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Spotlight on Molecular Targeted Therapy

Classical and novel retinoids: their targets in cancer therapy

Abstract

Retinoids are important mediators of cellular growth and differentiation. Retinoids modulate the growth of both normal and malignant cells through their binding to retinoid nuclear receptors and their subsequent activation. While retinoids have demonstrated therapeutic efficacy in the treatment of acute promyelocytic leukemia, their spectrum of activity remains limited. Other agents such as histone deacetylase inhibitors may significantly increase retinoid activity in a number of malignant cell types. The novel retinoids N-(4-hydroxyphenyl) retinamide (4-HPR) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437; AHPN) induce apoptosis in a wide variety of malignant cells. Their mechanism(s) of action remain unclear, although a number of potential targets have been identified. Whether the retinoid receptors are involved in 4-HPR and CD473/AHPN mediated apoptosis remains unclear. Both 4-HPR and CD437/AHPN display significant potential as therapeutic agents in the treatment of a number of premalignant and malignant conditions.

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References

  1. Boyle JO . Retinoid mechanisms and cyclins Curr Oncol Rep 2001 3: 301–305

    CAS  PubMed  Google Scholar 

  2. Dragnev KH, Rigas JR, Dmitrovsky E . The retinoids and cancer prevention mechanism Oncologist 2000 5: 361–368

    CAS  PubMed  Google Scholar 

  3. Hansen LA, Sigman CC, Andreola F, Ross SA, Kelloff GJ, DeLuca LM . Retinoids in chemoprevention and differentiation therapy Carcinogenesis 2000 21: 1271–1279

    CAS  PubMed  Google Scholar 

  4. Niles RM . Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer Nutrition 2000 16: 1084–1090

    CAS  PubMed  Google Scholar 

  5. Hong WK, Itri LM . Retinoids and human cancer. In: Sporn MB, Roberts AB, Goodman DS (eds) The Retinoids: Biology, Chemistry and Medicine Raven Press: New York 1994 579–630

    Google Scholar 

  6. Bollag W . Retinoids and interferon-α in the prevention and treatment of preneoplastic and neoplastic diseases. A review. In: Patel F (ed.) Retinoids Today and Tomorrow Mediscript: London 1995 26–31

    Google Scholar 

  7. Mangelsdorf DJ, Umesono K, Evans RM . The retinoid receptors In: Sporn MB, Roberts AB, Goodman DS (eds) The Retinoids. Biology, Chemistry and Medicine Raven Press: New York 1994 pp 319–350

    Google Scholar 

  8. Gudas LJ . Retinoids, retinoid responsive genes, cell diffferentiation and cancer Cell Growth Differ 1992 3: 655–662

    CAS  PubMed  Google Scholar 

  9. Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C . 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor Cell 1992 68: 397–406

    CAS  PubMed  Google Scholar 

  10. Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M . 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRα Nature 1992 355: 359–361

    CAS  PubMed  Google Scholar 

  11. Allegretto EZ, McClurg MR, Lazarchik SB, Clemm DL, Kerner SA, Elgort MG, Boehm MF, White SK, Pike JW, Heyman RA . Transactivation properties of retinoic acid and retinoid X receptors in mammalian cells and yeast J Biol Chem 1993 26: 625–633

    Google Scholar 

  12. Keidel S, LeMotte P, Apfel C . Different agonist- and antagonist-induced conformational changes in retinoic acid receptors analyzed by proteases mapping Mol Cell Biol 1994 14: 287–298

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Ostrowski J, Hammer L, Roalsvig T, Pokornowski K, Reczek PR . The N-terminal portion of domain E of retinoic acid receptors α and β is essential for the recognition of retinoic acid and various analogs Proc Natl Acad Sci USA 1995 92: 1812–1816

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Nagpal S, Saunders M, Kastner P, Durand B, Nakshatri H, Chambon P . Promoter content and responsive element-dependent specificity of the transcriptional activation and modulating function of the retinoic acid receptor Cell 1992 70: 1007–1119

    CAS  PubMed  Google Scholar 

  15. Boylan JF, Luftkin T, Achkar CL, Taneja R, Chambon P, Gudas LJ . Targeted disruption of retinoic acid receptor α (RARα) and RARγ results in receptor specific alternations in retinoic acid mediated differentiation and retinoic acid metabolism Mol Cell Biol 1995 15: 843–851

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Boylan JF, Lohnes D, Taneja R, Chambon P, Gudas LJ . Loss of retinoic acid receptor γ function in F9 cells by gene disruption in aberrant Hux 1 expression and differentiation upon retinoic acid treatment Proc Natl Acad Sci USA 1993 90: 9061–9065

