Effects of Natural and Synthetic Retinoids on the Differentiation and Growth of Squamous Cancers

  • Humam Kadara
  • Reuben LotanEmail author


A negative correlation between vitamin A intake and the incidence of epithelial tumors was observed about 80 years ago. This observation was followed by multiple studies, which have demonstrated that vitamin A and its metabolites as well as synthetic analogs (retinoids) could suppress carcinogenesis in a variety of epithelial tissues. In parallel, vitamin A and retinoids inhibit squamous cell differentiation in normal keratinocytes and in malignant squamous cell carcinomas (SCC) including those of the head and neck. Because the use of natural retinoids in the clinical setting was hampered by adverse side effects, synthetic retinoids were developed with the hope that they would exhibit potent anticancer chemopreventive and therapeutic properties but much lower toxicities than natural retinoids. In addition, synthetic retinoids and retinoid-related molecules, such as fenretinide [N-4-hydroxyphenyl)retinamide; 4HPR] and the adamantyl retinoid CD437, respectively, induce cancer cell apoptosis through retinoid receptor-dependent and more often independent mechanisms. This chapter reviews the major effects of retinoids on squamous cell differentiation, cancer cell growth and apoptosis, and aims to provide new insights into common and distinct mechanisms of action among the naturally occurring retinoic acid and the synthetic derivatives, 4HPR and CD437, in normal and malignant squamous head and neck cells.


Retinoic Acid Reactive Oxygen Species Generation Squamous Differentiation Normal Human Bronchial Epithelial Acute Promyelocytic Leukemia Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abou-Issa H, Moeschberger M, el-Masry W et al. (1995) Relative efficacy of glucarate on the initiation and promotion phases of rat mammary carcinogenesis. Anticancer Res 15:805–810PubMedGoogle Scholar
  2. Altucci L, Gronemeyer H (2001) The promise of retinoids to fight against cancer. Nat Rev Cancer 1:181–193PubMedCrossRefGoogle Scholar
  3. Appierto V, Cavadini E, Pergolizzi R et al. (2001) Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant ovarian tumour cell line. Br J Cancer 84:1528–1534PubMedCrossRefGoogle Scholar
  4. Asumendi A, Morales MC, Alvarez A et al. (2002) Implication of mitochondria-derived ROS and cardiolipin peroxidation in N-(4-hydroxyphenyl).retinamide-induced apoptosis. Br J Cancer 86:1951–1956PubMedCrossRefGoogle Scholar
  5. Bast RC Jr, Brewer M, Zou C et al. (2007) Prevention and early detection of ovarian cancer: Mission impossible? Recent Results Cancer Res 174:91–100PubMedCrossRefGoogle Scholar
  6. Batra S, Reynolds CP, Maurer BJ (2004) Fenretinide cytotoxicity for Ewing’s sarcoma and primitive neuroectodermal tumor cell lines is decreased by hypoxia and synergistically enhanced by ceramide modulators. Cancer Res 64:5415–5424PubMedCrossRefGoogle Scholar
  7. Beitch I (1970) The induction of keratinization in the corneal epithelium. A comparison of the “dry” and vitamin A-deficient eyes. Invest Ophthalmol 9:827–843PubMedGoogle Scholar
  8. Benedetti L, Levin AA, Scicchitano BM et al. (1997) Characterization of the retinoid binding properties of the major fusion products present in acute promyelocytic leukemia cells. Blood 90:1175–1185PubMedGoogle Scholar
  9. Bernard BA, Bernardon JM, Delescluse C et al. (1992) Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor gamma. Biochem Biophys Res Commun 186:977–983PubMedCrossRefGoogle Scholar
  10. Blomhoff R, Blomhoff HK (2006) Overview of retinoid metabolism and function. J Neurobiol 66:606–630PubMedCrossRefGoogle Scholar
  11. Blot WJ, Li JY, Taylor PR et al. (1993) Nutrition intervention trials in Linxian, China: Supple­mentation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 85:1483–1492PubMedCrossRefGoogle Scholar
  12. Boya P, Morales MC, Gonzalez-Polo RA et al. (2003) The chemopreventive agent N-(4-hydroxyphenyl).retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl-2 family. Oncogene 22:6220–6230PubMedCrossRefGoogle Scholar
  13. Brembeck FH, Opitz OG, Libermann TA et al. (2000) Dual function of the epithelial specific ets transcription factor, ELF3, in modulating differentiation. Oncogene 19:1941–1949PubMedCrossRefGoogle Scholar
