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Panobinostat

Description of Panobinostat: Panobinostat is a cinnamic hydroxamic acid analogue with potential antineoplastic activity. Panobinostat selectively inhibits histone deacetylase (HDAC), inducing hyperacetylation of core histone proteins, which may result in modulation of cell cycle protein expression, cell cycle arrest in the G2/M phase and apoptosis. In addition, this agent appears to modulate the expression of angiogenesis-related genes, such as hypoxia-inducible factor-1alpha (HIF-1a) and vascular endothelial growth factor (VEGF), thus impairing endothelial cell chemotaxis and invasion. HDAC is an enzyme that deacetylates chromatin histone proteins. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

Current developer:  Novartis Oncology.

Panobinostat (LBH-589) is an experimental drug developed by Novartis for the treatment of cancer. As of December 2008[update], it is being tested against cutaneous T cell lymphoma (CTCL), chronic myelogenous leukemia, myelodysplastic syndromes, breast cancer, prostate cancer and other types of malignant disease in a number of Phase II and III clinical trials, for example a Phase III study for CTCL.

Panobinostat has been found to synergistically act with sirolimus to kill pancreatic cancer cells in the laboratory in a Mayo Clinic study. In the study, investigators found that this combination destroyed up to 65 percent of cultured pancreatic tumor cells. The finding is significant because the three cell lines studies were all resistant to the effects of chemotherapy – as are many pancreatic tumors. see http://en.wikipedia.org/wiki/Panobinostat.  

  1: Roccaro AM, Sacco A, Jia X, Azab AK, Maiso P, Ngo HT, Azab F, Runnels J, Quang P, Ghobrial IM. microRNA-dependent modulation of histone acetylationin Waldenstrom macroglobulinemia. Blood. 2010 Jun 2. [Epub ahead of print] PubMed PMID: 20519629.

2: Buchwald M, Pietschmann K, Müller JP, Böhmer FD, Heinzel T, Krämer OH. Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradation. Leukemia. 2010 May 27. [Epub ahead of print] PubMed PMID: 20508617.

3: Kauh J, Fan S, Xia M, Yue P, Yang L, Khuri FR, Sun SY. c-FLIP degradation mediates sensitization of pancreatic cancer cells to TRAIL-induced apoptosis by the histone deacetylase inhibitor LBH589. PLoS One. 2010 Apr 28;5(4):e10376. PubMed PMID: 20442774; PubMed Central PMCID: PMC2860986.

4: Storch K, Eke I, Borgmann K, Krause M, Richter C, Becker K, Schröck E, Cordes N. Three-dimensional cell growth confers radioresistance by chromatin density modification. Cancer Res. 2010 May 15;70(10):3925-34. Epub 2010 May 4. PubMed PMID: 20442295.

5: Schmitt S, Ho AD, Goldschmidt H. The oral histone deacetylase inhibitor LBH589 is a potential and promising therapeutic agent in multiple myeloma after at least two lines of chemotherapy including bortezomib or lenalidomide. Onkologie. 2010;33(4):183-6. Epub 2010 Mar 19. PubMed PMID: 20389145.

6: Rao R, Nalluri S, Kolhe R, Yang Y, Fiskus W, Chen J, Ha K, Buckley KM, Balusu R, Coothankandaswamy V, Joshi A, Atadja P, Bhalla KN. Treatment with panobinostat induces glucose-regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells. Mol Cancer Ther. 2010 Apr;9(4):942-52. Epub 2010 Apr 6. PubMed PMID: 20371724.

7: Rathkopf D, Wong BY, Ross RW, Anand A, Tanaka E, Woo MM, Hu J, Dzik-Jurasz A, Yang W, Scher HI. A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol. 2010 May;66(1):181-9. Epub 2010 Mar 9. PubMed PMID: 20217089.

8: Fortunati N, Catalano MG, Marano F, Mugoni V, Pugliese M, Bosco O, Mainini F, Boccuzzi G. The pan-DAC inhibitor LBH589 is a multi-functional agent in breast cancer cells: cytotoxic drug and inducer of sodium-iodide symporter (NIS). Breast Cancer Res Treat. 2010 Mar 9. [Epub ahead of print] PubMed PMID: 20213084.