    Google Scholar 

  17. Dawson MI, Zhang X, Hobbs PD, Jong L . Synthetic retinoids and their usefulness in biology and medicine. In: MA Livera (ed.) Vitamin A and Retinoids: an Update of Biological Aspects and Clinical Applications Birkhauser Verlag: Basel 2000 161–196

    Google Scholar 

  18. Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM . Nuclear receptor that identifies a novel retinoic acid response pathway Nature 1990 345: 224–229

    CAS  PubMed  Google Scholar 

  19. Kagechika H, Kawachi E, Hashimoto Y, Himi T, Shudo K . Retinobenzoic acids 1 structure-activity relationships of aromatic amides with retinoidal activity J Med Chem 1988 31: 2182–2192

    CAS  PubMed  Google Scholar 

  20. Roy B, Taneja R, Chambon P . Synergistic activation of retinoic acid (RA)-responsive genes and induction of embryonal carcinoma cell differentiation by an RA receptor α (RARα)-, RARβ- or RARγ-selective ligand in combination with a retinoid X receptor specific ligand Mol Cell Biol 1995 15: 6481–6487

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Husmann M, Lehmann J, Hoffman B, Herman T, Tzukerman M, Pfahl M . Antagonism between retinoic acid receptors Mol Cell Biol 1991 11: 4097–4103

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Hembree JR, Agarwal C, Beard RL, Chandraratna RAS, Eckert RL . Retinoid X receptor-specific retinoids inhibit the ability of retinoic acid receptor specific retinoids to increase the level of insulin-like growth factor binding protein-3 in human ectocervical epithelial cells Cancer Res 1996 56: 1794–1799

    CAS  PubMed  Google Scholar 

  23. Kamei Y, Xu L, Heizel T, Torchia J, Kurokawa R, Gloss B, Lin S-C, Heyman RA, Rose DW, Glass CK, Rosenfeld MG . A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors Cell 1996 85: 403–414

    CAS  PubMed  Google Scholar 

  24. Chakravarti D, La Morte VJ, Nelson MC, Nakajima T, Schulman IG, Juguilon H, Montminy M, Evans RM . Role of CBP/300 in nuclear receptor signalling Nature 1996 383: 99–103

    CAS  PubMed  Google Scholar 

  25. Newton DL, Henderson WR, Sporn MB . Structure–activity relationships of retinoids in hamster tracheal organ culture Cancer Res 1980 40: 3413–3425

    CAS  PubMed  Google Scholar 

  26. Graupner G, Malle G, Maignan J, Lang G, Prunieras M, Pfahl M . 6′–Substituted naphthalene–2–carboxylic acid analogs, a new class of retinoic acid subtype–specific ligands Biochem Biophys Res Commun 1991 179: 1554–1561

    CAS  PubMed  Google Scholar 

  27. Bernard BA, Bernardon J-M, Deleiscluse C, Martin B, Lenoir M-C, Maignan J, Charpentier B, Pilgrim WR, Reichert U, Shroot B . Identification of synthetic retinoids with selectivity for human nuclear retinoic receptor γ Biochem Biophys Res Commun 1992 186: 977–983

    CAS  PubMed  Google Scholar 

  28. Yu K-L, Ostrowski J, Chen S, Tramposch KM, Reczek PR, Mansuri MM, Starrett JE . Structural modifications of 6–naphthalene–2–carboxylate retinoids Bioorg Med Chem Lett 1996 6: 2865–2870

    CAS  Google Scholar 

  29. Lehmann JM, Jong L, Fanjul A, Cameron JF, Lu XP, Haefner P, Dawson MI, Pfahl M . Retinoid selective for retinoid X receptor response pathways Science 1992 258: 1944–1946

    CAS  PubMed  Google Scholar 

  30. Dawson MI, Jong L, Hobbs PD, Cameron JF, Chao W, Pfahl M, Lee M-O, Shroot B, Pfahl M . Conformational effects on retinoid receptor selectivity 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity J Med Chem 1995 38: 3368–3383

    CAS  PubMed  Google Scholar 

  31. Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA . Synthesis and structure activity relationships of novel retinoid X receptor-selective retinoids J Med Chem 1994 37: 2930–2941

    CAS  PubMed  Google Scholar 

  32. Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhao L, Gu LJ, Wang ZY . Use of all-trans retinoic acid in the treatment of acute leukemias Blood 1988 72: 567–572