  14. Castaigne S, Chomienne C, Daniel MT et al. (1990) All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 76:1704–1709PubMedGoogle Scholar
  15. Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10:940–954PubMedGoogle Scholar
  16. Chan LN, Zhang S, Shao J et al. (1997) N-(4-hydroxyphenyl).retinamide induces apoptosis in T lymphoma and T lymphoblastoid leukemia cells. Leuk Lymphoma 25:271–280PubMedGoogle Scholar
  17. Chan AY, Coniglio SJ, Chuang YY et al. (2005) Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Oncogene 24:7821–7829PubMedCrossRefGoogle Scholar
  18. Chen YR, Zhou G, Tan TH (1999) c-Jun N-terminal kinase mediates apoptotic signaling induced by N-(4-hydroxyphenyl).retinamide. Mol Pharmacol 56:1271–1279PubMedGoogle Scholar
  19. Cheng G, Diebold BA, Hughes Y et al. (2006) Nox1-dependent reactive oxygen generation is regulated by Rac1. J Biol Chem 281:17718–17726PubMedCrossRefGoogle Scholar
  20. Chiesa F, Tradati N, Grigolato R et al. (2005) Randomized trial of fenretinide (4-HPR). to prevent recurrences, new localizations and carcinomas in patients operated on for oral leukoplakia: long-term results. Int J Cancer 115:625–629PubMedCrossRefGoogle Scholar
  21. Choi JH, Chun KH, Raz A et al. (2004) Inhibition of N-(4-hydroxyphenyl).retinamide-induced apoptosis in breast cancer cells by galectin-3. Cancer Biol Ther 3:447–452PubMedGoogle Scholar
  22. Clifford JL, Menter DG, Wang M et al. (1999) Retinoid receptor-dependent and -independent effects of N-(4-hydroxyphenyl).retinamide in F9 embryonal carcinoma cells. Cancer Res 59:14–18PubMedGoogle Scholar
  23. Collins MD, Mao GE (1999) Teratology of retinoids. Annu Rev Pharmacol Toxicol 39:399–430PubMedCrossRefGoogle Scholar
  24. Corazzari M, Lovat PE, Armstrong JL et al. (2007) Targeting homeostatic mechanisms of ­endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57. Br J Cancer 96:1062–1071PubMedCrossRefGoogle Scholar
  25. Costa A, De Palo G, Decensi A et al. (1995) Retinoids in cancer chemoprevention. Clinical trials with the synthetic analogue fenretinide. Ann NY Acad Sci 768:148–162PubMedCrossRefGoogle Scholar
  26. Crowe DL, Hu L, Gudas LJ et al. (1991) Variable expression of retinoic acid receptor (RAR beta). mRNA in human oral and epidermal keratinocytes; relation to keratin 19 expression and ­keratinization potential. Differentiation 48:199–208PubMedCrossRefGoogle Scholar
  27. Darwiche N, Celli G, Tennenbaum T et al. (1995) Mouse skin tumor progression results in ­differential expression of retinoic acid and retinoid X receptors. Cancer Res 55:2774–2782PubMedGoogle Scholar
  28. Darwiche N, Scita G, Jones C et al. (1996) Loss of retinoic acid receptors in mouse skin and skin tumors is associated with activation of the ras(Ha). oncogene and high risk for premalignant progression. Cancer Res 56:4942–4949PubMedGoogle Scholar
  29. Darwiche N, Abou-Lteif G, Bazarbachi A (2007) Reactive oxygen species mediate N-(4-hydroxyphenyl).retinamide-induced cell death in malignant T cells and are inhibited by the HTLV-I oncoprotein Tax. Leukemia 21:261–269PubMedCrossRefGoogle Scholar
  30. Dawson MI, Hobbs PD, Peterson VJ et al. (2001) Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl).-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptor transcriptional activation activity. Cancer Res 61:4723–4730PubMedGoogle Scholar
  31. De Leo FR, Ulman KV, Davis AR et al. (1996) Assembly of the human neutrophil NADPH ­oxidase involves binding of p67phox and flavocytochrome b to a common functional domain in p47phox. J Biol Chem 271:17013–17020PubMedCrossRefGoogle Scholar
  32. De Luca LM (1977) The direct involvement of vitamin A in glycosyl transfer reactions of ­mammalian membranes. Vitam Horm 35:1–57PubMedCrossRefGoogle Scholar
  33. De Luca LM (1991) Retinoids and their receptors in differentiation, embryogenesis, and ­neoplasia. FASEB J 5:2924–2933PubMedGoogle Scholar
  34. Delia D, Aiello A, Meroni L et al. (1997) Role of antioxidants and intracellular free radicals in retinamide-induced cell death. Carcinogenesis 18:943–948PubMedCrossRefGoogle Scholar
  35. Dmitrovsky E (2004) Fenretinide activates a distinct apoptotic pathway. J Natl Cancer Inst 96:1264–1265PubMedCrossRefGoogle Scholar
  36. Eckert RL (1989) Structure, function, and differentiation of the keratinocyte. Physiol Rev 69:1316–1346PubMedGoogle Scholar
