Targeting p53 by small molecules in hematological malignancies

Journal of Hematology & Oncology

Hong Chang²  Lugui Qiu¹  Manujendra N Saha³ 

[1] Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;Dept. of Laboratory Hematology and Medical Oncology, University Health Network, Toronto, Ontario, Canada;Dept. of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Canada

关键词: Apoptosis;    MIRA-1;    PRIMA-1;    RITA;    Nutlin;    p53;    Myeloma;    Lymphoma;    Leukemia;    Hematological malignancies;   

Others  :  812449
DOI  :  10.1186/1756-8722-6-23

 received in 2013-02-05, accepted in 2013-03-13,  发布年份 2013

【 摘 要 】

p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target. A breakthrough in cancer research came from the discovery of the drugs which are capable of reactivating p53 function. Most anti-cancer agents, from traditional chemo- and radiation therapies to more recently developed non-peptide small molecules exert their effects by enhancing the anti-proliferative activities of p53. Small molecules such as nutlin, RITA, and PRIMA-1 that can activate p53 have shown their anti-tumor effects in different types of hematological malignancies. Importantly, nutlin and PRIMA-1 have successfully reached the stage of phase I/II clinical trials in at least one type of hematological cancer. Thus, the pharmacological activation of p53 by these small molecules has a major clinical impact on prognostic use and targeted drug design. In the current review, we present the recent achievements in p53 research using small molecules in hematological malignancies. Anticancer activity of different classes of compounds targeting the p53 signaling pathway and their mechanism of action are discussed. In addition, we discuss how p53 tumor suppressor protein holds promise as a drug target for recent and future novel therapies in these diseases.

【 授权许可】

   
2013 Saha et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP: Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 2009, 9:862-873.
• [2]Meulmeester E, Jochemsen AG: p53: a guide to apoptosis. Curr Cancer Drug Targets 2008, 8:87-97.
• [3]Lim YP, Lim TT, Chan YL, Song AC, Yeo BH, Vojtesek B, Coomber D, Rajagopal G, Lane D: The p53 knowledgebase: an integrated information resource for p53 research. Oncogene 2007, 26:1517-1521.
• [4]Gomez-Lazaro M, Fernandez-Gomez FJ, Jordán J: p53: twenty five years understanding the mechanism of genome protection. J Physiol Biochem 2004, 60:287-307.
• [5]Lamb P, Crawford L: Characterization of the human p53 gene. Mol Cell Biol 1986, 6:1379-1385.
• [6]Soussi T, Dehouche K, Beroud C: p53 website and analysis of p53 gene mutations in human cancer: forging a link between epidemiology and carcinogenesis. Hum Mutat 2000, 2:105-213.
• [7]Pekova S, Mazal O, Cmejla R, Hardekopf DW, Plachy R, Zejskova L, Haugvicova R, Jancuskova T, Karas M, Koza V: A comprehensive study of TP53 mutations in chronic lymphocytic leukemia: Analysis of 1287 diagnostic and 1148 follow-up CLL samples. Leuk Res 2011, 35:889-898.
• [8]Nahi H, Selivanova G, Lehmann S, Möllgård L, Bengtzen S, Concha H, Svensson A, Wiman KG, Merup M, Paul C: Mutated and non-mutated TP53 as targets in the treatment of leukaemia. Br J Haematol 2008, 141:445-453.
• [9]Agirre X, Novo FJ, Calasanz MJ, Larráyoz MJ, Lahortiga I, Valgañón M, García-Delgado M, Vizmanos JL: TP53 is frequently altered by methylation, mutation, and/or deletion in acute lymphoblastic leukaemia. Mol Carcinog 2003, 38:201-208.
• [10]Avet-Loiseau H, Li JY, Godon C, Morineau N, Daviet A, Harousseau JL, Facon T, Bataille R: p53 deletion is not a frequent event in multiple myeloma. Br J Haematol 1999, 106:717-719.
• [11]Chng WJ, Price-Troska T, Gonzalea-Paz N, Van Wier S, Jacobus S, Blood E, Henderson K, Oken M, Van Ness B, Greipp P: Clinical significance of TP53 mutation in myeloma. Leukemia 2007, 21:582-584.
• [12]Chang H, Qi C, Yi Q, Reece D, Stewart AK: p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. Blood 2005, 105:358-360.