    CAS  PubMed  Google Scholar 

  33. Warrell RP, Frankel SR, Miller WH Jr, Scheinberg DA, Itri L, Hittelman WN, Vyas R, Andreef M, Tafuri A, Jakubowski A . Differentiation therapy of acute promyelocytic leukemia with tretinoin (all trans retinoic acid) N Engl J Med 1991 324: 1385–1392

    PubMed  Google Scholar 

  34. Chen Z-X, Xue Y-Q, Zhang R, Tao RF, Xia XM, Li C, Wang W, Zu WY, Yao XZ, Lin BJ . A clinical and experimental study on all trans retinoic acid-treated acute promyelocytic leukemia patients Blood 1991 78: 1413–1419

    CAS  PubMed  Google Scholar 

  35. Frankel SR, Eardley A, Heller G, Berman E, Miller WH Jr, Dimitrovsky F, Warrell RP Jr . All trans retinoic acid for promyelocytic leukemia-results of the New York study Ann Intern Med 1994 120: 278–286

    CAS  PubMed  Google Scholar 

  36. Miller W Jr, Jakubowski A, Tong W, Miller VA, Rigas JR, Bendetti F, Gill GM, Truglia JA, Ulm E, Shirley M, Warrell RP Jr . 9-cis retinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia Blood 1995 85: 3021–3027

    CAS  PubMed  Google Scholar 

  37. De The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A . The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR Cell 1991 66: 675–684

    CAS  PubMed  Google Scholar 

  38. Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM . Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML Cell 1991 66: 663–674

    CAS  PubMed  Google Scholar 

  39. Collins SJ, Robertson KA, Mueller L . Retinoic acid induced granulocytic differentiation of HL-60 myeloid leukemia cells is mediated through the retinoic acid receptor (RARα) Mol Cell Biol 1990 10: 2154–2163

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Onodera M, Kunisada T, Nishikawa S, Sakiyama Y, Matsumoto S, Nishikawa S . Over expression of retinoic acid receptor α suppresses myeloid cell differentiation at the promyelocyte stage Oncogene 1995 11: 1291–1298

    CAS  PubMed  Google Scholar 

  41. Tsai S, Collins SJ . A dominant negative retinoic acid receptor blocks neutrophil differentiation at the promyelocyte stage Proc Natl Acad Sci USA 1993 90: 7153–7157

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kastner P, Chan S . Function of RAR alpha during maturation of neutrophils Oncogene 2001 20: 7178–7185

    CAS  PubMed  Google Scholar 

  43. Lin RJ, Sternsdorf T, Tini M, Evans RM . Transcriptional regulation in acute promyelocytic leukemia Oncogene 2001 20: 7204–7215

    CAS  PubMed  Google Scholar 

  44. Kastner P, Lawrence HJ, Waltzinger C, Ghyseliack N, Chambon P, Chan S . Positive and negative regulation of granulopoiesis by endogenous RAR alpha Blood 2001 97: 1314–1320

    CAS  PubMed  Google Scholar 

  45. Melnick A, Licht JD . Deconstructing a disease: RARα, its fusion partners and their roles in the pathogenesis of acute promyelocytic leukemia Blood 1999 93: 3167–3215

    CAS  PubMed  Google Scholar 

  46. Slack JL, Gallagher RE . The molecular biology of acute promyelocytic leukemia Cancer Treat Res 1999 9: 75–124

    Google Scholar 

  47. Rousselot P, Hardas B, Patel A, Guidez F, Gaken J, Castaigne S, Dejean A, de The H, Degos L, Farzaneh F . The PML-RARα gene product of the t(15;17) translocation inhibits retinoic acid-induced granulocytic differentiation and mediated transactivation in human myeloid cells Oncogene 1994 9: 545–551

    CAS  PubMed  Google Scholar 

  48. Early E, Moore MAS, Kakizuka A, Nason-Burchenal K, Martin P, Evans RM, Dimitrovsky E . Transgenic expression of PML/RARα impairs myelopoiesis Proc Natl Acad Sci USA 1996 93: 7900–7904

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub M, Durand B, Lanotte M, Berger R, Chambon P . Structure, localization and transcriptional properties of two classes of retinoic acid receptor α fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins EMBO J 1992 11: 629–642

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Doucas V, Brocues JP, Yaniv M, de The H, Dejean A . The PML-retinoic acid receptor α translocation converts the receptor from an inhibitor to a retinoic acid-dependent activator of transcription factor AP-1 Proc Natl Acad Sci USA 1993 90: 9345–9349