  37. Faderl S, Lotan R, Kantarjian HM et al. (2003) N-(4-Hydroxylphenyl)retinamide (fenretinide, 4-HPR), a retinoid compound with antileukemic and proapoptotic activity in acute lymphoblastic leukemia (ALL). Leuk Res 27:259–266PubMedCrossRefGoogle Scholar
  38. Fanjul AN, Delia D, Pierotti MA et al. (1996) 4-Hydroxyphenyl retinamide is a highly selective activator of retinoid receptors. J Biol Chem 271:22441–22446PubMedCrossRefGoogle Scholar
  39. Flynn PJ, Miller WJ, Weisdorf DJ et al. (1983) Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations. Blood 62:1211–1217PubMedGoogle Scholar
  40. Formelli F, Barua AB, Olson JA (1996) Bioactivities of N-(4-hydroxyphenyl) retinamide and retinoyl beta-glucuronide. FASEB J 10:1014–1024PubMedGoogle Scholar
  41. Freemantle SJ, Spinella MJ, Dmitrovsky E (2003) Retinoids in cancer therapy and chemoprevention: promise meets resistance. Oncogene 22:7305–7315PubMedCrossRefGoogle Scholar
  42. Fujimoto W, Marvin KW, George MD et al. (1993) Expression of cornifin in squamous differentiating epithelial tissues, including psoriatic and retinoic acid-treated skin. J Invest Dermatol 101:268–274PubMedCrossRefGoogle Scholar
  43. Gao Y, Dickerson JB, Guo F et al. (2004) Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci USA 101:7618–7623PubMedCrossRefGoogle Scholar
  44. Gianni M, de The H (1999) In acute promyelocytic leukemia NB4 cells, the synthetic retinoid CD437 induces contemporaneously apoptosis, a caspase-3-mediated degradation of PML/RARalpha protein and the PML retargeting on PML-nuclear bodies. Leukemia 13:739–749PubMedCrossRefGoogle Scholar
  45. Giguere V, Ong ES, Segui P et al. (1987) Identification of a receptor for the morphogen retinoic acid. Nature 330:624–629PubMedCrossRefGoogle Scholar
  46. Goodwin WJ Jr, Bordash GD, Huijing F et al. (1986) Inhibition of hamster tongue carcinogenesis by selenium and retinoic acid. Ann Otol Rhinol Laryngol 95:162–166PubMedGoogle Scholar
  47. Hail N Jr, Lotan R (2000) Mitochondrial permeability transition is a central coordinating event in N-(4-hydroxyphenyl)retinamide-induced apoptosis. Cancer Epidemiol Biomark Prev 9:1293–1301Google Scholar
  48. Hail N Jr, Lotan R (2001a) Mitochondrial respiration is uniquely associated with the prooxidant and apoptotic effects of N-(4-hydroxyphenyl)retinamide. J Biol Chem 276:45614–45621PubMedCrossRefGoogle Scholar
  49. Hail N Jr, Lotan R (2001b) Synthetic retinoid CD437 promotes rapid apoptosis in malignant human epidermal keratinocytes and G1 arrest in their normal counterparts. J Cell Physiol 186:24–34PubMedCrossRefGoogle Scholar
  50. Hail N Jr, Youssef EM, Lotan R (2001) Evidence supporting a role for mitochondrial respiration in apoptosis induction by the synthetic retinoid CD437. Cancer Res 61:6698–6702PubMedGoogle Scholar
  51. Hail N Jr, Kim HJ, Lotan R (2006) Mechanisms of fenretinide-induced apoptosis. Apoptosis 11:1677–1694PubMedCrossRefGoogle Scholar
  52. Harris CC, Sporn MB, Kaufman DG et al. (1972) Histogenesis of squamous metaplasia in the hamster tracheal epithelium caused by vitamin A deficiency or benzo[a]pyrene-Ferric oxide. J Natl Cancer Inst 48:743–761PubMedGoogle Scholar
  53. Hayes KC, McCombs HL, Faherty TP (1970) The fine structure of vitamin A deficiency. I. Parotid duct metaplasia. Lab Invest 22:81–89PubMedGoogle Scholar
  54. Hicks RM (1968) Hyperplasia and cornification of the transitional epithelium in the vitamin A-deficient rat. Changes in fine structure of the cells. J Ultrastruct Res 22:206–230PubMedCrossRefGoogle Scholar
  55. Hill DS, Martin S, Armstrong JL et al. (2009) Combining the endoplasmic reticulum stress-inducing agents bortezomib and fenretinide as a novel therapeutic strategy for metastatic melanoma. Clin Cancer Res 15:1192–1198PubMedCrossRefGoogle Scholar
  56. Hislop TG, Band PR, Deschamps M et al. (1990) Diet and histologic types of benign breast disease defined by subsequent risk of breast cancer. Am J Epidemiol 131:263–270PubMedGoogle Scholar
  57. Holmes WF, Dawson MI, Soprano RD et al. (2000) Induction of apoptosis in ovarian carcinoma cells by AHPN/CD437 is mediated by retinoic acid receptors. J Cell Physiol 185:61–67PubMedCrossRefGoogle Scholar
  58. Holmes WF, Soprano DR, Soprano KJ (2002) Elucidation of molecular events mediating ­induction of apoptosis by synthetic retinoids using a CD437-resistant ovarian carcinoma cell line. J Biol Chem 277:45408–45419PubMedCrossRefGoogle Scholar