• [13]Reece D, Song KW, Fu T, Roland B, Chang H, Horsman DE, Mansoor A, Chen C, Masih-Khan E, Trieu Y: Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood 2009, 114:522-525.
• [14]Vogelstein B, Lane D, Levine AJ: Surfing the p53 network. Nature 2000, 408:307-310.
• [15]Bates S, Vousden KH: Mechanisms of p53-mediated apoptosis. Cell Mol Life Sci 1999, 55:28-37.
• [16]Ryan KM, Ernst MK, Rice NR, Vousden KH: Regulation and function of the p53 tumor suppressor protein. Curr Opin Cell Biol 2001, 13:332-337.
• [17]Stegh AH: Targeting the p53 signaling pathway in cancer therapy - the promises, challenges and perils. Expert Opin Ther Targets 2012, 16:67-83.
• [18]Essmann F, Schulze-Osthoff K: Translational approaches targeting the p53 pathway for anti-cancer therapy. Br J Pharmacol 2012, 165:328-344.
• [19]Joerger AC, Fersht AR: The tumor suppressor p53: from structures to drug discovery. Cold Spring Harb Perspect Biol 2010, 2:a000919.
• [20]Shangary S, Wang S: Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol 2009, 49:223-241.
• [21]Selivanova G: Therapeutic targeting of p53 by small molecules. Semin Cancer Biol 2010, 20:46-56.
• [22]Lane DP, Brown CJ, Verma C, Cheok CF: New insights into p53 based therapy. Discov Med 2011, 12:107-117.
• [23]Wang W, El-Deiry WS: Restoration of p53 to limit tumor growth. Curr Opin Oncol 2008, 20:90-96.
• [24]Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C: In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004, 303:844-848.
• [25]Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M, Pramanik A, Selivanova G: Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 2004, 10:1321-1328.
• [26]Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, Bergman J, Wiman KG, Selivanova G: Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 2002, 8:282-288.
• [27]Wiman KG: Pharmacological reactivation of mutant p53: from protein structure to cancer patient. Oncogene 2010, 29:4245-4252.
• [28]Foster BA, Coffey HA, Morin MJ, Rastinejad F: Pharmacological rescue of mutant p53 conformation and function. Science 1999, 286:2507-2510.
• [29]Seemann S, Maurici D, Olivier M, Caron de Fromentel C, Hainaut P: The tumor suppressor gene TP53: implications for cancer management and therapy. Crit Rev Clin Lab Sci 2004, 41:551-583.
• [30]Saha MN, Micallef J, Qiu L, Chang H: Pharmacological activation of the p53 pathway in haematological malignancies. J Clin Pathol 2010, 63:204-209.
• [31]Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Zhao X, Vu BT, Qing W, Packman K: Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci USA 2006, 103:1888-1893.
• [32]Gu L, Zhu N, Findley HW, Zhou M: MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2. Leukemia 2008, 22:730-739.
• [33]Zhu N, Gu L, Li F, Zhou M: Inhibition of the Akt/survivin pathway synergizes the antileukemia effect of nutlin-3 in acute lymphoblastic leukemia cells. Mol Cancer Ther 2008, 7:1101-1109.
• [34]Vilas-Zornoza A, Agirre X, Martín-Palanco V, Martín-Subero JI, San José-Eneriz E, Garate L, Álvarez S, Miranda E, Rodríguez-Otero P, Rifón J: Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia. PLoS One 2011, 6:e17012.
• [35]Kojima K, Konopleva M, Samudio IJ, Shikami M, Cabreira-Hansen M, McQueen T, Ruvolo V, Tsao T, Zeng Z, Vassilev LT: MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy. Blood 2005, 106:3150-3159.
• [36]Kojima K, Konopleva M, Samudio IJ, Schober WD, Bornmann WG, Andreeff M: Concomitant inhibition of MDM2 and Bcl-2 protein function synergistically induce mitochondrial apoptosis in AML. Cell Cycle 2006, 5:2778-2786.
• [37]Kojima K, Konopleva M, Samudio IJ, Ruvolo V, Andreeff M: Mitogen-activated protein kinase kinase inhibition enhances nuclear proapoptotic function of p53 in acute myelogenous leukemia cells. Cancer Res 2007, 67:3210-3219.