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Dyck JA, Maul GG, Miller WH Jr, Chen JD, Kazikuka A, Evans RM . A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein Cell 1994 76: 333–343

    CAS  PubMed  Google Scholar 

  52. Weiss K, Rambaud S, Lavau K, Jansen J, Carvalho T, Carmo-Fonseca M, Lamond A, Dejean A . Retinoic acid regulates aberrant nuclear localization of PML-RARα in acute promyelocytic leukemia cells Cell 1994 76: 345–346

    Google Scholar 

  53. Gianni M, Tera M, Fortino I, LiCalzi M, Viggiano M, Barbui T, Rambaldi A, Garattini E . STAT 1 is induced and activated by all-trans retinoic acid and in acute promyelocytic leukemia cells Blood 1997 89: 1001–1012

    CAS  PubMed  Google Scholar 

  54. Lin RJ, Evans RM . Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia though formation of homodimers Mol Cell 2001 5: 821–830

    Google Scholar 

  55. Minucci S, Maccarana M, Cioce M, De Luca P, Gelmetti V, Segalla S, Di Groce L, Giavara S, Matteucci C, Gobbi A, Colombo E, Schiavoni I, Badaracca G, Hu X, Lazar MA, Landsberger N, Nervi C, Pelicci PG . Oligomerization of RAR and AML 1 transcription factors as anovel mecahism of oncogene activation Mol Cell 2000 5: 811–820

    CAS  PubMed  Google Scholar 

  56. Cheng GX, Zu XH, Men XQ, Wang L, Huang QH, Jin XL, Xiong SM, Guo WM, Chen JQ, Xu SF, So E, Chan LC, Waxman S, Zelent A, Chen GQ, Dong S, Liu JX, Chen SJ . Distinct leukemia prototypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RAR alpha and NPM-RAR alpha Proc Natl Acad Sci USA 1999 96: 6318–6323

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ferrara FF, Fazi F, Bianchini A, Padula F, Gelmetti V, Minucci S, Mancini M, Pellicci G, LoCoco F, Nervi C . Histone deacetylase-targeted treatment restores retinoic acid signalling and differentiation in acute leukemia Cancer Res 2001 61: 2–7

    PubMed  Google Scholar 

  58. He LZ, Tolentino T, Grayson P, Zhang S, Warrell RP Jr, Rifkind RA, Richon VM, Pandolfi PP . Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia J Clin Invest 2001 108: 1321–1330

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Pili R, Kruszewski MP, Hager BW, Lantz J, Carducci MA . Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis Cancer Res 2001 61: 1477–1485

    CAS  PubMed  Google Scholar 

  60. Castaigne S, Chomienne C, Daniel MT, Balerini P, Berger R, Fenaux P, Degos L . All trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia patients Blood 1990 76: 1704–1709

    CAS  PubMed  Google Scholar 

  61. Degos L, Dombret H, Chomieene C, Daniel M-T, Michlea J-M, Chastang C, Castaigne S, Fenaux P . All-trans retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia Blood 1995 85: 2643–2653

    CAS  PubMed  Google Scholar 

  62. Muindi J, Frankel S, Huselton C, Degrazia F, Garland WA, Young CW, Warrell RP Jr . Clinical pharmacology of oral all trans retinoic acid with acute promyelocytic leukemia Cancer Res 1992 52: 2138–2142

    CAS  PubMed  Google Scholar 

  63. Muindi J, Young C . Lipid hydroperoxides greatly increase the rate of oxidative catabolism of all-trans-retinoic acid by human microsomes generically enriched in specified cytochrome p450 isoforms Cancer Res 1993 53: 1226–1229

    CAS  PubMed  Google Scholar 

  64. Zhou DC, Hallam SJ, Lee SJ, Klein RS, Wiernik PH, Tallman MS, Gallagher RE . Constitutive expression of cellular retinoic acid binding protein II and lack of correlation with sensitivity to all trans retinoic acid in acute promyelocytic leukemia cells Cancer Res 1998 58: 5770–5776

    CAS  PubMed  Google Scholar 

  65. Delva L, Cornic M, Balitrand N, Guidez F, Miclea JM, Delmer A, Teillet F, Fenaux P, Castaigne S, Degos L . Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: a study of in vitro sensitivity and cellular retinoic acid binding protein levels in leukemia cells Blood 1993 82: 2175–2181

    CAS  PubMed  Google Scholar 

  66. Cornic M, Delva L, Guidez F, Balitrand N, Degos W, Chomienne C . Induction of retinoic acid-binding protein in normal and malignant human myeloid cells by retinoic acid in acute promyelocytic leukemia patients Cancer Res 1992 52: 3329–3334