  59. Hsu CA, Rishi AK, Su-Li X et al. (1997) Retinoid induced apoptosis in leukemia cells through a retinoic acid nuclear receptor-independent pathway. Blood 89:4470–4479PubMedGoogle Scholar
  60. Hu L, Crowe DL, Rheinwald JG et al. (1991) Abnormal expression of retinoic acid receptors and keratin 19 by human oral and epidermal squamous cell carcinoma cell lines. Cancer Res 51:3972–3981PubMedGoogle Scholar
  61. Huang ME, Ye YC, Chen SR et al. (1988) Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72:567–572PubMedGoogle Scholar
  62. Hursting SD, Shen JC, Sun XY et al. (2002) Modulation of cyclophilin gene expression by N-4-(hydroxyphenyl).retinamide: association with reactive oxygen species generation and apoptosis. Mol Carcinog 33:16–24PubMedCrossRefGoogle Scholar
  63. Inoue I, Yamamoto Y, Ito T et al. (1993) Chemoprevention of tongue carcinogenesis in rats. Oral Surg Oral Med Oral Pathol 76:608–615PubMedCrossRefGoogle Scholar
  64. Jetten AM (1990) Multi-stage program of differentiation in human epidermal keratinocytes: regulation by retinoids. J Invest Dermatol 95:44S–46SCrossRefGoogle Scholar
  65. Jetten AM, Kim JS, Sacks PG et al. (1990) Inhibition of growth and squamous-cell differentiation markers in cultured human head and neck squamous carcinoma cells by beta-all-trans retinoic acid. Int J Cancer 45:195–202PubMedCrossRefGoogle Scholar
  66. Jin F, Liu X, Zhou Z et al. (2005) Activation of nuclear factor-kappaB contributes to induction of death receptors and apoptosis by the synthetic retinoid CD437 in DU145 human prostate cancer cells. Cancer Res 65:6354–6363PubMedCrossRefGoogle Scholar
  67. Kadara H, Schroeder CP, Lotan D et al. (2006) Induction of GDF-15/NAG-1/MIC-1 in human lung carcinoma cells by retinoid-related molecules and assessment of its role in apoptosis. Cancer Biol Ther 5:518–522PubMedCrossRefGoogle Scholar
  68. Kadara H, Lacroix L, Lotan D et al. (2007) Induction of endoplasmic reticulum stress by the pro-apoptotic retinoid N-(4-hydroxyphenyl).retinamide via a reactive oxygen species-dependent mechanism in human head and neck cancer cells. Cancer Biol Ther 6:705–711PubMedCrossRefGoogle Scholar
  69. Kadara H, Kim HJ, Tahara E et al. (2008a) Differential effects of 4HPR on gene expression and apoptosis in normal and malignant cells of the head and neck despite induction of reactive oxygen species in both cell types. Proceedings of the American Association of Cancer Research Vol. 2008, pp 2282AGoogle Scholar
  70. Kadara H, Tahara E, Kim HJ et al. (2008b) Involvement of Rac in fenretinide-induced apoptosis. Cancer Res 68:4416–4423PubMedCrossRefGoogle Scholar
  71. Kark JD, Smith AH, Switzer BR et al. (1981) Serum vitamin A (retinol). and cancer incidence in Evans County, Georgia. J Natl Cancer Inst 66:7–16PubMedGoogle Scholar
  72. Kastner P, Mark M, Chambon P (1995) Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83:859–869PubMedCrossRefGoogle Scholar
  73. Kim HJ, Lotan R (2004) Identification of retinoid-modulated proteins in squamous carcinoma cells using high-throughput immunoblotting. Cancer Res 64:2439–2448PubMedCrossRefGoogle Scholar
  74. Kim HJ, Chakravarti N, Oridate N et al. (2006) N-(4-hydroxyphenyl).retinamide-induced ­apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells. Oncogene 25:2785–2794PubMedCrossRefGoogle Scholar
  75. Koo JS, Yoon JH, Gray T et al. (1999) Restoration of the mucous phenotype by retinoic acid in retinoid-deficient human bronchial cell cultures: changes in mucin gene expression. Am J Respir Cell Mol Biol 20:43–52PubMedGoogle Scholar
  76. Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189PubMedCrossRefGoogle Scholar
  77. Langdon SP, Rabiasz GJ, Ritchie AA et al. (1998) Growth-inhibitory effects of the synthetic retinoid CD437 against ovarian carcinoma models in vitro and in vivo. Cancer Chemother Pharmacol 42:429–432PubMedCrossRefGoogle Scholar
  78. Lasnitzki I (1976) Reversal of methylcholanthrene-induced changes in mouse prostates in vitro by retinoic acid and its analogues. Br J Cancer 34:239–248PubMedGoogle Scholar
  79. Lau A, Villeneuve NF, Sun Z et al. (2008) Dual roles of Nrf2 in cancer. Pharmacol Res 58:262–270PubMedCrossRefGoogle Scholar