9: Di Fazio P, Schneider-Stock R, Neureiter D, Okamoto K, Wissniowski T, Gahr S, Quint K, Meissnitzer M, Alinger B, Montalbano R, Sass G, Hohenstein B, Hahn EG, Ocker M. The pan-deacetylase inhibitor panobinostat inhibits growth of hepatocellular carcinoma models by alternative pathways of apoptosis. Cell Oncol. 2010 Jan 1;32(4):285-300. PubMed PMID: 20208142.

10: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Dec;31(10):661-700. PubMed PMID: 20140276.

11: Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol. 2010 Feb 4;3:5. Review. PubMed PMID: 20132536; PubMed Central PMCID: PMC2827364.

12: Shao W, Growney JD, Feng Y, O'Connor G, Pu M, Zhu W, Yao YM, Kwon P, Fawell S, Atadja P. Activity of deacetylase inhibitor panobinostat (LBH589) in cutaneous T-cell lymphoma models: Defining molecular mechanisms of resistance. Int J Cancer. 2010 Feb 2. [Epub ahead of print] PubMed PMID: 20127862.

13: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Nov;31(9):597-633. PubMed PMID: 20094643.

14: De Bruyne E, Bos TJ, Schuit F, Van Valckenborgh E, Menu E, Thorrez L, Atadja P, Jernberg-Wiklund H, Vanderkerken K. IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms. Blood. 2010 Mar 25;115(12):2430-40. Epub 2010 Jan 19. PubMed PMID: 20086250.

15: Sayan BS, Yang AL, Conforti F, Bernardini S, Tucci P, Vasa-Nicotera M, Knight RA, Melino G. Induction of TAp63 by histone deacetylase inhibitors. Biochem Biophys Res Commun. 2010 Jan 22;391(4):1748-51. Epub 2009 Dec 30. PubMed PMID: 20043870.

16: Giommarelli C, Zuco V, Favini E, Pisano C, Dal Piaz F, De Tommasi N, Zunino F. The enhancement of antiproliferative and proapoptotic activity of HDAC inhibitors by curcumin is mediated by Hsp90 inhibition. Cell Mol Life Sci. 2010 Mar;67(6):995-1004. Epub 2009 Dec 29. PubMed PMID: 20039095.

17: Kaiser M, Lamottke B, Mieth M, Jensen MR, Quadt C, Garcia-Echeverria C, Atadja P, Heider U, von Metzler I, Türkmen S, Sezer O. Synergistic action of the novel HSP90 inhibitor NVP-AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma. Eur J Haematol. 2010 Apr;84(4):337-44. Epub 2009 Dec 17. PubMed PMID: 20028416.

18: Younes A. Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program. 2009:507-19. Review. PubMed PMID: 20008236.

19: Ocio EM, Vilanova D, Atadja P, Maiso P, Crusoe E, Fernández-Lázaro D, Garayoa M, San-Segundo L, Hernández-Iglesias T, de Alava E, Shao W, Yao YM, Pandiella A, San-Miguel JF. In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica. 2010 May;95(5):794-803. Epub 2009 Nov 30. PubMed PMID: 19951978; PubMed Central PMCID: PMC2864386.

20: LaBonte MJ, Wilson PM, Fazzone W, Groshen S, Lenz HJ, Ladner RD. DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines. BMC Med Genomics. 2009 Nov 30;2:67. PubMed PMID: 19948057; PubMed Central PMCID: PMC2799439.

21: Wang Y, Fiskus W, Chong DG, Buckley KM, Natarajan K, Rao R, Joshi A, Balusu R, Koul S, Chen J, Savoie A, Ustun C, Jillella AP, Atadja P, Levine RL, Bhalla KN. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood. 2009 Dec 3;114(24):5024-33. Epub 2009 Oct 14. PubMed PMID: 19828702; PubMed Central PMCID: PMC2788976.

22: Maiso P, Colado E, Ocio EM, Garayoa M, Martín J, Atadja P, Pandiella A, San-Miguel JF. The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair. Leukemia. 2009 Dec;23(12):2265-74. Epub 2009 Oct 8. PubMed PMID: 19812608.

23: Liu X, Gomez-Pinillos A, Liu X, Johnson EM, Ferrari AC. Induction of bicalutamide sensitivity in prostate cancer cells by an epigenetic Puralpha-mediated decrease in androgen receptor levels. Prostate. 2010 Feb 1;70(2):179-89. PubMed PMID: 19790234.

