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Bexarotene: a promising anticancer agent

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Abstract

Retinoids are biologically active derivatives of vitamin A, which play essential roles in embryonic or adult cell behavior modulating cell proliferation, differentiation and apoptosis. The biologic effects of retinoids are mediated by two distinct families of intracellular receptors: retinoid acid receptors (RARs)-α, -β and -γ and retinoid X receptors (RXR)-α, -β and -γ. Bexarotene is a selective RXR agonist, which exerts its effects in blocking cell cycle progression, inducing apoptosis and differentiation, preventing multidrug resistance, and inhibiting angiogenesis and metastasis, making it a promising chemopreventive agent against cancer.

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References

  1. Niederreither K, Subbarayan V, Dolle P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21:346–347

    Article  CAS  Google Scholar 

  2. Lotan R (1996) Retinoids in cancer prevention. FASEB 10:1031–1039

    CAS  Google Scholar 

  3. Fanjul A, Dawson MI, Hobbs PD et al (1994) A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature 372:107–111

    Article  PubMed  CAS  Google Scholar 

  4. Fenaux P, Chomienne C, Degos L (2001) All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Semin Hematol 38(1):13–25

    Article  PubMed  CAS  Google Scholar 

  5. Boehm MF, Zhang L, Badea BA et al (1994) Synthesis and structureactivity relationships of novel retinoid X receptor-selective retinoids. J Med Chem 37:2930–2941

    Article  PubMed  CAS  Google Scholar 

  6. Dragnev KH, Rigas JR, Dmitrovsky E (2000) The retinoids and cancer prevention mechanisms. Oncologist 5:361–368

    Article  PubMed  CAS  Google Scholar 

  7. Niles RM (2000) Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. Nutrition 16:1084–1089

    Article  PubMed  CAS  Google Scholar 

  8. Toma S, Raffo P, Isnardi L et al (1999) Retinoids in lung cancer chemoprevention and treatment. Ann Oncol 10:95–102

    Article  Google Scholar 

  9. Wong SF (2001) Oral bexarotene in the treatment of cutaneous T-cell lymphoma. Ann Pharmacother 35:1056–1065

    Article  PubMed  CAS  Google Scholar 

  10. Yocum RC, Miller VA, Warrell RP et al (2001) Long-term followup of patients with advanced non-small cell lung cancer treated with oral bexarotene. Proc Am Soc Clin Oncol 20:267

    Google Scholar 

  11. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R (2007) FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12:1247–1252

    Article  PubMed  CAS  Google Scholar 

  12. Blumenschein GR Jr, Khuri FR, von Pawel J et al (2008) 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 26:1879–1885

    Article  PubMed  CAS  Google Scholar 

  13. Tooker P, Yen WC, Ng SC et al (2007) Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. Cancer Res 67:4425–4433

    Article  PubMed  CAS  Google Scholar 

  14. Brown PH, Subbaramaiah K, Salmon AP et al (2008) Combination chemoprevention of HER2/neu-induced breast cancer using a cyclooxygenase-2 inhibitor and a retinoid X receptor-selective retinoid. Cancer Prev Res (Phila Pa) 1:208–214

    Google Scholar 

  15. Zanardi S, Serrano D, Argusti A et al (2006) Clinical trials with retinoids for breast cancer chemoprevention. Endocr Relat Cancer 13:51–68

    Article  PubMed  CAS  Google Scholar 

  16. Abbott RA, Whittaker SJ, Morris SL et al (2009) Bexarotene therapy for mycosis fungoides and Sézary syndrome. Br J Dermatol 160:1299–1307

    Article  PubMed  CAS  Google Scholar 

  17. Lessin SR, Ross EA, Wu H (2008) Treatment of parapsoriasis with bexarotene 1% gel. Int J Dermatol 47:1325–1327

    Article  PubMed  Google Scholar 

  18. Breneman D, Sheth P, Berger V et al (2007) Phase II clinical trial of bexarotene gel 1% in psoriasis. J Drugs Dermatol 6:501–506

    PubMed  Google Scholar 

  19. Bedikian AY, Plager C, Papadopoulos N et al (2000) A phase II evaluation of bexarotene (Targretin) capsules in patients with metastatic melanoma. Oncol Rep 7:883–886

    PubMed  CAS  Google Scholar 

  20. Tsai DE, Luger SM, Andreadis C et al (2008) A phase I study of bexarotene, a retinoic X receptor agonist, in non-M3 acute myeloid leukemia. Clin Cancer Res 14:5619–5625

    Article  PubMed  CAS  Google Scholar 

  21. Read WL, Baggstrom MQ, Fracasso PM, Govindan R (2008) A phase I study of bexarotene and rosiglitazone in patients with refractory cancers. Chemotherapy 54:236–241

    Article  PubMed  CAS  Google Scholar 

  22. Dragnev KH, Petty WJ, Shah S et al (2005) Bexarotene and erlotinib for aerodigestive tract cancer. J Clin Oncol 23:8757–8764