  80. Lee JS, Lippman SM, Benner SE et al. (1994) Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia. J Clin Oncol 12:937–945PubMedGoogle Scholar
  81. Lee HY, Dawson MI, Walsh GL et al. (1996) Retinoic acid receptor- and retinoid X receptor-selective retinoids activate signaling pathways that converge on AP-1 and inhibit squamous differentiation in human bronchial epithelial cells. Cell Growth Differ 7:997–1004PubMedGoogle Scholar
  82. Li JY, Taylor PR, Li B et al. (1993) Nutrition intervention trials in Linxian, China: multiple ­vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst 85:1492–1498PubMedCrossRefGoogle Scholar
  83. Lippman SM, Lee JJ, Karp DD et al. (2001) Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst 93:605–618PubMedCrossRefGoogle Scholar
  84. Lippman SM, Lee JJ, Martin JW et al. (2006) Fenretinide activity in retinoid-resistant oral leukoplakia. Clin Cancer Res 12:3109–3114PubMedCrossRefGoogle Scholar
  85. Liu G, Wu M, Levi G et al. (1998) Inhibition of cancer cell growth by all-trans retinoic acid and its analog N-(4-hydroxyphenyl) retinamide: a possible mechanism of action via regulation of retinoid receptors expression. Int J Cancer 78:248–254PubMedCrossRefGoogle Scholar
  86. Lotan R (1980) Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells. Biochim Biophys Acta 605:33–91PubMedGoogle Scholar
  87. Lotan R (1993) Squamous cell differentiation markers in normal, premalignant, and malignant epithelium: effects of retinoids. J Cell Biochem Suppl 17F:167–174PubMedCrossRefGoogle Scholar
  88. Lotan R (1994) Suppression of squamous cell carcinoma growth and differentiation by retinoids. Cancer Res 54:1987s–1990sPubMedGoogle Scholar
  89. Lotan R (1997) Retinoids and chemoprevention of aerodigestive tract cancers. Cancer Metastasis Rev 16:349–356PubMedCrossRefGoogle Scholar
  90. Lotan R (2003) Receptor-independent induction of apoptosis by synthetic retinoids. J Biol Regul Homeost Agents 17:13–28PubMedGoogle Scholar
  91. Lotan R, Nicolson GL (1977) Inhibitory effects of retinoic acid or retinyl acetate on the growth of untransformed, transformed, and tumor cells in vitro. J Natl Cancer Inst 59:1717–1722PubMedGoogle Scholar
  92. Lotan R, Xu XC, Lippman SM et al. (1995) Suppression of retinoic acid receptor-beta in ­premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med 332:1405–1410PubMedCrossRefGoogle Scholar
  93. Lovat PE, Ranalli M, Annichiarrico-Petruzzelli M et al. (2000) Effector mechanisms of ­fenretinide-induced apoptosis in neuroblastoma. Exp Cell Res 260:50–60PubMedCrossRefGoogle Scholar
  94. Lovat PE, Oliverio S, Ranalli M et al. (2002) GADD153 and 12-lipoxygenase mediate fenretinide-induced apoptosis of neuroblastoma. Cancer Res 62:5158–5167PubMedGoogle Scholar
  95. Lovat PE, Di Sano F, Corazzari M et al. (2004) Gangliosides link the acidic sphingomyelinase-mediated induction of ceramide to 12-lipoxygenase-dependent apoptosis of neuroblastoma in response to fenretinide. J Natl Cancer Inst 96:1288–1299PubMedCrossRefGoogle Scholar
  96. Lovat PE, Corazzari M, Armstrong JL et al. (2008) Increasing melanoma cell death using inhibitors of protein disulfide isomerases to abrogate survival responses to endoplasmic reticulum stress. Cancer Res 68:5363–5369PubMedCrossRefGoogle Scholar
  97. Lu XP, Fanjul A, Picard N et al. (1997) Novel retinoid-related molecules as apoptosis inducers and effective inhibitors of human lung cancer cells in vivo. Nat Med 3:686–690PubMedCrossRefGoogle Scholar
  98. Marchetti P, Zamzami N, Joseph B et al. (1999) The novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid can trigger apoptosis through a mitochondrial pathway independent of the nucleus. Cancer Res 59:6257–6266PubMedGoogle Scholar
  99. Marchok AC, Cone V, Nettesheim P (1975) Induction of squamous metaplasia (vitamin A ­deficiency) and hypersecretory activity in tracheal organ cultures. Lab Investig 33:451–460PubMedGoogle Scholar
  100. Maurer BJ, Metelitsa LS, Seeger RC et al. (1999) Increase of ceramide and induction of mixed apoptosis/necrosis by N-(4-hydroxyphenyl)- retinamide in neuroblastoma cell lines. J Natl Cancer Inst 91:1138–1146PubMedCrossRefGoogle Scholar
  101. McCormick DL, Moon RC (1986) Antipromotional activity of dietary N-(4-hydroxyphenyl) ­retinamide in two-stage skin tumorigenesis in CD-1 and SENCAR mice. Cancer Lett 31:133–138PubMedCrossRefGoogle Scholar