    CAS  PubMed  Google Scholar 

  67. Degos L, Dombret H, Chomienne C, Daniel MT, Miclea JM, Chastang C, Castaigne S, Fenaux P . All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia Blood 1995 85: 2643–2653

    CAS  PubMed  Google Scholar 

  68. Delva L, Cornic M, Balitrand N, Guidez F, Michlea JM, Delmer A, Teillet F, Fenaux P, Castaigne S, Degos L . Resistance to all trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells Blood 1993 82: 75–81

    Google Scholar 

  69. Visani G, Buonamici S, Malagola M, Isidori A, Piccaluga PP, Martinelli G, Ottaviani E, Grafone T, Baccarani M, Tura S . Pulsed ATRA as a single therapy restores long term remission in PML-RAR alpha positive acute promyelocytic leukemia patients: real time quantification of minimal residual disease. A pilot study Leukemia 2001 15: 1696–1700

    CAS  PubMed  Google Scholar 

  70. Ding W, Li YP, Nobile LM, Grills G, Carrera I, Paietta E, Tallman MS, Wiernik PH, Gallagher RE . Leukemic cellular retinoic acid resistance and missense mutations in the PML-RARα fusion gene after relapse of acute promyelocytic leukemia from treatment with all-trans retinoic acid and intensive chemotherapy Blood 1998 92: 1172–1183

    CAS  PubMed  Google Scholar 

  71. Delia D, Aiello A, Lombardi L, Pelicci PG, Gringnani F, Grignani F, Formelli F, Menard S, Costa A, Veronesi U, Aerotti MA . N-(4-hydroxyphenyl) retinamide induces apoptosis of malignant cell lines including those unresponsive to retinoic acid Cancer Res 1993 53: 6036–6041

    CAS  PubMed  Google Scholar 

  72. Dermine S, Grignani F, Clerici M, Nervi C, Sozzi G, Talamo GP, Marchesi E, Formelli F, Parmiani G, Pellici PG, Gambacorti-Passerini C . The occurrence of resistance to retinoic acid in the acute promyelocytic leukemia cell line NB306 is associated with altered expression of pml/RAR protein Blood 1993 82: 1573–1577

    Google Scholar 

  73. Sheikh MS, Shao ZM, Li XS, Ordonez JV, Conley BA, Wu S, Dawson MI, Han QX, Chao WR, Quick T, Niles RM, Fontana JA . N-(4-hydroxyphenyl) retinamide (4-HPR)-mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma Carcinogenesis 1995 16: 2477–2486

    CAS  PubMed  Google Scholar 

  74. Fanjul AN, Delia D, Pierotti MA, Rideout D, Yu JQ, Pfahl M, Yu J . 4-hydroxyphenyl retinamide is a highly selective activator of retinoid receptors J Biol Chem 1996 271: 22441–22446

    CAS  PubMed  Google Scholar 

  75. Swisshelm K, Ryan K, Lee X, Tsou HC, Peacocke M, Sager R . Down-regulation of retinoic acid receptor beta in mammary carcinoma cell lines and its up-regulation in senesing normal mammary epithelial cells Cell Growth Diff 1994 5: 133–141

    CAS  PubMed  Google Scholar 

  76. Sabichi Al, Hendricks DT, Bober MA, Birrer MJ . Retinoic acid beta expression and growth inhibition of gynecological cancer cells by the synthetic retinoid N-(4-hydroxyphenyl) retinamide J Natl Cancer Inst 1998 90: 597–605

    CAS  PubMed  Google Scholar 

  77. Liu G, Wu M, Leui G, Ferrari N . 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 1998 78: 248–54

    CAS  PubMed  Google Scholar 

  78. Supino R, Crosti M, Clerici M, Wariters A, Cleris L, Zunino F, Formell F . Induction of apoptosis by fenretinide (4HPR) in human ovarian carcinoma cells and its association with retinoic acid receptor expression Int J Cancer 1996 65: 491–497

    CAS  PubMed  Google Scholar 

  79. Clifford JL, Menter DG, Wang M, Lotan R, Lippman SM . Retinoid receptor-dependent and -independent effects of N-(4-hydroxyphenyl) retinamide in F9 embryonal carcinoma cells Cancer Res 1999 59: 14–18