• [38]Zhang W, Konopleva M, Burks JK, Dywer KC, Schober WD, Yang JY, McQueen TJ, Hung MC, Andreeff M: Blockade of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase and murine double minute synergistically induces Apoptosis in acute myeloid leukemia via BH3-only proteins Puma and Bim. Cancer Res 2010, 70:2424-2434.
• [39]Secchiero P, Zerbinati C, di Iasio MG, Melloni E, Tiribelli M, Grill V, Zauli G: Synergistic cytotoxic activity of recombinant TRAIL plus the non-genotoxic activator of the p53 pathway nutlin-3 in acute myeloid leukemia cells. Curr Drug Metab 2007, 8:395-403.
• [40]Carter BZ, Mak DH, Schober WD, Dietrich MF, Pinilla C, Vassilev LT, Reed JC, Andreeff M: Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5. Blood 2008, 111:3742-3750.
• [41]Kojima K, Konopleva M, Tsao T, Andreeff M, Ishida H, Shiotsu Y, Jin L, Tabe Y, Nakakuma H: Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis. Leukemia 2010, 24:33-43.
• [42]Thompson T, Andreeff M, Studzinski GP, Vassilev LT: 1,25-dihydroxyvitamin D3 enhances the apoptotic activity of MDM2 antagonist nutlin-3a in acute myeloid leukemia cells expressing wild-type p53. Mol Cancer Ther 2010, 9:1158-1168.
• [43]McCormack E, Haaland I, Venås G, Forthun RB, Huseby S, Gausdal G, Knappskog S, Micklem DR, Lorens JB, Bruserud O: Synergistic induction of p53 mediated apoptosis by valporic acid and nutlin-3 in acute myeloid leukemia. Leukemia 2012, 26:910-917.
• [44]Kojima K, Shimanuki M, Shikami M, Samudio IJ, Ruvolo V, Corn P, Hanaoka N, Konopleva M, Andreeff M, Nakakuma H: The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 2008, 22:1728-1736.
• [45]Zauli G, Celeghini C, Melloni E, Voltan R, Ongari M, Tiribelli M, di Iasio MG, Lanza F, Secchiero P: The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status. Haematologica 2012, 97:1722-1730.
• [46]Secchiero P, Zerbinati C, Melloni E, Milani D, Campioni D, Fadda R, Tiribelli M, Zauli G: The MDM-2 antagonist nutlin-3 promotes the maturation of acute myeloid leukemic blasts. Neoplasia 2007, 9:853-861.
• [47]Lew QJ, Tan CH, Gurumurthy M, Chu KL, Cheong N, Lane DP, Chao SH: NPMc(+) AML cell line shows differential protein expression and lower sensitivity to DNA-damaging and p53-inducing anticancer compounds. Cell Cycle 2011, 10:1978-1987.
• [48]Long J, Parkin B, Ouillette P, Bixby D, Shedden K, Erba H, Wang S, Malek SN: Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia. Blood 2010, 116:71-80.
• [49]Voltan R, Celeghini C, Melloni E, Secchiero P, Zauli G: Perifosine plus nutlin-3 combination shows a synergistic anti-leukaemic activity. Br J Haematol 2010, 148:957-961.
• [50]Lu K, Wang X: Therapeutic advancement of chronic lymphocytic leukemia. J Hematol Oncol 2012, 5:55. BioMed Central Full Text
• [51]Maddocks KJ, Lin TS: Update in the management of chronic lymphocytic leukemia. J Hematol Oncol 2009, 2:29. BioMed Central Full Text
• [52]Secchiero P, di Iasio MG, Melloni E, Voltan R, Celeghini C, Tiribelli M, Dal Bo M, Gattei V, Zauli G: The expression levels of the pro-apoptotic XAF-1 gene modulate the cytotoxic response to Nutlin-3 in B chronic lymphocytic leukemia. Leukemia 2010, 24:480-483.
• [53]Secchiero P, Melloni E, Tiribelli M, Gonelli A, Zauli G: Combined treatment of CpG-oligodeoxynucleotide with Nutlin-3 induces strong immune stimulation coupled to cytotoxicity in B-chronic lymphocytic leukemic (B-CLL) cells. J Leukoc Biol 2008, 83:434-437.
• [54]Secchiero P, Barbarotto E, Tiribelli M, Zerbinati C, di Lasio MG, Gonelli A, Cavazzini F, Campioni D, Fanin R, Cuneo A: Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood 2006, 107:4122-4129.