24: Mühlenberg T, Zhang Y, Wagner AJ, Grabellus F, Bradner J, Taeger G, Lang H, Taguchi T, Schuler M, Fletcher JA, Bauer S. Inhibitors of deacetylases suppress oncogenic KIT signaling, acetylate HSP90, and induce apoptosis in gastrointestinal stromal tumors. Cancer Res. 2009 Sep 1;69(17):6941-50. Epub 2009 Aug 25. PubMed PMID: 19706776.

25: Crisanti MC, Wallace AF, Kapoor V, Vandermeers F, Dowling ML, Pereira LP, Coleman K, Campling BG, Fridlender ZG, Kao GD, Albelda SM. The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer. Mol Cancer Ther. 2009 Aug;8(8):2221-31. Epub 2009 Aug 11. PubMed PMID: 19671764.

26: Dickinson M, Ritchie D, DeAngelo DJ, Spencer A, Ottmann OG, Fischer T, Bhalla KN, Liu A, Parker K, Scott JW, Bishton M, Prince HM. Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin Lymphoma. Br J Haematol. 2009 Oct;147(1):97-101. Epub 2009 Aug 5. PubMed PMID: 19663825.

27: Gupta M, Ansell SM, Novak AJ, Kumar S, Kaufmann SH, Witzig TE. Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood. 2009 Oct 1;114(14):2926-35. Epub 2009 Jul 29. PubMed PMID: 19641186; PubMed Central PMCID: PMC2756203.

28: Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H, Jillella A, Ustun C, Rao R, Fernandez P, Chen J, Balusu R, Koul S, Atadja P, Marquez VE, Bhalla KN. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood. 2009 Sep 24;114(13):2733-43. Epub 2009 Jul 28. PubMed PMID: 19638619; PubMed Central PMCID: PMC2756128.

29: Garbes L, Riessland M, Hölker I, Heller R, Hauke J, Tränkle C, Coras R, Blümcke I, Hahnen E, Wirth B. LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate. Hum Mol Genet. 2009 Oct 1;18(19):3645-58. Epub 2009 Jul 7. PubMed PMID: 19584083.

30: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 May;31(4):263-98. PubMed PMID: 19557204.

31: Prince HM, Bishton MJ, Johnstone RW. Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors. Future Oncol. 2009 Jun;5(5):601-12. Review. PubMed PMID: 19519200.

32: Floris G, Debiec-Rychter M, Sciot R, Stefan C, Fieuws S, Machiels K, Atadja P, Wozniak A, Faa G, Schöffski P. High efficacy of panobinostat towards human gastrointestinal stromal tumors in a xenograft mouse model. Clin Cancer Res. 2009 Jun 15;15(12):4066-76. Epub 2009 Jun 9. PubMed PMID: 19509176.

33: Prince HM, Bishton MJ, Harrison SJ. Clinical studies of histone deacetylase inhibitors. Clin Cancer Res. 2009 Jun 15;15(12):3958-69. Epub 2009 Jun 9. Review. PubMed PMID: 19509172.

34: Piekarz RL, Bates SE. Epigenetic modifiers: basic understanding and clinical development. Clin Cancer Res. 2009 Jun 15;15(12):3918-26. Epub 2009 Jun 9. PubMed PMID: 19509169.

35: Prystowsky MB, Adomako A, Smith RV, Kawachi N, McKimpson W, Atadja P, Chen Q, Schlecht NF, Parish JL, Childs G, Belbin TJ. The histone deacetylase inhibitor LBH589 inhibits expression of mitotic genes causing G2/M arrest and cell death in head and neck squamous cell carcinoma cell lines. J Pathol. 2009 Aug;218(4):467-77. PubMed PMID: 19402126.

36: Fazzone W, Wilson PM, Labonte MJ, Lenz HJ, Ladner RD. Histone deacetylase inhibitors suppress thymidylate synthase gene expression and synergize with the fluoropyrimidines in colon cancer cells. Int J Cancer. 2009 Jul 15;125(2):463-73. PubMed PMID: 19384949.

37: Ellis L, Bots M, Lindemann RK, Bolden JE, Newbold A, Cluse LA, Scott CL, Strasser A, Atadja P, Lowe SW, Johnstone RW. The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy. Blood. 2009 Jul 9;114(2):380-93. Epub 2009 Apr 21. PubMed PMID: 19383971.