    Article  PubMed  CAS  Google Scholar 

  23. Hanifin JM, Stevens V, Sheth P, Breneman D (2004) Novel treatment of chronic severe hand dermatitis with bexarotene gel. Br J Dermatol 150:545–553

    Article  PubMed  CAS  Google Scholar 

  24. Talpur R, Vu J, Bassett R, Stevens V, Duvic M (2009) Phase I/II randomized bilateral half-head comparison of topical bexarotene 1% gel for alopecia areata. J Am Acad Dermatol 2009 Aug 12. [Epub ahead of print]

  25. Liu YY, Stokkel MP, Pereira AM et al (2006) Bexarotene increases uptake of radioiodide in metastases of differentiated thyroid carcinoma. Eur J Endocrinol 154:525–531

    Article  PubMed  CAS  Google Scholar 

  26. Krathen RA, Ward S, Duvic M (2003) Bexarotene is a new treatment option for lymphomatoid papulosis. Dermatology 206:142–147

    Article  PubMed  CAS  Google Scholar 

  27. Duvic M, Hymes K, Heald P et al (2001) Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II–III trial results. J Clin Oncol 19:2456–2471

    PubMed  CAS  Google Scholar 

  28. Duvic M, Martin AG, Kim Y et al (2001) 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 137:581–593

    PubMed  CAS  Google Scholar 

  29. Kannangara AP, Levitan D, Fleischer AB Jr (2009) Evaluation of the efficacy of the combination of oral bexarotene and methotrexate for the treatment of early stage treatment-refractory cutaneous T-cell lymphoma. J Dermatolog Treat 20:169–176

    Article  PubMed  CAS  Google Scholar 

  30. Papadavid E, Antoniou C, Nikolaou V et al (2008) Safety and efficacy of low-dose bexarotene and PUVA in the treatment of patients with mycosis fungoides. Am J Clin Dermatol 9:169–173

    Article  PubMed  Google Scholar 

  31. Ramlau R, Zatloukal P, Jassem J et al (2008) 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 26:1886–1892

    Article  PubMed  CAS  Google Scholar 

  32. Rigas JR, Dragnev KH (2005) Emerging role of rexinoids in non-small cell lung cancer: focus on bexarotene. Oncologist 10:22–33

    Article  PubMed  CAS  Google Scholar 

  33. Rizvi N, Hawkins MJ, Eisenberg PD et al (2001) Placebo-controlled trial of bexarotene, a retinoid x receptor agonist, as maintenance therapy for patients treated with chemotherapy for advanced non-small-cell lung cancer. Clin Lung Cancer 2:210–215

    Article  PubMed  CAS  Google Scholar 

  34. Esteva FJ, Glaspy J, Baidas S et al (2003) Multicenter phase II study of oral bexarotene for patients with metastatic breast cancer. J Clin Oncol 21:999–1006

    Article  PubMed  CAS  Google Scholar 

  35. D’Acunto C, Gurioli C, Neri I (2009) Plaque stage mycosis fungoides treated with bexarotene at low dosage and UVB-NB. J Dermatolog Treat 1:1–4

    Article  Google Scholar 

  36. Foss F, Demierre MF, DiVenuti G (2005) A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 106:454–457

    Article  PubMed  CAS  Google Scholar 

  37. Yen WC, Lamph WW (2006) A selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced prostate cancer. Prostate 66:305–316

    Article  PubMed  CAS  Google Scholar 

  38. Steinhoff M, Beyer M, Roewert-Huber J et al (2008) Complete clinical remission of tumor-stage mycosis fungoides after acute extensive skin necroses, granulomatous reaction, and fever under treatment with bexarotene, vorinostat, and high-dose fenofibrate. J Am Acad Dermatol 58:S88–S91

    Article  PubMed  Google Scholar 

  39. Lokitz ML, Wong HK (2007) Bexarotene and narrowband ultraviolet B phototherapy combination treatment for mycosis fungoides. Photodermatol Photoimmunol Photomed 23:255–257

    Article  PubMed  CAS  Google Scholar 

  40. Altucci L, Rossin A, Hirsch O et al (2005) Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor. Cancer Res 65:8754–8765

    Article  PubMed  CAS  Google Scholar 

  41. Straus DJ, Duvic M, Kuzel T et al (2007) 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 109:1799–1803

    Article  PubMed  CAS  Google Scholar 

  42. Feng Q, Sekula D, Guo Y et al (2008) UBE1L causes lung cancer growth suppression by targeting cyclin D1. Mol Cancer Ther 7:3780–3788

    Article  PubMed  CAS  Google Scholar 

  43. Langenfeld J, Kiyokawa H, Sekula D et al (1997) Posttranslational regulation of cyclin D1 by retinoic acid: a chemoprevention mechanism. Proc Natl Acad Sci USA 94:12070–12074

    Article  PubMed  CAS  Google Scholar 

  44. Nieto-Rementería N, Pérez-Yarza G, Boyano MD et al (2008) Bexarotene activates the p53/p73 pathway in human cutaneous T-cell lymphoma. Br J Dermatol 25:519–526