• [55]Coll-Mulet L, Iglesias-Serret D, Santidrian AF, Cosialls AM, de Frias M, Castano E, Campàs C, Barragán M, de Sevilla AF, Domingo A: MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood 2006, 107:4109-4114.
• [56]Zauli G, di Iasio MG, Secchiero P, Dal Bo M, Marconi D, Bomben R, Del Poeta G, Gattei V: Exposure of B cell chronic lymphocytic leukemia (B-CLL) cells to nutlin-3 induces a characteristic gene expression profile, which correlates with nutlin-3-mediated cytotoxicity. Curr Cancer Drug Targets 2009, 9:510-518.
• [57]Bo MD, Secchiero P, Degan M, Marconi D, Bomben R, Pozzato G, Gaidano G, Del Poeta G, Forconi F, Zauli G, Gattei V: MDM4 (MDMX) is overexpressed in chronic lymphocytic leukaemia (CLL) and marks a subset of p53wild-type CLL with a poor cytotoxic response to Nutlin-3. Br J Haematol 2010, 150:237-239.
• [58]Kojima K, Konopleva M, McQueen T, O’Brien S, Plunkett W, Andreeff M: Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia. Blood 2006, 108:993-1000.
• [59]Zauli G, Voltan R, Bosco R, Melloni E, Marmiroli S, Rigolin GM, Cuneo A, Secchiero P: Dasatinib plus Nutlin-3 shows synergistic antileukemic activity in both p53 wild-type and p53 mutated B chronic lymphocytic leukemias by inhibiting the Akt pathway. Clin Cancer Res 2011, 17:762-770.
• [60]Steele AJ, Prentice AG, Hoffbrand AV, Yogashangary BC, Hart SM, Nacheva EP, Howard-Reeves JD, Duke VM, Kottaridis PD, Cwynarski K: p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism. Blood 2008, 112:3827-3834.
• [61]Peterson LF, Mitrikeska E, Giannola D, Lui Y, Sun H, Bixby D, Malek SN, Donato NJ, Wang S, Talpaz M: p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells. Leukemia 2011, 25:761-769.
• [62]Kurosu T, Wu N, Oshikawa G, Kagechika H, Miura O: Enhancement of imatinib-induced apoptosis of BCR/ABL-expressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway. Apoptosis 2010, 15:608-620.
• [63]Stuhmer T, Chatterjee M, Hildebrandt M, Herrmann P, Gollasch H, Gerecke C, Theurich S, Cigliano L, Manz RA, Daniel PT: Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma. Blood 2005, 106:3609-3617.
• [64]Ooi MG, Hayden PJ, Kotoula V, McMillin DW, Charalambous E, Daskalaki E, Raje NS, Munshi NC, Chauhan D, Hideshima T: Interactions of the Hdm2/p53 and proteasome pathways may enhance the antitumor activity of bortezomib. Clin Cancer Res 2009, 15:7153-7160.
• [65]Saha MN, Jiang H, Chang H: Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma: evidence for p53-transcription-dependent and -independent pathways. Cancer Biol Ther 2010, 10:567-578.
• [66]Zhang Q, Lu H: Nutlin’s two roads toward apoptosis. Cancer Biol Ther 2010, 10:579-581.
• [67]Drakos E, Thomaides A, Medeiros LJ, Li J, Leventaki V, Konopleva M, Andreeff M, Rassidakis GZ: Inhibition of p53-murine double minute 2 interaction by nutlin stabilizes p53 and induces cell cycle arrest and apoptosis in Hodgkin lymphoma. Clin Cancer Res 2007, 13:3380-3387.
• [68]Janz M, Stühmer T, Vassilev LT, Bargou RC: Pharmacologic activation of p53-dependent and p53-independent apoptotic pathways in Hodgkin/Reed-Sternberg cells. Leukemia 2007, 21:772-779.
• [69]Jones RJ, Baladandayuthapani V, Neelapu S, Fayad LE, Romaguera JE, Wang M, Sharma R, Yang D, Orlowski RZ: HDM-2 inhibition suppresses expression of ribonucleotide reductase subunit M2, and synergistically enhances gemcitabine-induced cytotoxicity in mantle cell lymphoma. Blood 2011, 118:4140-4149.
• [70]Drakos E, Atsaves V, Li J, Leventaki V, Andreeff M, Medeiros LJ, Rassidakis GZ: Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma. Leukemia 2009, 23:784-790.