38: Atadja P. Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett. 2009 Aug 8;280(2):233-41. Epub 2009 Apr 2. Review. PubMed PMID: 19344997.

39: Kim IA, No M, Lee JM, Shin JH, Oh JS, Choi EJ, Kim IH, Atadja P, Bernhard EJ. Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER-2 signaling: potential role of histone deacetylase 6. Radiother Oncol. 2009 Jul;92(1):125-32. Epub 2009 Mar 28. PubMed PMID: 19329208.

40: Dedes KJ, Dedes I, Imesch P, von Bueren AO, Fink D, Fedier A. Acquired vorinostat resistance shows partial cross-resistance to 'second-generation' HDAC inhibitors and correlates with loss of histone acetylation and apoptosis but not with altered HDAC and HAT activities. Anticancer Drugs. 2009 Jun;20(5):321-33. PubMed PMID: 19322073.

41: Ricciardi S, Tomao S, de Marinis F. Toxicity of targeted therapy in non-small-cell lung cancer management. Clin Lung Cancer. 2009 Jan;10(1):28-35. Review. PubMed PMID: 19289369.

42: Fiskus W, Buckley K, Rao R, Mandawat A, Yang Y, Joshi R, Wang Y, Balusu R, Chen J, Koul S, Joshi A, Upadhyay S, Atadja P, Bhalla KN. Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol Ther. 2009 May;8(10):939-50. Epub 2009 May 18. PubMed PMID: 19279403; PubMed Central PMCID: PMC2775142.

43: De Schutter H, Kimpe M, Isebaert S, Nuyts S. A systematic assessment of radiation dose enhancement by 5-Aza-2'-deoxycytidine and histone deacetylase inhibitors in head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):904-12. PubMed PMID: 19215824.

44: Cha TL, Chuang MJ, Wu ST, Sun GH, Chang SY, Yu DS, Huang SM, Huan SK, Cheng TC, Chen TT, Fan PL, Hsiao PW. Dual degradation of aurora A and B kinases by the histone deacetylase inhibitor LBH589 induces G2-M arrest and apoptosis of renal cancer cells. Clin Cancer Res. 2009 Feb 1;15(3):840-50. Erratum in: Clin Cancer Res. 2009 Mar 1;15(5):1843. PubMed PMID: 19188154.

45: Symanowski J, Vogelzang N, Zawel L, Atadja P, Pass H, Sharma S. A histone deacetylase inhibitor LBH589 downregulates XIAP in mesothelioma cell lines which is likely responsible for increased apoptosis with TRAIL. J Thorac Oncol. 2009 Feb;4(2):149-60. PubMed PMID: 19179889.

46: Welsbie DS, Xu J, Chen Y, Borsu L, Scher HI, Rosen N, Sawyers CL. Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer. Cancer Res. 2009 Feb 1;69(3):958-66. Epub 2009 Jan 27. PubMed PMID: 19176386.

47: Chen J, Fiskus W, Eaton K, Fernandez P, Wang Y, Rao R, Lee P, Joshi R, Yang Y, Kolhe R, Balusu R, Chappa P, Natarajan K, Jillella A, Atadja P, Bhalla KN. Cotreatment with BCL-2 antagonist sensitizes cutaneous T-cell lymphoma to lethal action of HDAC7-Nur77-based mechanism. Blood. 2009 Apr 23;113(17):4038-48. Epub 2008 Dec 12. PubMed PMID: 19074726.

48: Rossi M, Inoue S, Walewska R, Knight RA, Dyer MJ, Cohen GM, Melino G. Caspase cleavage of Itch in chronic lymphocytic leukemia cells. Biochem Biophys Res Commun. 2009 Feb 13;379(3):659-64. Epub 2008 Dec 13. PubMed PMID: 19073138.

49: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Sep;30(7):543-88. PubMed PMID: 18985183.

50: Emanuele S, Lauricella M, Tesoriere G. Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review). Int J Oncol. 2008 Oct;33(4):637-46. Review. PubMed PMID: 18813776.