  102. Mendelsohn MG, Dilorenzo TP, Abramson AL et al. (1991) Retinoic acid regulates, in vitro, the two normal pathways of differentiation of human laryngeal keratinocytes. In Vitro Cell Dev Biol 27A:137–141PubMedCrossRefGoogle Scholar
  103. Meyskens FL Jr, Surwit E, Moon TE et al. (1994) Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia). with topically applied all-trans-retinoic acid: a ­randomized trial. J Natl Cancer Inst 86:539–543PubMedCrossRefGoogle Scholar
  104. Miller WH Jr, Reyno LM, Loewen GR et al. (2000) A phase I-II study of 9-cis retinoic acid and interferon-alpha2b in patients with advanced renal-cell carcinoma: an NCIC Clinical Trials Group study. Ann Oncol 11:1387–1389PubMedCrossRefGoogle Scholar
  105. Mologni L, Ponzanelli I, Bresciani F et al. (1999) The novel synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) causes apoptosis in acute promyelocytic leukemia cells through rapid activation of caspases. Blood 93:1045–1061PubMedGoogle Scholar
  106. Moon RC (1994) Vitamin A, retinoids and breast cancer. Adv Exp Med Biol 364:101–107PubMedGoogle Scholar
  107. Moon RC, Thompson HJ, Becci PJ et al. (1979) N-(4-Hydroxyphenyl)retinamide, a new retinoid for prevention of breast cancer in the rat. Cancer Res 39:1339–1346PubMedGoogle Scholar
  108. Muindi J, Frankel SR, Miller WH Jr et al. (1992) Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid “resistance” in patients with acute promyelocytic leukemia. Blood 79:299–303PubMedGoogle Scholar
  109. Myatt SS, Redfern CP, Burchill SA (2005) p38MAPK-Dependent sensitivity of Ewing’s sarcoma family of tumors to fenretinide-induced cell death. Clin Cancer Res 11:3136–3148PubMedCrossRefGoogle Scholar
  110. Ohshima M, Ward JM, Wenk ML (1985) Preventive and enhancing effects of retinoids on the development of naturally occurring tumors of skin, prostate gland, and endocrine pancreas in aged male ACI/segHapBR rats. J Natl Cancer Inst 74:517–524PubMedGoogle Scholar
  111. Olson JA (1968) Some aspects of vitamin A metabolism. Vitam Horm 26:1–63PubMedCrossRefGoogle Scholar
  112. Oridate N, Suzuki S, Higuchi M et al. (1997) Involvement of reactive oxygen species in N-(4-hydroxyphenyl)retinamide-induced apoptosis in cervical carcinoma cells. J Natl Cancer Inst 89:1191–1198PubMedCrossRefGoogle Scholar
  113. Osone S, Hosoi H, Kuwahara Y et al. (2004) Fenretinide induces sustained-activation of JNK/p38 MAPK and apoptosis in a reactive oxygen species-dependent manner in neuroblastoma cells. Int J Cancer 112:219–224PubMedCrossRefGoogle Scholar
  114. Ouhayoun JP, Gosselin F, Forest N et al. (1985) Cytokeratin patterns of human oral epithelia: ­differences in cytokeratin synthesis in gingival epithelium and the adjacent alveolar mucosa. Differentiation 30:123–129PubMedCrossRefGoogle Scholar
  115. Parrella E, Gianni M, Fratelli M et al. (2006) Antitumor activity of the retinoid-related molecules (E).-3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid (ST1926) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) in F9 teratocarcinoma: Role of retinoic acid receptor gamma and retinoid-independent pathways. Mol Pharmacol 70:909–924PubMedCrossRefGoogle Scholar
  116. Pastorino U, Infante M, Maioli M et al. (1993) Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 11:1216–1222PubMedGoogle Scholar
  117. Paulson JD, Oldham JW, Preston RF et al. (1985) Lack of genotoxicity of the cancer chemopreventive agent N-(4-hydroxyphenyl).retinamide. Fundam Appl Toxicol 5:144–150PubMedCrossRefGoogle Scholar
  118. Poddar S, Hong WK, Thacher SM et al. (1991) Retinoic acid suppression of squamous ­differentiation in human head-and-neck squamous carcinoma cells. Int J Cancer 48:239–247PubMedCrossRefGoogle Scholar
  119. Ponzanelli I, Gianni M, Giavazzi R et al. (2000) Isolation and characterization of an acute promyelocytic leukemia cell line selectively resistant to the novel antileukemic and apoptogenic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid. Blood 95:2672–2682PubMedGoogle Scholar
  120. Reiss M, Pitman SW, Sartorelli AC (1985) Modulation of the terminal differentiation of human squamous carcinoma cells in vitro by all-trans-retinoic acid. J Natl Cancer Inst 74:1015–1023PubMedGoogle Scholar