• [71]Jin L, Tabe Y, Kojima K, Zhou Y, Pittaluga S, Konopleva M, Miida T, Raffeld M: MDM2 antagonist Nutlin-3 enhances bortezomib-mediated mitochondrial apoptosis in TP53-mutated mantle cell lymphoma. Cancer Lett 2010, 299:161-170.
• [72]Tabe Y, Sebasigari D, Jin L, Rudelius M, Davies-Hill T, Miyake K, Miida T, Pittaluga S, Raffeld M: MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma. Clin Cancer Res 2009, 15:933-942.
• [73]Drakos E, Atsaves V, Schlette E, Li J, Papanastasi I, Rassidakis GZ, Medeiros LJ: The therapeutic potential of p53 reactivation by nutlin-3a in ALK + anaplastic large cell lymphoma with wild-type or mutated p53. Leukemia 2009, 23:2290-2299.
• [74]Sosin AM, Burger AM, Siddiqi A, Abrams J, Mohammad RM, Al-Katib AM: HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas. J Hematol Oncol 2012, 5:57. BioMed Central Full Text
• [75]Drakos E, Singh RR, Rassidakis GZ, Schlette E, Li J, Claret FX, Ford RJ Jr, Vega F, Medeiros LJ: Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21). Leukemia 2011, 25:856-867.
• [76]Renouf B, Hollville E, Pujals A, Tétaud C, Garibal J, Wiels J: Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein-Barr virus (EBV)-positive and EBV-negative Burkitt’s lymphoma cells. Leukemia 2009, 23:1557-1563.
• [77]Tageja N, Padheye S, Dandawate P, Al-Katib A, Mohammad RM: New targets for the treatment of follicular lymphoma. J Hematol Oncol 2009, 2:50. BioMed Central Full Text
• [78]Mohammad RM, Wu J, Azmi AS, Aboukameel A, Sosin A, Wu S, Yang D, Wang S, Al-Katib AM: An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals. Mol Cancer 2009, 8:115. BioMed Central Full Text
• [79]Hasegawa H, Yamada Y, Iha H, Tsukasaki K, Nagai K, Atogami S, Sugahara K, Tsuruda K, Ishizaki A, Kamihira S: Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells. Leukemia 2009, 23:2090-2101.
• [80]Enge M, Bao W, Hedström E, Jackson SP, Moumen A, Selivanova G: MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53. Cancer Cell 2009, 15:171-183.
• [81]Jones RJ, Bjorklund CC, Baladandayuthapani V, Kuhn DJ, Orlowski RZ: Drug Resistance to Inhibitors of the Human Double Minute-2 E3 Ligase Is Mediated by Point Mutations of p53, but Can Be Overcome with the p53 Targeting Agent RITA. Mol Cancer Ther 2012, 11:2243-2253.
• [82]Kazemi A, Safa M, Shahbazi A: RITA enhances chemosensivity of pre-B ALL cells to doxorubicin by inducing p53-dependent apoptosis. Hematology 2011, 16:225-231.
• [83]Saha MN, Jiang H, Muaki A, Chang H: RITA inhibits multiple myeloma cell growth through induction of p53-mediated caspase-dependent apoptosis and synergistically enhances nutlin-induced cytotoxic responses. Mol Cancer Ther 2010, 9:3041-3051.
• [84]Saha MN, Jiang H, Yang Y, Zhu X, Wang X, Schimmer AD, Chang H: RITA-induced apoptosis of multiple myeloma cells is mediated by activation of JNK signaling. Blood (ASH Annual Meeting Abstracts) 2011, 118:1836.
• [85]Saha MN, Yang Y, Chang H: Targeting p53 by small molecule p53 activators in multiple myeloma [abstract]. J Hematol Oncol 2012, 5(Suppl 1):A7.
• [86]Krajewski M, Ozdowy P, D’Silva L, Rothweiler U, Holak TA: NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro. Nat Med 2005, 11:1135-1136.
• [87]Saha MN, Jiang H, Yang Y, Zhu X, Wang X, Schimmer AD, Qiu L, Chang H: Targeting p53 via JNK Pathway: A Novel Role of RITA for Apoptotic Signaling in Multiple Myeloma. PLoS One 2012, 7:e30215.
• [88]Nahi H, Merup M, Lehmann S, Bengtzen S, Möllgård L, Selivanova G, Wiman KG, Paul C: PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion. Br J Haematol 2006, 132:230-236.