51: Fiskus W, Rao R, Fernandez P, Herger B, Yang Y, Chen J, Kolhe R, Mandawat A, Wang Y, Joshi R, Eaton K, Lee P, Atadja P, Peiper S, Bhalla K. Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor-resistant acute myeloid leukemia cells. Blood. 2008 Oct 1;112(7):2896-905. Epub 2008 Jul 25. PubMed PMID: 18660379.

52: Ellis L, Pan Y, Smyth GK, George DJ, McCormack C, Williams-Truax R, Mita M, Beck J, Burris H, Ryan G, Atadja P, Butterfoss D, Dugan M, Culver K, Johnstone RW, Prince HM. Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma. Clin Cancer Res. 2008 Jul 15;14(14):4500-10. PubMed PMID: 18628465.

53: Yokoyama S, Feige E, Poling LL, Levy C, Widlund HR, Khaled M, Kung AL, Fisher DE. Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage. Pigment Cell Melanoma Res. 2008 Aug;21(4):457-63. Epub 2008 Jun 27. PubMed PMID: 18627530.

54: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Apr;30(3):231-51. PubMed PMID: 18597009.

55: Haefner M, Bluethner T, Niederhagen M, Moebius C, Wittekind C, Mossner J, Caca K, Wiedmann M. Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors. World J Gastroenterol. 2008 Jun 21;14(23):3681-92. PubMed PMID: 18595135; PubMed Central PMCID: PMC2719231.

56: Yang Y, Rao R, Shen J, Tang Y, Fiskus W, Nechtman J, Atadja P, Bhalla K. Role of acetylation and extracellular location of heat shock protein 90alpha in tumor cell invasion. Cancer Res. 2008 Jun 15;68(12):4833-42. PubMed PMID: 18559531; PubMed Central PMCID: PMC2665713.

57: Verheul HM, Salumbides B, Van Erp K, Hammers H, Qian DZ, Sanni T, Atadja P, Pili R. Combination strategy targeting the hypoxia inducible factor-1 alpha with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res. 2008 Jun 1;14(11):3589-97. PubMed PMID: 18519793.

58: Zhou Q, Agoston AT, Atadja P, Nelson WG, Davidson NE. Inhibition of histone deacetylases promotes ubiquitin-dependent proteasomal degradation of DNA methyltransferase 1 in human breast cancer cells. Mol Cancer Res. 2008 May;6(5):873-83. PubMed PMID: 18505931.

59: De Bruyne E, Bos TJ, Asosingh K, Vande Broek I, Menu E, Van Valckenborgh E, Atadja P, Coiteux V, Leleu X, Thielemans K, Van Camp B, Vanderkerken K, Van Riet I. Epigenetic silencing of the tetraspanin CD9 during disease progression in multiple myeloma cells and correlation with survival. Clin Cancer Res. 2008 May 15;14(10):2918-26. PubMed PMID: 18483358.

60: Simms-Waldrip T, Rodriguez-Gonzalez A, Lin T, Ikeda AK, Fu C, Sakamoto KM. The aggresome pathway as a target for therapy in hematologic malignancies. Mol Genet Metab. 2008 Jul;94(3):283-6. Epub 2008 May 9. Review. Erratum in: Mol Genet Metab.2009 Jun;97(2):164. PubMed PMID: 18472289; PubMed Central PMCID: PMC2587432.

61: Yu C, Friday BB, Yang L, Atadja P, Wigle D, Sarkaria J, Adjei AA. Mitochondrial Bax translocation partially mediates synergistic cytotoxicity between histone deacetylase inhibitors and proteasome inhibitors in glioma cells. Neuro Oncol. 2008 Jun;10(3):309-19. Epub 2008 Apr 29. PubMed PMID: 18445700; PubMed Central PMCID: PMC2563053.

62: Gridelli C, Rossi A, Maione P. The potential role of histone deacetylase inhibitors in the treatment of non-small-cell lung cancer. Crit Rev Oncol Hematol. 2008 Oct;68(1):29-36. Epub 2008 Apr 18. Review. PubMed PMID: 18424067.

63: Rasheed W, Bishton M, Johnstone RW, Prince HM. Histone deacetylase inhibitors in lymphoma and solid malignancies. Expert Rev Anticancer Ther. 2008 Mar;8(3):413-32. Review. PubMed PMID: 18366289.

