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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

The Killing of Human Neuroblastoma Cells by the Small Molecule JQ1 Occurs in a p53-Dependent Manner

Author(s): Joseph Mazar*, Caleb Gordon, Varun Naga and Tamarah J. Westmoreland

Volume 20, Issue 13, 2020

Page: [1613 - 1625] Pages: 13

DOI: 10.2174/1871520620666200424123834

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Abstract

Background: MYCN amplification is a prognostic biomarker associated with poor prognosis of neuroblastoma in children. The overall survival of children with MYCN-amplified neuroblastoma has only marginally improved within the last 20 years. The Bromodomain and Extra-Terminal motif (BET) inhibitor, JQ1, has been shown to downregulate MYCN in neuroblastoma cells.

Objective: To determine if JQ1 downregulation of MYCN in neuroblastomas can offer a target- specific therapy for this, difficult to treat, pediatric cancer.

Methods: Since MYCN-amplified neuroblastoma accounts for as much as 40 to 50 percent of all high-risk cases, we compared the effect of JQ1 on both MYCN-amplified and non-MYCN-amplified neuroblastoma cell lines and investigated its mechanism of action.

Results: In this study, we show that JQ1 can specifically target MYCN for downregulation, though this effect is not specific to only MYCN-amplified cells. And although we can confirm that the loss of MYCN alone can induce apoptosis, the exogenous rescue of MYCN expression can abrogate much of this cytotoxicity. More fascinating, however, was the discovery that the JQ1-induced knockdown of MYCN, which led to the loss of the human double minute 2 homolog (HDM2) protein, also led to the accumulation of tumor protein 53 (also known as TP53 or p53), which ultimately induced apoptosis. Likewise, the knockdown of p53 also blunted the cytotoxic effects of JQ1.

Conclusion: These data suggest a mechanism of action for JQ1 cytotoxicity in neuroblastomas and offer a possible prognostic target for determining its efficacy as a therapeutic.

Keywords: Cancer, oncology, neuroblastoma, BET inhibitors, p53, pediatric, MYCN amplifications, JQ1.