  121. Rowley JD, Golomb HM, Dougherty C (1977) 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet 1:549–550PubMedCrossRefGoogle Scholar
  122. Rubin AL, Rice RH (1986) Differential regulation by retinoic acid and calcium of transglutaminases in cultured neoplastic and normal human keratinocytes. Cancer Res 46:2356–2361PubMedGoogle Scholar
  123. Sabichi AL, Hendricks DT, Bober MA et al. (1998) Retinoic acid receptor beta expression and growth inhibition of gynecologic cancer cells by the synthetic retinoid N-(4-hydroxyphenyl) retinamide. J Natl Cancer Inst 90:597–605PubMedCrossRefGoogle Scholar
  124. Schadendorf D, Kern MA, Artuc M et al. (1996) Treatment of melanoma cells with the synthetic retinoid CD437 induces apoptosis via activation of AP-1 in vitro, and causes growth inhibition in xenografts in vivo. J Cell Biol 135:1889–1898PubMedCrossRefGoogle Scholar
  125. Schroeder CP, Kadara H, Lotan D et al. (2006) Involvement of mitochondrial and Akt signaling pathways in augmented apoptosis induced by a combination of low doses of celecoxib and N-(4-hydroxyphenyl) retinamide in premalignant human bronchial epithelial cells. Cancer Res 66:9762–9770PubMedCrossRefGoogle Scholar
  126. Shao ZM, Dawson MI, Li XS et al. (1995) p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. Oncogene 11:493–504PubMedGoogle Scholar
  127. Sherman M, Multhoff G (2007) Heat shock proteins in cancer. Ann NY Acad Sci 1113:192–201PubMedCrossRefGoogle Scholar
  128. Shin DM, Gimenez IB, Lee JS et al. (1990) Expression of epidermal growth factor receptor, polyamine levels, ornithine decarboxylase activity, micronuclei, and transglutaminase I in a 7, 12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model. Cancer Res 50:2505–2510PubMedGoogle Scholar
  129. Simeone AM, Ekmekcioglu S, Broemeling LD et al. (2002) A novel mechanism by which N-(4-hydroxyphenyl)retinamide inhibits breast cancer cell growth: the production of nitric oxide. Mol Cancer Ther 1:1009–1017PubMedGoogle Scholar
  130. Sporn MB (1977) Retinoids and carcinogenesis. Nutr Rev 35:65–69PubMedCrossRefGoogle Scholar
  131. Steele VE, Kelloff GJ, Wilkinson BP et al. (1990) Inhibition of transformation in cultured rat tracheal epithelial cells by potential chemopreventive agents. Cancer Res 50:2068–2074PubMedGoogle Scholar
  132. Sun SY, Yue P, Dawson MI et al. (1997) Differential effects of synthetic nuclear retinoid receptor-selective retinoids on the growth of human non-small cell lung carcinoma cells. Cancer Res 57:4931–4939PubMedGoogle Scholar
  133. Sun SY, Li W, Yue P et al. (1999a) Mediation of N-(4-hydoxyphenyl)retinamide-induced apoptosis in human cancer cells by different mechanisms. Cancer Res 59:2493–2498PubMedGoogle Scholar
  134. Sun SY, Yue P, Lotan R (1999b) Induction of apoptosis by N-(4-hydroxyphenyl)retinamide and its association with reactive oxygen species, nuclear retinoic acid receptors, and apoptosis-related genes in human prostate carcinoma cells. Mol Pharmacol 55:403–410PubMedGoogle Scholar
  135. Sun SY, Yue P, Wu GS et al. (1999c) Implication of p53 in growth arrest and apoptosis induced by the synthetic retinoid CD437 in human lung cancer cells. Cancer Res 59:2829–2833PubMedGoogle Scholar
  136. Sun SY, Yue P, Chandraratna RA et al. (2000a) Dual mechanisms of action of the retinoid CD437: nuclear retinoic acid receptor-mediated suppression of squamous differentiation and receptor-independent induction of apoptosis in UMSCC22B human head and neck squamous cell carcinoma cells. Mol Pharmacol 58:508–514PubMedGoogle Scholar
  137. Sun SY, Yue P, Mao L et al. (2000b) Identification of receptor-selective retinoids that are potent inhibitors of the growth of human head and neck squamous cell carcinoma cells. Clin Cancer Res 6:1563–1573PubMedGoogle Scholar
  138. Sun SY, Yue P, Chen X et al. (2002) The synthetic retinoid CD437 selectively induces apoptosis in human lung cancer cells while sparing normal human lung epithelial cells. Cancer Res 62:2430–2436PubMedGoogle Scholar
  139. Sundqvist K, Liu Y, Arvidson K et al. (1991) Growth regulation of serum-free cultures of epithelial cells from normal human buccal mucosa. In Vitro Cell Dev Biol 27A:562–568PubMedCrossRefGoogle Scholar
  140. Suzuki S, Higuchi M, Proske RJ et al. (1999) Implication of mitochondria-derived reactive oxygen species, cytochrome C and caspase-3 in N-(4-hydroxyphenyl).retinamide-induced apoptosis in cervical carcinoma cells. Oncogene 18:6380–6387PubMedCrossRefGoogle Scholar