64: Scuto A, Kirschbaum M, Kowolik C, Kretzner L, Juhasz A, Atadja P, Pullarkat V, Bhatia R, Forman S, Yen Y, Jove R. The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells. Blood. 2008 May 15;111(10):5093-100. Epub 2008 Mar 18. PubMed PMID: 18349321; PubMed Central PMCID: PMC2384136.

65: Prince HM, Bishton M, Harrison S. The potential of histone deacetylase inhibitors for the treatment of multiple myeloma. Leuk Lymphoma. 2008 Mar;49(3):385-7. PubMed PMID: 18297514.

66: Zhang L, Lebwohl D, Masson E, Laird G, Cooper MR, Prince HM. Clinically relevant QTc prolongation is not associated with current dose schedules of LBH589 (panobinostat). J Clin Oncol. 2008 Jan 10;26(2):332-3; discussion 333-4. Erratum in: J Clin Oncol.2008 Apr 20;26(12):2066. PubMed PMID: 18182676.

67: Kalff A, Shortt J, Farr J, McLennan R, Lui A, Scott J, Spencer A. Laboratory tumor lysis syndrome complicating LBH589 therapy in a patient with acute myeloid leukaemia. Haematologica. 2008 Jan;93(1):e16-7. PubMed PMID: 18166770.

68: Mitsiades CS, Hayden PJ, Anderson KC, Richardson PG. From the bench to the bedside: emerging new treatments in multiple myeloma. Best Pract Res Clin Haematol. 2007 Dec;20(4):797-816. Review. PubMed PMID: 18070720.

69: Arts J, Angibaud P, Mariën A, Floren W, Janssens B, King P, van Dun J, Janssen L, Geerts T, Tuman RW, Johnson DL, Andries L, Jung M, Janicot M, van Emelen K. R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies. Br J Cancer. 2007 Nov 19;97(10):1344-53. Epub 2007 Nov 13. PubMed PMID: 18000499; PubMed Central PMCID: PMC2360244.

70: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Sep;29(7):467-509. PubMed PMID: 17982511.

71: Natoni A, MacFarlane M, Inoue S, Walewska R, Majid A, Knee D, Stover DR, Dyer MJ, Cohen GM. TRAIL signals to apoptosis in chronic lymphocytic leukaemia cells primarily through TRAIL-R1 whereas cross-linked agonistic TRAIL-R2 antibodies facilitate signalling via TRAIL-R2. Br J Haematol. 2007 Nov;139(4):568-77. Epub 2007 Oct 8. PubMed PMID: 17922877.

72: Edwards A, Li J, Atadja P, Bhalla K, Haura EB. Effect of the histone deacetylase inhibitor LBH589 against epidermal growth factor receptor-dependent human lung cancer cells. Mol Cancer Ther. 2007 Sep;6(9):2515-24. PubMed PMID: 17876048.

73: Ciossek T, Julius H, Wieland H, Maier T, Beckers T. A homogeneous cellular histone deacetylase assay suitable for compound profiling and robotic screening. Anal Biochem. 2008 Jan 1;372(1):72-81. Epub 2007 Aug 2. PubMed PMID: 17868634.

74: Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N, Qian X, Mills E, Berghs SC, Carey N, Finn PW, Collins LS, Tumber A, Ritchie JW, Jensen PB, Lichenstein HS, Sehested M. Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J. 2008 Jan 15;409(2):581-9. PubMed PMID: 17868033.

75: Bluethner T, Niederhagen M, Caca K, Serr F, Witzigmann H, Moebius C, Mossner J, Wiedmann M. Inhibition of histone deacetylase for the treatment of biliary tract cancer: a new effective pharmacological approach. World J Gastroenterol. 2007 Sep 21;13(35):4761-70. PubMed PMID: 17729398.

76: Fiskus W, Ren Y, Mohapatra A, Bali P, Mandawat A, Rao R, Herger B, Yang Y, Atadja P, Wu J, Bhalla K. Hydroxamic acid analogue histone deacetylase inhibitors attenuate estrogen receptor-alpha levels and transcriptional activity: a result of hyperacetylation and inhibition of chaperone function of heat shock protein 90. Clin Cancer Res. 2007 Aug 15;13(16):4882-90. PubMed PMID: 17699868.

