 May 1;118(9):2359–2362. PubMed PMID: 16331605. DOI:10.1002/ijc.21618
  • Wang Y, Zhang Z, Yao R, et al. Prevention of lung cancer progression by bexarotene in mouse models. Oncogene. 2006 Mar 2;25(9):1320–1329. PubMed PMID: 16247446. DOI:10.1038/sj.onc.1209180
  • Fu J, Ding Y, Huang D, et al. The retinoid X receptor-selective ligand, LGD1069, inhibits tumor-induced angiogenesis via suppression of VEGF in human non-small cell lung cancer. Cancer Lett. 2007 Apr 8;248(1):153–163. PubMed PMID: 17027148. DOI:10.1016/j.canlet.2006.06.012
  • Dragnev KH, Petty WJ, Shah SJ, et al. A proof-of-principle clinical trial of bexarotene in patients with non-small cell lung cancer. Clin Cancer Res. 2007 Mar 15;13(6):1794–1800. PubMed PMID: 17363535. DOI:10.1158/1078-0432.CCR-06-1836
  • Feng Q, Sekula D, Guo Y, et al. UBE1L causes lung cancer growth suppression by targeting cyclin D1. Mol Cancer Ther. 2008 Dec;7(12):3780–3788. PubMed PMID: 19074853; PubMed Central PMCID: PMC2638083. DOI:10.1158/1535-7163.MCT-08-0753
  • Govindan R, Crowley J, Schwartzberg L, et al. Phase II trial of bexarotene capsules in patients with advanced non-small-cell lung cancer after failure of two or more previous therapies. J Clin Oncol. 2006 Oct 20;24(30):4848–4854. PubMed PMID: 17050870. DOI:10.1200/JCO.2006.07.7404
  • Hermann TW, Yen WC, Tooker P, et al. The retinoid X receptor agonist bexarotene (Targretin) synergistically enhances the growth inhibitory activity of cytotoxic drugs in non-small cell lung cancer cells. Lung Cancer. 2005 Oct;50(1):9–18. PubMed PMID: 15993980. DOI:10.1016/j.lungcan.2005.05.008
  • Tooker P, Yen WC, Ng SC, et al. Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. Cancer Res. 2007 May 1;67(9):4425–4433. PubMed PMID: 17483357. DOI:10.1158/0008-5472.CAN-06-4495
  • Yen WC, Corpuz MR, Prudente RY, et al. A selective retinoid X receptor agonist bexarotene (Targretin) prevents and overcomes acquired paclitaxel (Taxol) resistance in human non-small cell lung cancer. Clin Cancer Res. 2004 Dec 15;10(24):8656–8664. PubMed PMID: 15623650. DOI:10.1158/1078-0432.CCR-04-0979
  • Khuri FR, Rigas JR, Figlin RA, et al. Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2001 May 15;19(10):2626–2637. PubMed PMID: 11352954. DOI:10.1200/jco.2001.19.10.2626
  • Available from: http://www.cancer.net/cancer-types/lung-cancer-non-small-cell/treatment-options
  • Li J, Zhao M, He P, et al. Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007 Jun 15;13(12):3731–3737. PubMed PMID: 17575239. DOI:10.1158/1078-0432.CCR-07-0088
  • Kizaki M, Dawson M, Heyman R, et al. Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro. Blood. 1996;87(5):1977–1984.
  • DiNardo CD, Ky B, Vogl DT, et al. Differentiation syndrome in non-M3 acute myeloid leukemia treated with the retinoid X receptor agonist bexarotene [journal article]. Med Oncol. 2008;25(3):299–302.