    CAS  PubMed  Google Scholar 

  80. Sun SY, Yue P, Lotan R . 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 1999 55: 403–410

    CAS  PubMed  Google Scholar 

  81. Sun SY, Li W, Yue P, Lippman SM, Hong WK, Lotan R . Mediation of N-(4-hydroxyphenyl) retinamide-induced apoptosis in human cancer cells by different mechanisms Cancer Res 1999 59: 2493–2498

    CAS  PubMed  Google Scholar 

  82. Lovat PE, Ranalli M, Annichiarrico-Petruzzelli M, Bernassola F, Placentini M, Malcolm AJ, Pearson AD, Melino G, Redfern CP . Effector mechanisms of fenretinide-induced apoptosis in neuroblastoma Exp Cell Res 2000 260: 50–60

    CAS  PubMed  Google Scholar 

  83. Oridate N, Suzuki S, Higuchi M, Mitchell MF, Hong WK, Lotan R . Involvement of reactive oxygen species in N-(4-hydroxyphenyl) retinamide-induced apoptosis in cervical carcinoma cells J Natl Cancer Inst 1997 89: 1119–1181

    Google Scholar 

  84. Delia D, Aiello A, Meroni L, Nicolini M, Reed JC, Pierotti MA . Role of antioxidants and intracellular free radicals in retinamide-induced cell death Carcinogenesis 1997 18: 943–948

    CAS  PubMed  Google Scholar 

  85. Suzuki S, Higuchi M, Proske RJ, Oridate N, Hong WK, Lotan R . Implication of mitochondria-derived reactive oxygen species, cytochrome C and caspase 3 in N-(4-hydroxyphenyl) retinamide-induced apoptosis in cervical carcinoma cells Oncogene 1999 18: 6380–6387

    CAS  PubMed  Google Scholar 

  86. Bednarik A, Shilkaitis A, Green A, Lubet R, Kelloff G, Chistov K, Aldaz CM . Suppression of cell proliferation and telomerase activity in 4-(hydroxyphenyl) retinamide-treated mammary tumors Carcinogenesis 1999 20: 879–883

    Google Scholar 

  87. Delia D, Aiello A, Formelli F, Fontanella E, Costa A, Miyashita T, Reed JC, Pierotti A . Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2 Blood 1995 85: 359–367

    CAS  PubMed  Google Scholar 

  88. Panigone S, Debernardi S, Taya Y, Fontanella E, Airoldi R, Delia D . pRb and Cdk regulation by N-(4-hydroxyphenyl) retinamide Oncogene 2000 19: 4035–4041

    CAS  PubMed  Google Scholar 

  89. Dipietrantanio A, Hsieh TC, Wu JM . Differential effects of retinoic acid (RA) and N-(4-hydroxyphenyl) retinamide (4-HPR) on cell growth, induction of differentiation and changes in p34 cdc 2, Bcl-2, and actin expression in the human promyelocytic HL-60 leukemia cells Biochem Biophys Res Commun 1996 224: 837–42

    Google Scholar 

  90. Camerini T, Marian L, DePalo G, Marubini E, Mauro MG, Decensi A, Costa A, Veronisi V . Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer J Clin Oncol 2001 19: 1664–1670

    CAS  PubMed  Google Scholar 

  91. Torrisi R, Decensi A . Fenretinide and cancer prevention Curr Oncol Rep 2000 2: 262–270

    Google Scholar 

  92. Chiesa F, Tradati N, Marazza M, Ross N, Boracchi P, Mariani L, Clerici M, Formelli F, Barzon A, Carrassi A, Pastorini A, Camerini T, Giardini R, Zurrida S, Minn FL, Costa A, DePalo G, Veronesi U . Prevention of local relapses and new localisations of oral leukoplakias with the synthetic retinoid fenretinide (4-HPR). Preliminary results Oral Oncol Eur J Cancer 1992 28B: 97–102

    CAS  Google Scholar 

  93. Chao W, Hobbs PD, Long L, Zhang X, Zheng Y, Wu Q, Shroot B, Dawson MI . Effects of receptor class and subtype: selective retinoids and an apoptosis inducing retinoid on the adherent growth of the NIH: OVCAR-3 ovarian cancer cell line in culture Cancer Lett 1997 113: 1–7

    Google Scholar 

  94. Shao Z-M, Dawson MI, Li X-S, Rishi AK, Sheikh MS, Han QX, Ordonez JV, Shroot B, Fontana JA . P53 independent G1/G0 arrest and apoptosis induced by a novel retinoid in human breast cancer cells Oncogene 1995 11: 493–504

