Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Drug Repurposing Screen Identifies Novel Classes of Drugs with Anticancer Activity in Mantle Cell Lymphoma

Author(s): Chengwu Han, Xueying Yu, Chunxia Zhang, Ying Cai, Yongyue Cao, Sijie Wang and Jun Shen*

Volume 22, Issue 7, 2019

Page: [483 - 495] Pages: 13

DOI: 10.2174/1386207322666190916120128

Price: $65

Abstract

Aim and Objective: Mantle Cell Lymphoma (MCL) is typically an aggressive and rare disease with poor prognosis, therefore new effective therapeutics are urgently needed. Drug repurposing for cancer treatment is becoming increasingly more attractive as an alternative approach to discover clinically approved drugs that demonstrate antineoplastic effect. The objective of this study was to screen an approved drug library and identify candidate compounds with an antineoplastic effect in MCL cells using High-Throughput Screening (HTS) technique.

Materials and Methods: Using the HTS technique, nearly 3,800 clinically approved drugs and drug candidates were screened in Jeko and Mino MCL cell lines. We also demonstrated the selectivity window of the candidate compounds in six normal cell lines. Further validations were performed in caspase-3/7 apoptosis assay and three-dimensional (3D) multicellular aggregates model using Z138 cell line.

Results: We identified 98 compounds showing >50% inhibition in either MCL cell line screened, they were distributed across eight unique therapeutic categories and have different mechanisms of action (MOA). We selected alisertib, carfilzomib, pracinostat and YM155 for further validation based on their antiproliferative activity in two MCL cell lines, selectivity to normal cell lines, and drug developing stages in terms of clinical research. Alisertib and carfilzomib showed antiproliferative effect on MCL cell with EC50 = 6 nM and >100-fold selectivity to normal cell lines, especially for alisertib which demonstrated >1000-fold selectivity to 5 out of 6 normal cell lines. Pracinostat and YM155 had potency of 11 and 12 nM in MCL cell with >20-fold selectivity to normal cell lines. All four compounds had been tested in caspase-dependent apoptosis assay. We further validated and demonstrated their anti-MCL effect on cell proliferation and (3D) multicellular aggregates model using Z138 cell line.

Conclusion: This is the first study to examine such a large library of clinically approved compounds for the identification of novel drug candidates for MCL treatment, the results could be rapidly translated into clinical practice in patients with MCL.

Keywords: Mantel cell lymphoma, high-throughput screening, approved drugs, drug repurposing, chemotherapy.