  • Sanchez PV, Glantz ST, Scotland S, et al. Induced differentiation of acute myeloid leukemia cells by activation of retinoid X and liver X receptors. Leukemia. 2014 Apr;28(4):749–760. PubMed PMID: WOS:000334350900005. DOI:10.1038/leu.2013.202
  • Norsworthy KJ, Cho E, Arora J, et al. Differentiation therapy in poor risk myeloid malignancies: results of companion phase II studies. Leuk Res. 2016 Oct;49:90–97. PubMed PMID: 27619199. DOI:10.1016/j.leukres.2016.09.003
  • Ying SX, Seal S, Abbassi N, et al. Differential effects of bexarotene on intrinsic and extrinsic pathways in TRAIL-induced apoptosis in two myeloid leukemia cell lines. Leuk Lymphoma. 2007;48(5):1003–1014. PubMed PMID: WOS:000246719800023. DOI:10.1080/10428190701242358
  • Bischoff ED, Heyman RA, Lamph WW. Effect of the retinoid X receptor-selective ligand LGD1069 on mammary carcinoma after tamoxifen failure [reports]. J Natl Cancer I. 1999;91(24):2118–2123.
  • Yen W, Prudente R, Lamph WW. Synergistic effect of a retinoid X receptor-selective ligand bexarotene(LGD1069, Targretin) and paclitaxel (Taxol) in mammary carcinoma. Breast Cancer Res Tr. 2004;88:141–148.
  • Yen W, Lamph WW. The selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced breast carcinoma. Mol Cancer Ther. 2005;4(5):824–834.
  • Seo HS, Woo JK, Shin YC, et al. Identification of biomarkers regulated by rexinoids (LGD1069, LG100268 and Ro25-7386) in human breast cells using Affymetrix microarray. Mol Med Rep. 2015 Jul;12(1):800–818. PubMed PMID: 25778982; PubMed Central PMCID: PMC4438952. DOI:10.3892/mmr.2015.3480
  • Kim MS, Lim DY, Kim JE, et al. Src is a novel potential off-target of RXR agonists, 9-cis-UAB30 and Targretin, in human breast cancer cells. Mol Carcinog. 2015 Dec;54(12):1596–1604. PubMed PMID: 25328014; PubMed Central PMCID: PMC4402118. DOI:10.1002/mc.22232
  • Gottardis MM, Bischoff ED, Shirley MA, et al. Chemoprevention of mammary carcinoma by LGD1069 (Targretin): an RXR-selective ligand. Cancer Res. 1996 Dec 15;56(24):5566–5570. PubMed PMID: 8971154.
  • Wu K, Zhang Y, Xu XC, et al. The retinoid X receptor-selective retinoid, LGD1069, prevents the development of estrogen receptor-negative mammary tumors in transgenic mice. Cancer Res. 2002 Nov 15;62(22):6376–6380. PubMed PMID: 12438218.
  • Wu K, Kim HT, Rodriquez JL, et al. Suppression of mammary tumorigenesis in transgenic mice by the RXR-selective retinoid, LGD1069. Cancer Epidemiol Biomarkers Prev. 2002 May;11(5):467–474. PubMed PMID: 12010861.
  • Kong G, Kim H, Wu K, et al. The retinoid X receptor-selective retinoid, LGD1069, down-regulates cyclooxygenase-2 expression in human breast cells through transcription factor crosstalk: implications for molecular-based chemoprevention. Cancer Res. 2005;65(8):3462–3469.