  141. Ta BM, Gallagher GT, Chakravarty R et al. (1990) Keratinocyte transglutaminase in human skin and oral mucosa: cytoplasmic localization and uncoupling of differentiation markers. J Cell Sci 95(Pt 4):631–638PubMedGoogle Scholar
  142. Tiwari M, Kumar A, Sinha RA et al. (2006) Mechanism of 4-HPR-induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress. Carcinogenesis 27:2047–2058PubMedCrossRefGoogle Scholar
  143. Valli C, Paroni G, Di Francesco AM et al. (2008) Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity. Mol Cancer Ther 7:2941–2954PubMedCrossRefGoogle Scholar
  144. Veronesi U, Decensi A (2001) Retinoids for ovarian cancer prevention: laboratory data set the stage for thoughtful clinical trials. J Natl Cancer Inst 93:486–488PubMedCrossRefGoogle Scholar
  145. Veronesi U, Mariani L, Decensi A et al. (2006) Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Ann Oncol 17:1065–1071PubMedCrossRefGoogle Scholar
  146. Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604PubMedCrossRefGoogle Scholar
  147. Wald G (1968) Molecular basis of visual excitation. Science 162:230–239PubMedCrossRefGoogle Scholar
  148. Wan H, Oridate N, Lotan D et al. (1999) Overexpression of retinoic acid receptor beta in head and neck squamous cell carcinoma cells increases their sensitivity to retinoid-induced suppression of squamous differentiation by retinoids. Cancer Res 59:3518–3526PubMedGoogle Scholar
  149. Wanner R, Henseleit-Walter U, Wittig B et al. (2002) Proliferation-dependent induction of apoptosis by the retinoid CD437 in p53-mutated keratinocytes. J Mol Med 80:61–67PubMedCrossRefGoogle Scholar
  150. Watanabe Y, Tsuchiya H, Sakabe T et al. (2008) CD437 induces apoptosis in ovarian adenocarcinoma cells via ER stress signaling. Biochem Biophys Res Commun 366:840–847PubMedCrossRefGoogle Scholar
  151. Wolbach SB, Howe PR (1925) Tissue changes following deprivation of fat-soluble A vitamin. J Experimen Med 42:753–777PubMedCrossRefGoogle Scholar
  152. Wong YC, Buck RC (1971) An electron microscopic study of metaplasia of the rat tracheal epithelium in vitamin A deficiency. Lab Investig 24:55–66PubMedGoogle Scholar
  153. Wu WS (2006) The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev 25:695–705PubMedCrossRefGoogle Scholar
  154. Wu J, Kaufman RJ (2006) From acute ER stress to physiological roles of the Unfolded Protein Response. Cell Death Differ 13:374–384PubMedCrossRefGoogle Scholar
  155. Xu XC, Ro JY, Lee JS et al. (1994) Differential expression of nuclear retinoid receptors in normal, premalignant, and malignant head and neck tissues. Cancer Res 54:3580–3587PubMedGoogle Scholar
  156. Xu XC, Sneige N, Liu X et al. (1997a) Progressive decrease in nuclear retinoic acid receptor beta messenger RNA level during breast carcinogenesis. Cancer Res 57:4992–4996PubMedGoogle Scholar
  157. Xu XC, Sozzi G, Lee JS et al. (1997b) Suppression of retinoic acid receptor beta in non-small-cell lung cancer in vivo: implications for lung cancer development. J Natl Cancer Inst 89:624–629PubMedCrossRefGoogle Scholar
  158. Xu XC, Wong WY, Goldberg L et al. (2001) Progressive decreases in nuclear retinoid receptors during skin squamous carcinogenesis. Cancer Res 61:4306–4310PubMedGoogle Scholar
  159. Yokoyama M, Nakao Y, Iwasaka T et al. (2001) Retinoic acid and interferon-alpha effects on cell growth and differentiation in cervical carcinoma cell lines. Obstet Gynecol 98:332–340PubMedCrossRefGoogle Scholar
  160. Zhang Y, Dawson MI, Mohammad R et al. (2002) Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its nonretinoidal analog. Blood 100:2917–2925PubMedCrossRefGoogle Scholar
  161. Zhao X, Demary K, Wong L et al. (2001) Retinoic acid receptor-independent mechanism of ­apoptosis of melanoma cells by the retinoid CD437 (AHPN). Cell Death Differ 8:878–886PubMedCrossRefGoogle Scholar
  162. Zou CP, Hong WK, Lotan R (1999) Expression of retinoic acid receptor beta is associated with inhibition of keratinization in human head and neck squamous carcinoma cells. Differentiation 64:123–132PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Thoracic/Head and Neck Medical OncologyUniversity of Texas, M.D. Anderson Cancer CenterHoustonUSA

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