    CAS  PubMed  Google Scholar 

  95. Robertson KA, Emami B, Collins SJ . Retinoic acid resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand-binding domain that confers dominant negative activity Blood 1997 89: 4470–4478

    Google Scholar 

  96. Sun SY, Yue P, Shroot B, Hong WK, Lotan R . Induction of apoptosis in human non-small cell lung carcinoma cells by the novel synthetic retinoid CD437 J Cell Physiol 1997 173: 279–284

    CAS  PubMed  Google Scholar 

  97. Sun SY, Kurie JM, Yue P, Dawson MI, Shroot B, Chandraratha RA, Hong WK, Lotan R . Differential responses of normal, premalignant and malignant bronchial epithelial cells to receptor selective retinoids Clin Cancer Res 1999 5: 431–437

    CAS  PubMed  Google Scholar 

  98. Sun SY, Yue P, Chandraratna RA, Tesfaigzi Y, Hong WK, Lotan R . Dual mechanisms of action of the retinoid CD437: nuclear retinoic acid receptor-mediated suppression of squamous differentiation and receptor-independent apoptosis in UMSCC2B human head and neck squamous cell carcinoma cells Mol Pharmacol 2000 58: 508–514

    CAS  PubMed  Google Scholar 

  99. Holmes WF, Dawson MI, Soprano RD, Soprano KJ . Induction of apoptosis in ovarian carcinoma cells by AHPN/CD437 is mediated by retinoic acid receptors J Cell Physiol 2000 183: 61–67

    Google Scholar 

  100. Zhang Y, Huang Y, Rishi AK, Sheikh MS, Shroot B, Reichert U, Dawson MI, Poirer G, Fontana JA . Activation of the p38 and JNK/SAPK mitogen-activated protein kinase pathways during apoptosis is mediated by a novel retinoid Exp Cell Res 1999 247: 233–240

    CAS  PubMed  Google Scholar 

  101. Li XS, Rishi AK, Shao ZM, Dawson MI, Jong L, Shroot B, Reichert U, Ordonez J, Fontana JA . Posttranscriptional regulation of p21 WAF1/CIP1 expression in human breast carcinoma cells Cancer Res 1996 56: 5055–62

    CAS  PubMed  Google Scholar 

  102. Liang JY, Fontana JA, Rao JN, Ordonez JV, Dawson MI, Shroot B, Wilber JF, Feng P . Synthetic retinoid CD437 induces S-phase arrest and apoptosis in human prostate cancer cells LNCaP and PC-3 Prostate 1999 38: 228–236

    CAS  PubMed  Google Scholar 

  103. Zhang Y, Rishi AK, Dawson MI, Tschang R, Farhana L, Boyanapalli M, Reichert U, Shroot B, Van Buren EC, Fontana JA . S-phase arrest and apoptosis in normal mammary epithelial cells by a novel retinoid Cancer Res 2000 60: 2025–2032

    CAS  PubMed  Google Scholar 

  104. Krek W, Xu G, Livingston D . Cyclin A-kinase regulation of E2F-1 DNA binding function underlines suppression of an S phase checkpoint Cell 1995 83: 1149–1158

    CAS  PubMed  Google Scholar 

  105. Almasan A, Yin Y, Kelley RE, Lee EY-H, Bradley A, Li W, Bertino JR, Wahl GM . Deficiency of retinoblastoma protein leads to inappropriate S phase entry, activation of E2F-responsive genes and apoptosis Proc Natl Acad Sci USA 1995 92: 5436–5440

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Hsiek J-K, Fredersdorf S, Kouzarides T, Martin K, Lu X . E2F-1 induced apoptosis requires DNA binding but not transactivation and is inhibited by retinoblastoma protein through direct interaction Genes Dev 1997 11: 1840–1852

    Google Scholar 

  107. Sun SY, Yue P, Wu GS, El-Deiry WS, Shroot B, Hong WK, Lotan R . Implication of p53 in growth arrest and apoptosis induced by the synthetic retinoid CD437 in human lung cancer cells Cancer Res 1999 59: 2829–2833

    CAS  PubMed  Google Scholar 

  108. Sun SY, Yue P, Hong WK, Lotan R . Augmentation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the synthetic retinoid G-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) through up-regulation of trail receptors in human lung cancer cells Cancer Res 2000 60: 7149–7155

    CAS  PubMed  Google Scholar 

  109. Sun SY, Yue P, Hong WK, Lotan R . Induction of Fas expression and augmentation of Fas/Fas ligand-mediated apoptosis by the synthetic retinoid CD437 in human lung cancer cells Cancer Res 2000 60: 6537–6543