  • Li Y, Shen Q, Kim HT, et al. The rexinoid bexarotene represses cyclin D1 transcription by inducing the DEC2 transcriptional repressor. Breast Cancer Res Treat. 2011 Aug;128(3):667–677. PubMed PMID: 20821348; PubMed Central PMCID: PMC3444826. DOI:10.1007/s10549-010-1083-9
  • Uray IP, Shen Q, Seo HS, et al. Rexinoid-induced expression of IGFBP-6 requires RARbeta-dependent permissive cooperation of retinoid receptors and AP-1. J Biol Chem. 2009 Jan 2;284(1):345–353. PubMed PMID: 18957410; PubMed Central PMCID: PMC2610495. DOI:10.1074/jbc.M804721200
  • Bach LA. Recent insights into the actions of IGFBP-6. J Cell Commun Signal. 2015 Jun;9(2):189–200. PubMed PMID: 25808083; PubMed Central PMCID: PMC4458248. DOI:10.1007/s12079-015-0288-4
  • Brown PH, Subbaramaiah K, Salmon AP, et al. Combination chemoprevention of HER2/neu-induced breast cancer using a cyclooxygenase-2 inhibitor and a retinoid X receptor-selective retinoid. Cancer Prev Res. 2008 Aug;1(3):208–214. PubMed PMID: 19138958; PubMed Central PMCID: PMC2612594. DOI:10.1158/1940-6207.CAPR-08-0021
  • Disis ML, Gad E, Herendeen DR, et al. A multiantigen vaccine targeting neu, IGFBP-2, and IGF-IR prevents tumor progression in mice with preinvasive breast disease. Cancer Prev Res. 2013 Dec;6(12):1273–1282. PubMed PMID: 24154719; PubMed Central PMCID: PMC3864759. DOI:10.1158/1940-6207.CAPR-13-0182
  • Marzbani E, Inatsuka C, Lu H, et al. The invisible arm of immunity in common cancer chemoprevention agents. Cancer Prev Res. 2013 Aug;6(8):764–773. PubMed PMID: 23918793; PubMed Central PMCID: PMC3773490. DOI:10.1158/1940-6207.CAPR-13-0036
  • Haugen BR, Larson LL, Pugazhenthi U, et al. Retinoic acid and retinoid X receptors are differentially expressed in thyroid cancer and thyroid carcinoma cell lines and predict response to treatment with retinoids. J Clin Endocrinol Metab. 2004 Jan;89(1):272–280. PubMed PMID: 14715861. DOI:10.1210/jc.2003-030770
  • Klopper JP, Berenz A, Hays WR, et al. In vivo and microarray analysis of rexinoid-responsive anaplastic thyroid carcinoma. Clin Cancer Res. 2008 Jan 15;14(2):589–596. PubMed PMID: 18223235. DOI:10.1158/1078-0432.CCR-07-0269
  • Cras A, Politis B, Balitrand N, et al. Bexarotene via CBP/p300 induces suppression of NF-kappaB-dependent cell growth and invasion in thyroid cancer. Clin Cancer Res. 2012 Jan 15;18(2):442–453. PubMed PMID: 22142826. DOI:10.1158/1078-0432.CCR-11-0510
  • Liu YY, Stokkel MP, Pereira AM, et al. Bexarotene increases uptake of radioiodide in metastases of differentiated thyroid carcinoma. Eur J Endocrinol. 2006 Apr;154(4):525–531. PubMed PMID: 16556714. DOI:10.1530/eje.1.02123
  • Liu YY, Stokkel MP, Morreau HA, et al. Radioiodine therapy after pretreatment with bexarotene for metastases of differentiated thyroid carcinoma. Clin Endocrinol. 2008 Apr;68(4):605–609. PubMed PMID: 17986279. DOI:10.1111/j.1365-2265.2007.03096.x
  • Ohashi E, Kogai T, Kagechika H, et al. Activation of the PI3 kinase pathway by retinoic acid mediates sodium/iodide symporter induction and iodide transport in MCF-7 breast cancer cells. Cancer Res. 2009 Apr 15;69(8):3443–3450. PubMed PMID: 19351850; PubMed Central PMCID: PMC2852426. DOI:10.1158/0008-5472.CAN-08-3234
  • Langlois F, McCartney S, Fleseriu M. Recent progress in the medical therapy of pituitary tumors. Endocrinol Metabolism. 2017 Jun;32(2):162–170. PubMed PMID: 28685507; PubMed Central PMCID: PMC5503860. DOI:10.3803/EnM.2017.32.2.162
  • Kennedy L, Recinos PF. Cushing disease: are we making progress? J Clin Endocrinol Metab. 2017 Jul 01;102(7):2133–2135. PubMed PMID: 28899077. DOI:10.1210/jc.2017-00775
  • Atmaca H, Işıklı G, Sentürk N. Bexarotene and hypopituitarism. AACE Clin Case Rep. 2015;1(3):e175–e177.