    Google Scholar 

  45. Dragnev KH, Petty WJ, Shah SJ et al (2007) A proof-of-principle clinical trial of bexarotene in patients with non-small cell lung cancer. Clin Cancer Res 13:1794–1800

    Article  PubMed  CAS  Google Scholar 

  46. Uray IP, Shen Q, Seo HS et al (2009) Rexinoid-induced expression of IGFBP-6 requires RARbeta-dependent permissive cooperation of retinoid receptors and AP-1. J Biol Chem 284(1):345–353

    Article  PubMed  CAS  Google Scholar 

  47. Reddig PJ, Juliano RL (2005) Clinging to life: cell to matrix adhesion and cell survival. Cancer Metastasis Rev 24:425–439

    Article  PubMed  Google Scholar 

  48. Ying SX, Seal S, Abbassi N et al (2007) Differential effects of bexarotene on intrinsic and extrinsic pathways in TRAIL-induced apoptosis in two myeloid leukemia cell lines. Leuk Lymphoma 48:1003–1014

    Article  PubMed  CAS  Google Scholar 

  49. Tamm I, Wang Y, Sausville E et al (1998) IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas(CD95), Bax, Caspases, and anticancer drugs. Cancer Res 58:5315–5320

    PubMed  CAS  Google Scholar 

  50. Zhang C, Hazarika P, Ni X et al (2002) Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. Clin Cancer Res 8:1234–1240

    PubMed  CAS  Google Scholar 

  51. Alyaqoub FS, Liu Y, Tao L et al (2008) Modulation by bexarotene of mRNA expression of genes in mouse lung tumors. Mol Carcinog 47:165–171

    Article  PubMed  CAS  Google Scholar 

  52. Cesario RM, Stone J, Yen WC, Bissonnette RP, Lamph WW (2006) Differentiation and growth inhibition mediated via the RXR:PPARgamma heterodimer in colon cancer. Cancer Lett 240:225–233

    Article  PubMed  CAS  Google Scholar 

  53. Kizaki M, Dawson MI, Heyman R et al (1996) Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro. Blood 87:1977–1984

    PubMed  CAS  Google Scholar 

  54. Kuo MT (2009) Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 11:99–133

    Article  PubMed  CAS  Google Scholar 

  55. Thiebaut F, Tsuruo T, Hamada H et al (1987) Cellular localization of the multidrug resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci 84:7735–7738

    Article  PubMed  CAS  Google Scholar 

  56. Wu K, Zhang Y, Xu XC et al (2002) The retinoid X receptor-selective retinoid, LGD1069, prevents the development of estrogen receptor-negative mammary tumors in transgenic mice. Cancer Res 62:6376–6380

    PubMed  CAS  Google Scholar 

  57. Yen WC, Lamph WW (2005) The selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced breast carcinoma. Mol Cancer Ther 4:824–834

    Article  PubMed  CAS  Google Scholar 

  58. Yen WC, Corpuz MR, Prudente RY et al (2004) 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 10:8656–8664

    Article  PubMed  CAS  Google Scholar 

  59. Yen WC, Prudente RY, Lamph WW (2004) Synergistic effect of a retinoid X receptor-selective ligand bexarotene (LGD1069, Targretin) and paclitaxel (Taxol) in mammary carcinoma. Breast Cancer Res Treat 88:141–148

    Article  PubMed  CAS  Google Scholar 

  60. Jones DR, Broad RM, Comeau LD et al (2002) Inhibition of nuclear factor kappaB chemosensitizes non-small-cell lung cancer through cytochrome c release and caspase activation. J Thorac Cardiovasc Surg 123:310–317

    Article  PubMed  CAS  Google Scholar 

  61. Bentires-Alj M, Barbu V, Fillet M et al (2003) NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 22:90–97

    Article  PubMed  CAS  Google Scholar 

  62. García MG, Alaniz LD, Cordo Russo RI et al (2009) PI3K/Akt inhibition modulates multidrug resistance and activates NF-kappaB in murine lymphoma cell lines. Leuk Res 33:288–296

    Article  PubMed  CAS  Google Scholar 

  63. Nakajima Y, Madhyastha R, Maruyama M (2009) 2-Deoxy-d-ribose, a downstream mediator of thymidine phosphorylase, regulates tumor angiogenesis and progression. Anticancer Agents Med Chem 9:239–245

    PubMed  CAS  Google Scholar 

  64. Kumar R, Fidler IJ (1998) Angiogenic molecules and cancer metastasis. In Vivo 12:27–34

    PubMed  CAS  Google Scholar 

  65. Yen WC, Prudente RY, Corpuz MR et al (2006) A selective retinoid X receptor agonist bexarotene (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours. Br J Cancer 94:654–660

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Ministry of Health of PR China (419100-W10754) and Zhejiang University Research Grant (419100-812653).

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Correspondence to Xiuwen Tang.

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Qu, L., Tang, X. Bexarotene: a promising anticancer agent. Cancer Chemother Pharmacol 65, 201–205 (2010). https://doi.org/10.1007/s00280-009-1140-4

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