    CAS  PubMed  Google Scholar 

  110. Sun SY, Yue P, Lotan R . Implication of multiple mechanisms in apoptosis induced by the synthetic retinoid CD437 in human prostate carcinoma cells Oncogene 2000 19: 4513–4522

    CAS  PubMed  Google Scholar 

  111. Li Y, Lin B, Agadir B, Liu R, Dawson MI, Reed JC, Fontana JA, Bost F, Hobbs PD, Zheng Y, Chen GQ, Shroot B, Mercola D, Zhang XK . Molecular determinants of AHPN (CD437)-induced growth arrest and apoptosis in human lung cancer cell lines Mol Cell Biol 1998 18: 4719–4731

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Marchetti P, Zamzami P, Joseph B, Schraen-Maschke S, Mereau-Richard C, Costantini P, Metivier D, Susin SA, Kroemer G, Formstecher P . The novel retinoid 6-[3-(1adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid can trigger apoptosis through a mitochondrial pathway independent of the nucleus Cancer Res 1999 59: 6257–6266

    CAS  PubMed  Google Scholar 

  113. Zhang Y, Beard RL, Chadraratna RAS, Kang JX . Evidence of lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia cells Cell Death Diff 2001 8: 477–485

    Google Scholar 

  114. Hsu CA, Rishi AK, Su-Li X, Gerald TM, Dawson MI, Schiffer C, Reichert U, Shroot B, Poirer GC, Fontana JA . Retinoid induced apoptosis through a retinoic acid nuclear receptor independent pathway Blood 1997 89: 4470–4479

    CAS  PubMed  Google Scholar 

  115. Fontana JA, Dawson MI, Lied M, Rishi AK, Zhang Y, Hsu CA, Lu JS, Peterson VJ, Jong L, Hobbs P, Chao W-R, Shoot B, Reichert U . Identification of a unique binding protein specific for a novel retinoid inducing cellular apoptosis Int J Cancer 2000 86: 474–479

    CAS  PubMed  Google Scholar 

  116. Schadendorf D, Kern M, Artuc M, Pahl H, Rosenbach T, Fichtner I, Nurnberg W, Stuting S, Stebut V, Worm M, Makki A, Jurgovsky K, Kolde G, Henz BM . 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 1996 135: 1889–1898

    CAS  PubMed  Google Scholar 

  117. Langdon SP, Rabiasz GJ, Ritchie AA, Reichert U, Buchan P, Miller WR, Smyth JF . Growth-inhibitory effects of the synthetic retinoid CD437 against ovarian carcinoma models in vitro and in vivo Cancer Chemother Pharmacol 1998 42: 429–432

    CAS  PubMed  Google Scholar 

  118. Lu X-P, Fanjul A, Picard N, Rungta D, Nared-Hood K, Carter B, Piedrafita J, Tang S, Fabbrizio E, Pfahl M . Novel retinoid-related molecules as apoptosis inducers and effective inhibitors of human lung cancer cells in vivo Nature Med 1997 3: 686–690

    CAS  PubMed  Google Scholar 

  119. Fanjul AN, Piedrafita J, Al-Shamma H, Pfahl M . Apoptosis induction and potent antiestrogen receptor-negative activity in vivo by a retinoid antagonist Cancer Res 1998 58: 4607–4610

    CAS  PubMed  Google Scholar 

  120. Ponzanelli I, Gianni M, Giavazzi R, Garofalo A, Nicoletti I, Reichert U, Erba E, Rambaldi A, Terao T, Garattini E . 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 2000 95: 2672–2682

    CAS  PubMed  Google Scholar 

  121. Dawson MI, Hobbs PD, Peterson VJ, Leid M, Lange CW, Feng K-C, Chen Q-Q, Gu J, Li H, Kolluri K, Zhang X-Z, Zhang Y, Fontana JA . Apoptosis induction in cancer cells by a novel analog of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid lacking retinoid transcriptional activity Cancer Res 2001 61: 4723–4730

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a NIH PO1 grant CA 51993 (JAF, AKR), merit review grant from the medical research services of the Department of Veterans Affairs (JAF, AKR) and a grant from the Leukemia and Lymphoma Society of America (JAF). We thank Bill Browning for his expert assistance in preparing the illustrations and Donna Bennett for expert preparation of the manuscript.

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Fontana, J., Rishi, A. Classical and novel retinoids: their targets in cancer therapy. Leukemia 16, 463–472 (2002). https://doi.org/10.1038/sj.leu.2402414

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