77: Nishioka C, Ikezoe T, Yang J, Komatsu N, Bandobashi K, Taniguchi A, Kuwayama Y, Togitani K, Koeffler HP, Taguchi H. Histone deacetylase inhibitors induce growth arrest and apoptosis of HTLV-1-infected T-cells via blockade of signaling by nuclear factor kappaB. Leuk Res. 2008 Feb;32(2):287-96. Epub 2007 Jul 20. PubMed PMID: 17644177.

78: Glaser KB. HDAC inhibitors: clinical update and mechanism-based potential. Biochem Pharmacol. 2007 Sep 1;74(5):659-71. Epub 2007 Apr 7. PubMed PMID: 17498667.

79: Soverini S, Iacobucci I, Baccarani M, Martinelli G. Targeted therapy and the T315I mutation in Philadelphia-positive leukemias. Haematologica. 2007 Apr;92(4):437-9. PubMed PMID: 17488653.

80: Beckers T, Burkhardt C, Wieland H, Gimmnich P, Ciossek T, Maier T, Sanders K. Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. Int J Cancer. 2007 Sep 1;121(5):1138-48. PubMed PMID: 17455259.

81: Yu C, Friday BB, Lai JP, McCollum A, Atadja P, Roberts LR, Adjei AA. Abrogation of MAPK and Akt signaling by AEE788 synergistically potentiates histone deacetylase inhibitor-induced apoptosis through reactive oxygen species generation. Clin Cancer Res. 2007 Feb 15;13(4):1140-8. PubMed PMID: 17317822.

82: Jakubowska J, Czyz M. [Novel inhibitors of Bcr-Abl]. Postepy Hig Med Dosw (Online). 2006;60:697-706. Review. Polish. PubMed PMID: 17245319.

83: Zhou Q, Atadja P, Davidson NE. Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol Ther. 2007 Jan;6(1):64-9. PubMed PMID: 17172825.

84: Fiskus W, Pranpat M, Balasis M, Herger B, Rao R, Chinnaiyan A, Atadja P, Bhalla K. Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells. Mol Cancer Ther. 2006 Dec;5(12):3096-104. PubMed PMID: 17172412.

85: Geng L, Cuneo KC, Fu A, Tu T, Atadja PW, Hallahan DE. Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma-H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer. Cancer Res. 2006 Dec 1;66(23):11298-304. PubMed PMID: 17145876.

86: Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F, Masson E, Rae P, Laird G, Sharma S, Kantarjian H, Dugan M, Albitar M, Bhalla K. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res. 2006 Aug 1;12(15):4628-35. PubMed PMID: 16899611.

87: Meeting highlights from: 47th Annual Meeting of the American Society of Hematology December 2005, Atlanta, GA. Clin Lymphoma Myeloma. 2006 May;6(6):448-54. PubMed PMID: 16796774.

88: Maiso P, Carvajal-Vergara X, Ocio EM, López-Pérez R, Mateo G, Gutiérrez N, Atadja P, Pandiella A, San Miguel JF. The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res. 2006 Jun 1;66(11):5781-9. PubMed PMID: 16740717.

89: Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P, Tassone P, Atadja P, Chauhan D, Munshi NC, Anderson KC. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood. 2006 Nov 15;108(10):3441-9. Epub 2006 May 25. PubMed PMID: 16728695; PubMed Central PMCID: PMC1895432.

90: Fiskus W, Pranpat M, Bali P, Balasis M, Kumaraswamy S, Boyapalle S, Rocha K, Wu J, Giles F, Manley PW, Atadja P, Bhalla K. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Blood. 2006 Jul 15;108(2):645-52. Epub 2006 Mar 14. PubMed PMID: 16537804.

91: Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B, Sanni T, Atadja P, Pili R. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res. 2006 Jan 15;12(2):634-42. PubMed PMID: 16428510.

92: Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P, Seto E, Bhalla K. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem. 2005 Jul 22;280(29):26729-34. Epub 2005 Jun 2. PubMed PMID: 15937340.

93: Evans L. The American Society of Hematology--46th Annual Meeting and Exposition. HDAC, Flt and farnesyl transferase inhibitors. IDrugs. 2005 Jan;8(1):4-6. PubMed PMID: 15650931.

94: George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F, Sigua C, Sondarva G, Moscinski L, Atadja P, Bhalla K. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood. 2005 Feb 15;105(4):1768-76. Epub 2004 Oct 28. PubMed PMID: 15514006.