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[1]
Neuroblastoma Treatment. (PDQ®)–Patient Version; National Cancer Institute, 2017.
[2]
Brodeur, G.M. Neuroblastoma: Biological insights into a clinical enigma. Nat. Rev. Cancer, 2003, 3(3), 203-216.
[http://dx.doi.org/10.1038/nrc1014] [PMID: 12612655]
[3]
Maris, J.M.; Hogarty, M.D.; Bagatell, R.; Cohn, S.L. Neuroblastoma. Lancet, 2007, 369(9579), 2106-2120.
[http://dx.doi.org/10.1016/S0140-6736(07)60983-0] [PMID: 17586306]
[4]
Pandey, G.K.; Kanduri, C. Long noncoding RNAs and neuroblastoma. Oncotarget, 2015, 6(21), 18265-18275.
[http://dx.doi.org/10.18632/oncotarget.4251] [PMID: 26087192]
[5]
Papaioannou, G.; McHugh, K. Neuroblastoma in childhood: Review and radiological findings. Cancer Imaging, 2005, 5, 116-127.
[http://dx.doi.org/10.1102/1470-7330.2005.0104] [PMID: 16305949]
[6]
Cohn, S.L.; Pearson, A.D.; London, W.B.; Monclair, T.; Ambros, P.F.; Brodeur, G.M.; Faldum, A.; Hero, B.; Iehara, T.; Machin, D.; Mosseri, V.; Simon, T.; Garaventa, A.; Castel, V.; Matthay, K.K. INRG Task Force. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J. Clin. Oncol., 2009, 27(2), 289-297.
[http://dx.doi.org/10.1200/JCO.2008.16.6785] [PMID: 19047291]
[7]
Louis, C.U.; Shohet, J.M. Neuroblastoma: Molecular pathogenesis and therapy. Annu. Rev. Med., 2015, 66, 49-63.
[http://dx.doi.org/10.1146/annurev-med-011514-023121] [PMID: 25386934]
[8]
Ward, E.; DeSantis, C.; Robbins, A.; Kohler, B.; Jemal, A. Childhood and adolescent cancer statistics, 2014. CA Cancer J. Clin., 2014, 64(2), 83-103.
[http://dx.doi.org/10.3322/caac.21219] [PMID: 24488779]
[9]
Gurney, J.G. Neuroblastoma, childhood cancer survivorship, and reducing the consequences of cure. Bone Marrow Transplant., 2007, 40(8), 721-722.
[http://dx.doi.org/10.1038/sj.bmt.1705815] [PMID: 17912265]
[10]
Kuroda, T.; Saeki, M.; Honna, T.; Kumagai, M.; Masaki, H. Late complications after surgery in patients with neuroblastoma. J. Pediatr. Surg., 2006, 41(12), 2037-2040.
[http://dx.doi.org/10.1016/j.jpedsurg.2006.08.003] [PMID: 17161200]
[11]
Tonini, G.P.; Pistoia, V. Molecularly guided therapy of neuroblastoma: a review of different approaches. Curr. Pharm. Des., 2006, 12(18), 2303-2317.
[http://dx.doi.org/10.2174/138161206777585193] [PMID: 16787256]
[12]
Alferiev, I.S.; Iyer, R.; Croucher, J.L.; Adamo, R.F.; Zhang, K.; Mangino, J.L.; Kolla, V.; Fishbein, I.; Brodeur, G.M.; Levy, R.J.; Chorny, M. Nanoparticle-mediated delivery of a rapidly activatable prodrug of SN-38 for neuroblastoma therapy. Biomaterials, 2015, 51, 22-29.
[http://dx.doi.org/10.1016/j.biomaterials.2015.01.075] [PMID: 25770994]
[13]
Alili, L.; Sack, M.; von Montfort, C.; Giri, S.; Das, S.; Carroll, K.S.; Zanger, K.; Seal, S.; Brenneisen, P. Downregulation of tumor growth and invasion by redox-active nanoparticles. Antioxid. Redox Signal., 2013, 19(8), 765-778.
[http://dx.doi.org/10.1089/ars.2012.4831] [PMID: 23198807]
[14]
Kumari, M.; Singh, S.P.; Chinde, S.; Rahman, M.F.; Mahboob, M.; Grover, P. Toxicity study of cerium oxide nanoparticles in human neuroblastoma cells. Int. J. Toxicol., 2014, 33(2), 86-97.
[http://dx.doi.org/10.1177/1091581814522305] [PMID: 24510415]
[15]
Lin, W.; Huang, Y.W.; Zhou, X.D.; Ma, Y. Toxicity of cerium oxide nanoparticles in human lung cancer cells. Int. J. Toxicol., 2006, 25(6), 451-457.
[http://dx.doi.org/10.1080/10915810600959543] [PMID: 17132603]
[16]
Huang, M.; Weiss, W.A. Neuroblastoma and MYCN. Cold Spring Harb. Perspect. Med., 2013, 3(10) a014415
[http://dx.doi.org/10.1101/cshperspect.a014415] [PMID: 24086065]
[17]
Irwin, M.S.; Park, J.R. Neuroblastoma: Paradigm for precision medicine. Pediatr. Clin. North Am., 2015, 62(1), 225-256.
[http://dx.doi.org/10.1016/j.pcl.2014.09.015] [PMID: 25435121]
[18]
Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W.B.; Fedorov, O.; Morse, E.M.; Keates, T.; Hickman, T.T.; Felletar, I.; Philpott, M.; Munro, S.; McKeown, M.R.; Wang, Y.; Christie, A.L.; West, N.; Cameron, M.J.; Schwartz, B.; Heightman, T.D.; La Thangue, N.; French, C.A.; Wiest, O.; Kung, A.L.; Knapp, S.; Bradner, J.E. Selective inhibition of BET bromodomains. Nature, 2010, 468(7327), 1067-1073.
[http://dx.doi.org/10.1038/nature09504] [PMID: 20871596]
[19]
Delmore, J.E.; Issa, G.C.; Lemieux, M.E.; Rahl, P.B.; Shi, J.; Jacobs, H.M.; Kastritis, E.; Gilpatrick, T.; Paranal, R.M.; Qi, J.; Chesi, M.; Schinzel, A.C.; McKeown, M.R.; Heffernan, T.P.; Vakoc, C.R.; Bergsagel, P.L.; Ghobrial, I.M.; Richardson, P.G.; Young, R.A.; Hahn, W.C.; Anderson, K.C.; Kung, A.L.; Bradner, J.E.; Mitsiades, C.S. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell, 2011, 146(6), 904-917.
[http://dx.doi.org/10.1016/j.cell.2011.08.017] [PMID: 21889194]
[20]
Ott, C.J.; Kopp, N.; Bird, L.; Paranal, R.M.; Qi, J.; Bowman, T.; Rodig, S.J.; Kung, A.L.; Bradner, J.E.; Weinstock, D.M. BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood, 2012, 120(14), 2843-2852.
[http://dx.doi.org/10.1182/blood-2012-02-413021] [PMID: 22904298]
[21]
Schwartz, B.E.; Hofer, M.D.; Lemieux, M.E.; Bauer, D.E.; Cameron, M.J.; West, N.H.; Agoston, E.S.; Reynoird, N.; Khochbin, S.; Ince, T.A.; Christie, A.; Janeway, K.A.; Vargas, S.O.; Perez-Atayde, A.R.; Aster, J.C.; Sallan, S.E.; Kung, A.L.; Bradner, J.E.; French, C.A. Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Res., 2011, 71(7), 2686-2696.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-3513] [PMID: 21447744]
[22]
Belkina, A.C.; Denis, G.V. BET domain co-regulators in obesity, inflammation and cancer. Nat. Rev. Cancer, 2012, 12(7), 465-477.
[http://dx.doi.org/10.1038/nrc3256] [PMID: 22722403]
[23]
Shi, J.; Vakoc, C.R. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol. Cell, 2014, 54(5), 728-736.
[http://dx.doi.org/10.1016/j.molcel.2014.05.016] [PMID: 24905006]
[24]
Da Costa, D.; Agathanggelou, A.; Perry, T.; Weston, V.; Petermann, E.; Zlatanou, A.; Oldreive, C.; Wei, W.; Stewart, G.; Longman, J.; Smith, E.; Kearns, P.; Knapp, S.; Stankovic, T. BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia. Blood Cancer J., 2013, 3 e126
[http://dx.doi.org/10.1038/bcj.2013.24] [PMID: 23872705]
[25]
Anand, P.; Brown, J.D.; Lin, C.Y.; Qi, J.; Zhang, R.; Artero, P.C.; Alaiti, M.A.; Bullard, J.; Alazem, K.; Margulies, K.B.; Cappola, T.P.; Lemieux, M.; Plutzky, J.; Bradner, J.E.; Haldar, S.M. BET bromodomains mediate transcriptional pause release in heart failure. Cell, 2013, 154(3), 569-582.
[http://dx.doi.org/10.1016/j.cell.2013.07.013] [PMID: 23911322]
[26]
Banerjee, C.; Archin, N.; Michaels, D.; Belkina, A.C.; Denis, G.V.; Bradner, J.; Sebastiani, P.; Margolis, D.M.; Montano, M. BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J. Leukoc. Biol., 2012, 92(6), 1147-1154.
[http://dx.doi.org/10.1189/jlb.0312165] [PMID: 22802445]
[27]
Matzuk, M.M.; McKeown, M.R.; Filippakopoulos, P.; Li, Q.; Ma, L.; Agno, J.E.; Lemieux, M.E.; Picaud, S.; Yu, R.N.; Qi, J.; Knapp, S.; Bradner, J.E. Small-molecule inhibition of BRDT for male contraception. Cell, 2012, 150(4), 673-684.
[http://dx.doi.org/10.1016/j.cell.2012.06.045] [PMID: 22901802]
[28]
Puissant, A.; Frumm, S.M.; Alexe, G.; Bassil, C.F.; Qi, J.; Chanthery, Y.H.; Nekritz, E.A.; Zeid, R.; Gustafson, W.C.; Greninger, P.; Garnett, M.J.; McDermott, U.; Benes, C.H.; Kung, A.L.; Weiss, W.A.; Bradner, J.E.; Stegmaier, K. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov., 2013, 3(3), 308-323.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0418] [PMID: 23430699]
[29]
Xu, Y. Regulation of p53 responses by post-translational modifications. Cell Death Differ., 2003, 10(4), 400-403.
[http://dx.doi.org/10.1038/sj.cdd.4401182] [PMID: 12719715]
[30]
Jain, A.K.; Barton, M.C. Making sense of ubiquitin ligases that regulate p53. Cancer Biol. Ther., 2010, 10(7), 665-672.
[http://dx.doi.org/10.4161/cbt.10.7.13445] [PMID: 20930521]
[31]