• [89]Lambert JM, Gorzov P, Veprintsev DB, Söderqvist M, Segerbäck D, Bergman J, Fersht AR, Hainaut P, Wiman KG, Bykov VJ: PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 2009, 15:376-388.
• [90]Bykov VJ, Issaeva N, Selivanova G, Wiman KG: Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the National Cancer Institute database. Carcinogenesis 2002, 23:2011-2018.
• [91]Lehmann S, Bykov VJ, Ali D, Andrén O, Cherif H, Tidefelt U, Uggla B, Yachnin J, Juliusson G, Moshfegh A: Targeting p53 in vivo: A first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol 2012, 30:3633-3639.
• [92]Nahi H, Lehmann S, Mollgard L, Bengtzen S, Selivanova G, Wiman KG, Paul C, Merup M: Effects of PRIMA-1 on chronic lymphocytic leukaemia cells with and without hemizygous p53 deletion. Br J Haematol 2004, 127:285-291.
• [93]Ali D, Jönsson-Videsäter K, Deneberg S, Bengtzén S, Nahi H, Paul C, Lehmann S: APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells. Eur J Haematol 2011, 86:206-215.
• [94]Saha MN, Jiang H, Mei-His C, Chang H: p53-independent anti-myeloma activity of Prima-1met. Blood (ASH Annual Meeting Abstracts) 2011, 118:1826.
• [95]Bykov VJ, Issaeva N, Zache N, Shilov A, Hultcrantz M, Bergman J, Selivanova G, Wiman KG: Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. J Biol Chem 2005, 280:30384-30391.
• [96]Saha MN, Jiang H, Chang H: A novel small molecule MIRA-1 induces cytotoxicity in multiple myeloma cells harbouring wild type or mutant p53. Modern Pathology 2012, 25((Suppl 2)):1534.
• [97]Leiba M, Jakubikova J, Klippel S, Mitsiades CS, Hideshima T, Tai YT, Leiba A, Pines M, Richardson PG, Nagler A, Anderson KC: Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents. Br J Haematol 2012, 157:718-731.
• [98]Kojima K, Duvvuri S, Ruvolo V, Samaniego F, Younes A, Andreeff M: Decreased sensitivity of 17p-deleted chronic lymphocytic leukemia cells to a small molecule BCL-2 antagonist ABT-737. Cancer 2012, 118:1023-1031.
• [99]Kojima K, Burks JK, Arts J, Andreeff M: The novel tryptamine derivative JNJ-26854165 induces wild-type p53- and E2F1-mediated apoptosis in acute myeloid and lymphoid leukemias. Mol Cancer Ther 2010, 9:2545-2557.
• [100]Görgün G, Calabrese E, Hideshima T, Ecsedy J, Perrone G, Mani M, Ikeda H, Bianchi G, Hu Y, Cirstea D: A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood 2010, 115:5202-5213.
• [101]Wang S, Zhao Y, Bernard D, Aguilar A, Kumar S: Targeting the MDM2-p53 protein-protein interaction for new cancer therapeutics. Top Med Chem 2012, 8:57-80.
• [102]Saha MN, Jiang H, Jayakar J, Reece D, Branch DR, Chang H: MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biol Ther 2010, 9:936-944.
• [103]Surget S, Chiron D, Gomez-Bougie P, Descamps G, Ménoret E, Bataille R, Moreau P, Le Gouill S, Amiot M, Pellat-Deceunynck C: Cell death via DR5, but not DR4, is regulated by p53 in myeloma cells. Cancer Res 2012, 72:4562-4573.
• [104]Ambrosini G, Sambol EB, Carvajal D, Vassilev LT, Singer S, Schwartz GK: Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1. Oncogene 2007, 26:3473-3481.
• [105]Lau LM, Nugent JK, Zhao X, Irwin MS: HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function. Oncogene 2008, 27:997-1003.
• [106]Kravchenko JE, Ilyinskaya GV, Komarov PG, Agapova LS, Kochetkov DV, Strom E, Frolova EI, Kovriga I, Gudkov AV, Feinstein E: Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway. Proc Natl Acad Sci USA 2008, 105:6302-6307.
• [107]Alsafadi S, Tourpin S, André F, Vassal G, Ahomadegbe JC: p53 family: at the crossroads in cancer therapy. Curr Med Chem 2009, 16:4328-4344.