  • Atmaca H, Islek I, Sentürk N. Reversible pituitary insufficiency due to bexarotene therapy in a patient with mycosis fungoides. Pituitary. 2013;17(5):492–493.
  • Castillo V, Giacomini D, Paez-Pereda M, et al. Retinoic acid as a novel medical therapy for Cushing’s disease in dogs. Endocrinology. 2006 Sep;147(9):4438–4444. PubMed PMID: 16740975. DOI:10.1210/en.2006-0414
  • Saito-Hakoda A, Uruno A, Yokoyama A, et al. Effects of RXR agonists on cell proliferation/apoptosis and ACTH secretion/pomc expression. PloS One. 2015;10(12):e0141960. PubMed PMID: 26714014; PubMed Central PMCID: PMC4695086. DOI:10.1371/journal.pone.0141960
  • Du L, Bergsneider M, Mirsadraei L, et al. Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease. Proc Natl Acad Sci USA. 2013 May 21;110(21):8555–8560. PubMed PMID: 23653479; PubMed Central PMCID: PMC3666748. DOI:10.1073/pnas.1306182110
  • Sbiera S, Deutschbein T, Weigand I, et al. The new molecular landscape of cushing’s disease. Trends Endocrinol Metab. 2015 Oct;26(10):573–583. PubMed PMID: 26412158. DOI:10.1016/j.tem.2015.08.003
  • Zhang D, Bergsneider M, Wang MB, et al. Targeting the ERK pathway for the treatment of Cushing’s disease. Oncotarget. 2016;7(43):69149–69158.
  • Zhang D, Du L, Heaney AP. Testicular receptor-4: novel regulator of glucocorticoid resistance. J Clin Endocrinol Metab. 2016 Aug;101(8):3123–3133. PubMed PMID: 27253665. DOI:10.1210/jc.2016-1379
  • Available from: http://www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/colorectal-cancer-key-statistics
  • Janakiram NB, Mohammed A, Qian L, et al. Chemopreventive effects of RXR-selective rexinoid bexarotene on intestinal neoplasia of Apc(Min/+) mice. Neoplasia. 2012 Feb;14(2):159–168. PubMed PMID: 22431924; PubMed Central PMCID: PMC3306261.
  • Cesario RM, Stone J, Yen WC, et al. Differentiation and growth inhibition mediated via the RXR:pPARgamma heterodimer in colon cancer. Cancer Lett. 2006 Aug 28;240(2):225–233. PubMed PMID: 16271436. DOI:10.1016/j.canlet.2005.09.010
  • Janakiram NB, Mohammed A, Zhang Y, et al. Chemopreventive efficacy of raloxifene, bexarotene, and their combination on the progression of chemically induced colon adenomas to adenocarcinomas in rats. Cancer Prev Res. 2013 Dec;6(12):1251–1261. PubMed PMID: 24080207; PubMed Central PMCID: PMC4655595. DOI:10.1158/1940-6207.CAPR-13-0249
  • Klopper JP, Sharma V, Berenz A, et al. Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression. Mol Cancer. 2009 Mar 06;8:16. PubMed PMID: 19267912; PubMed Central PMCID: PMC2654861. DOI:10.1186/1476-4598-8-16
  • Yen WC, Lamph WW. A selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced prostate cancer. Prostate. 2006 Feb 15;66(3):305–316. PubMed PMID: 16245282. DOI:10.1002/pros.20347
  • Tang XH, Osei-Sarfo K, Urvalek AM, et al. Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide. Proc Natl Acad Sci USA. 2014 Jun 17;111(24):8907–8912. PubMed PMID: 24927566; PubMed Central PMCID: PMC4066471. DOI:10.1073/pnas.1404828111
  • Lubet RA, Clapper ML, McCormick DL, et al. Chemopreventive efficacy of Targretin in rodent models of urinary bladder, colon/ intestine,head and neck and mammary cancers. Oncol Rep. 2012 May;27(5):1400–1406. PubMed PMID: 22307264. DOI:10.3892/or.2012.1673

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.