Chen, L.; Tweddle, D.A. p53, SKP2, and DKK3 as MYCN target genes and their potential therapeutic significance. Front. Oncol., 2012, 2, 173.
[http://dx.doi.org/10.3389/fonc.2012.00173] [PMID: 23226679]
[32]
Okoshi, R.; Ando, K.; Suenaga, Y.; Sang, M.; Kubo, N.; Kizaki, H.; Nakagawara, A.; Ozaki, T. Transcriptional regulation of tumor suppressor p53 by cAMP-responsive element-binding protein/AMP-activated protein kinase complex in response to glucose deprivation. Genes Cells, 2009, 14(12), 1429-1440.
[http://dx.doi.org/10.1111/j.1365-2443.2009.01359.x] [PMID: 19930465]
[33]
Tumilowicz, J.J.; Nichols, W.W.; Cholon, J.J.; Greene, A.E. Definition of a continuous human cell line derived from neuroblastoma. Cancer Res., 1970, 30(8), 2110-2118.
[PMID: 5459762]
[34]
El-Badry, O.M.; Romanus, J.A.; Helman, L.J.; Cooper, M.J.; Rechler, M.M.; Israel, M.A. Autonomous growth of a human neuroblastoma cell line is mediated by insulin-like growth factor II. J. Clin. Invest., 1989, 84(3), 829-839.
[http://dx.doi.org/10.1172/JCI114243] [PMID: 2547840]
[35]
Wada, R.K.; Seeger, R.C.; Brodeur, G.M.; Einhorn, P.A.; Rayner, S.A.; Tomayko, M.M.; Reynolds, C.P. Human neuroblastoma cell lines that express N-myc without gene amplification. Cancer, 1993, 72(11), 3346-3354.
[http://dx.doi.org/10.1002/1097-0142(19931201)72:11<3346:AID-CNCR2820721134>3.0.CO;2-E] [PMID: 8242562]
[36]
Keshelava, N.; Seeger, R.C.; Groshen, S.; Reynolds, C.P. Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Res., 1998, 58(23), 5396-5405.
[PMID: 9850071]
[37]
Reynolds, C.P.; Biedler, J.L.; Spengler, B.A.; Reynolds, D.A.; Ross, R.A.; Frenkel, E.P.; Smith, R.G. Characterization of human neuroblastoma cell lines established before and after therapy. J. Natl. Cancer Inst., 1986, 76(3), 375-387.
[PMID: 3456456]
[38]
Biedler, J.L.; Roffler-Tarlov, S.; Schachner, M.; Freedman, L.S. Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones. Cancer Res., 1978, 38(11 Pt 1), 3751-3757.
[PMID: 29704]
[39]
Thompson, P.M.; Maris, J.M.; Hogarty, M.D.; Seeger, R.C.; Reynolds, C.P.; Brodeur, G.M.; White, P.S. Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma. Cancer Res., 2001, 61(2), 679-686.
[PMID: 11212268]
[40]
Kaghad, M.; Bonnet, H.; Yang, A.; Creancier, L.; Biscan, J.C.; Valent, A.; Minty, A.; Chalon, P.; Lelias, J.M.; Dumont, X.; Ferrara, P.; McKeon, F.; Caput, D. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell, 1997, 90(4), 809-819.
[http://dx.doi.org/10.1016/S0092-8674(00)80540-1] [PMID: 9288759]
[41]
Ciccarone, V.; Spengler, B.A.; Meyers, M.B.; Biedler, J.L.; Ross, R.A. Phenotypic diversification in human neuroblastoma cells: Expression of distinct neural crest lineages. Cancer Res., 1989, 49(1), 219-225.
[PMID: 2535691]
[42]
Keshelava, N.; Zuo, J.J.; Chen, P.; Waidyaratne, S.N.; Luna, M.C.; Gomer, C.J.; Triche, T.J.; Reynolds, C.P. Loss of p53 function confers high-level multidrug resistance in neuroblastoma cell lines. Cancer Res., 2001, 61(16), 6185-6193.
[PMID: 11507071]
[43]
Mazar, J.; Rosado, A.; Shelley, J.; Marchica, J.; Westmoreland, T.J. The long non-coding RNA GAS5 differentially regulates cell cycle arrest and apoptosis through activation of BRCA1 and p53 in human neuroblastoma. Oncotarget, 2017, 8(4), 6589-6607.
[http://dx.doi.org/10.18632/oncotarget.14244] [PMID: 28035057]
[44]
May, P.; May, E. Twenty years of p53 research: Structural and functional aspects of the p53 protein. Oncogene, 1999, 18(53), 7621-7636.
[http://dx.doi.org/10.1038/sj.onc.1203285] [PMID: 10618702]
[45]
Ko, L.J.; Prives, C. p53: Puzzle and paradigm. Genes Dev., 1996, 10(9), 1054-1072.
[http://dx.doi.org/10.1101/gad.10.9.1054] [PMID: 8654922]
[46]
Look, A.T.; Hayes, F.A.; Shuster, J.J.; Douglass, E.C.; Castleberry, R.P.; Bowman, L.C.; Smith, E.I.; Brodeur, G.M. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: A Pediatric Oncology Group study. J. Clin. Oncol., 1991, 9(4), 581-591.
[http://dx.doi.org/10.1200/JCO.1991.9.4.581] [PMID: 2066755]

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