« Previous Next »
[1]
Skarbnik, A.P.; Goy, A.H. Mantle cell lymphoma: State of the art. Clin. Adv. Hematol. Oncol., 2015, 13(1), 44-55.
[PMID: 25679973]
[2]
Fakhri, B.; Kahl, B. Current and emerging treatment options for mantle cell lymphoma. Ther. Adv. Hematol., 2017, 8(8), 223-234.
[http://dx.doi.org/10.1177/2040620717719616] [PMID: 28811872]
[3]
Rajabi, B.; Sweetenham, J.W. Mantle cell lymphoma: Observation to transplantation. Ther. Adv. Hematol., 2015, 6(1), 37-48.
[http://dx.doi.org/10.1177/2040620714561579] [PMID: 25642314]
[4]
Steiner, R.E.; Romaguera, J.; Wang, M. Current trials for frontline therapy of mantle cell lymphoma. J. Hematol. Oncol., 2018, 11(1), 13.
[http://dx.doi.org/10.1186/s13045-018-0556-x] [PMID: 29374487]
[5]
Hambley, B.; Caimi, P.F.; William, B.M. Bortezomib for the treatment of mantle cell lymphoma: An update. Ther. Adv. Hematol., 2016, 7(4), 196-208.
[http://dx.doi.org/10.1177/2040620716648566] [PMID: 27493710]
[6]
Stephens, D.M.; Spurgeon, S.E. Ibrutinib in mantle cell lymphoma patients: glass half full? Evidence and opinion. Ther. Adv. Hematol., 2015, 6(5), 242-252.
[http://dx.doi.org/10.1177/2040620715592569] [PMID: 26425337]
[7]
Martin, P.; Ghione, P.; Dreyling, M. Mantle cell lymphoma - Current standards of care and future directions. Cancer Treat. Rev., 2017, 58, 51-60.
[http://dx.doi.org/10.1016/j.ctrv.2017.05.008] [PMID: 28651117]
[8]
Campo, E.; Rule, S. Mantle cell lymphoma: Evolving management strategies. Blood, 2015, 125(1), 48-55.
[http://dx.doi.org/10.1182/blood-2014-05-521898] [PMID: 25499451]
[9]
McCabe, B.; Liberante, F.; Mills, K.I. Repurposing medicinal compounds for blood cancer treatment. Ann. Hematol., 2015, 94(8), 1267-1276.
[http://dx.doi.org/10.1007/s00277-015-2412-1] [PMID: 26048243]
[10]
Ho, W.J.; Pham, E.A.; Kim, J.W.; Ng, C.W.; Kim, J.H.; Kamei, D.T.; Wu, B.M. Incorporation of multicellular spheroids into 3-D polymeric scaffolds provides an improved tumor model for screening anticancer drugs. Cancer Sci., 2010, 101(12), 2637-2643.
[http://dx.doi.org/10.1111/j.1349-7006.2010.01723.x] [PMID: 20849469]
[11]
Trédan, O.; Galmarini, C.M.; Patel, K.; Tannock, I.F. Drug resistance and the solid tumor microenvironment. J. Natl. Cancer Inst., 2007, 99(19), 1441-1454.
[http://dx.doi.org/10.1093/jnci/djm135] [PMID: 17895480]
[12]
Kim, H.; Phung, Y.; Ho, M. Changes in global gene expression associated with 3D structure of tumors: An ex vivo matrix-free mesothelioma spheroid model. PLoS One, 2012, 7(6)e39556
[http://dx.doi.org/10.1371/journal.pone.0039556] [PMID: 22737246]
[13]
Manfredi, M.G.; Ecsedy, J.A.; Chakravarty, A.; Silverman, L.; Zhang, M.; Hoar, K.M.; Stroud, S.G.; Chen, W.; Shinde, V.; Huck, J.J.; Wysong, D.R.; Janowick, D.A.; Hyer, M.L.; Leroy, P.J.; Gershman, R.E.; Silva, M.D.; Germanos, M.S.; Bolen, J.B.; Claiborne, C.F.; Sells, T.B. Characterization of alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin. Cancer Res., 2011, 17(24), 7614-7624.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1536] [PMID: 22016509]
[14]
Görgün, G.; Calabrese, E.; Hideshima, T.; Ecsedy, J.; Perrone, G.; Mani, M.; Ikeda, H.; Bianchi, G.; Hu, Y.; Cirstea, D.; Santo, L.; Tai, Y.T.; Nahar, S.; Zheng, M.; Bandi, M.; Carrasco, R.D.; Raje, N.; Munshi, N.; Richardson, P.; Anderson, K.C. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood, 2010, 115(25), 5202-5213.
[http://dx.doi.org/10.1182/blood-2009-12-259523] [PMID: 20382844]
[15]
Liewer, S.; Huddleston, A. Alisertib: A review of pharmacokinetics, efficacy and toxicity in patients with hematologic malignancies and solid tumors. Expert Opin. Investig. Drugs, 2018, 27(1), 105-112.
[http://dx.doi.org/10.1080/13543784.2018.1417382] [PMID: 29260599]
[16]
Jain, S.; Diefenbach, C.; Zain, J.; O’Connor, O.A. Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evid., 2011, 6, 43-57.
[http://dx.doi.org/10.2147/CE.S13838] [PMID: 21654882]
[17]
Wright, J.J. Combination therapy of bortezomib with novel targeted agents: An emerging treatment strategy. Clin. Cancer Res., 2010, 16(16), 4094-4104.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-2882] [PMID: 20682705]
[18]
Demo, S.D.; Kirk, C.J.; Aujay, M.A.; Buchholz, T.J.; Dajee, M.; Ho, M.N.; Jiang, J.; Laidig, G.J.; Lewis, E.R.; Parlati, F.; Shenk, K.D.; Smyth, M.S.; Sun, C.M.; Vallone, M.K.; Woo, T.M.; Molineaux, C.J.; Bennett, M.K. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res., 2007, 67(13), 6383-6391.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4086] [PMID: 17616698]
[19]
Novotny-Diermayr, V.; Sangthongpitag, K.; Hu, C.Y.; Wu, X.; Sausgruber, N.; Yeo, P.; Greicius, G.; Pettersson, S.; Liang, A.L.; Loh, Y.K.; Bonday, Z.; Goh, K.C.; Hentze, H.; Hart, S.; Wang, H.; Ethirajulu, K.; Wood, J.M. SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer. Mol. Cancer Ther., 2010, 9(3), 642-652.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0689] [PMID: 20197387]
[20]
Ganai, S.A. Histone deacetylase inhibitor pracinostat in doublet therapy: a unique strategy to improve therapeutic efficacy and to tackle herculean cancer chemoresistance. Pharm. Biol., 2016, 54(9), 1926-1935.
[http://dx.doi.org/10.3109/13880209.2015.1135966] [PMID: 26853619]
[21]
Eckschlager, T.; Plch, J.; Stiborova, M.; Hrabeta, J. Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci., 2017, 18(7), 1414.
[http://dx.doi.org/10.3390/ijms18071414] [PMID: 28671573]
[22]
Ryan, B.M.; O’Donovan, N.; Duffy, M.J. Survivin: A new target for anti-cancer therapy. Cancer Treat. Rev., 2009, 35(7), 553-562.
[http://dx.doi.org/10.1016/j.ctrv.2009.05.003] [PMID: 19559538]
[23]
Cheson, B.D.; Bartlett, N.L.; Vose, J.M.; Lopez-Hernandez, A.; Seiz, A.L.; Keating, A.T.; Shamsili, S.; Papadopoulos, K.P. A phase II study of the survivin suppressant YM155 in patients with refractory diffuse large B-cell lymphoma. Cancer, 2012, 118(12), 3128-3134.
[http://dx.doi.org/10.1002/cncr.26510] [PMID: 22006123]
[24]
Nakahara, T.; Kita, A.; Yamanaka, K.; Mori, M.; Amino, N.; Takeuchi, M.; Tominaga, F.; Hatakeyama, S.; Kinoyama, I.; Matsuhisa, A.; Kudoh, M.; Sasamata, M. YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res., 2007, 67(17), 8014-8021.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-1343] [PMID: 17804712]
[25]
Cohen, J.L.; Jao, J.Y. Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat. J. Pharmacol. Exp. Ther., 1970, 174(2), 206-210.
[PMID: 4393764]

Rights & Permissions Print Cite
Article Metrics
33
3
© 2024 Bentham Science Publishers | Privacy Policy