Generic placeholder image

Current Cancer Drug Targets

Author(s): Man Zhu, Yanhong Liu, Panpan Lei, Xianpeng Shi, Wenjuan Tang, Xiaoyue Huang, Xiaoyan Pan, Cheng Wang and Weina Ma*

DOI: 10.2174/1568009622666220225121009

DownloadDownload PDF Flyer Cite As
ND-16: A Novel Compound for Inhibiting the Growth of Cutaneous T Cell Lymphoma by Targeting JAK2

Page: [328 - 339] Pages: 12

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Objective: Cutaneous T cell lymphoma (CTCL) is a kind of extranodal non-Hodgkin Tcell lymphoma without healable treatment in the clinic. JAK2 amplification in CTCL patients makes it a potential target for CTCL treatment. In the present study, we aimed to evaluate the anticancer effect of ND-16, a novel nilotinib derivate, on CTCL cells and the underlying mechanism targeting JAK2.

Methods and Results: We found that ND-16 was capable of regulating JAK2 and had a selective inhibitory effect on CTCL H9 cells. The surface plasmon resonance and molecular docking study indicated ND-16 bound to JAK2 with a high binding affinity. Further investigation revealed that ND-16 inhibited the downstream cascades of JAK2, including STATs, PI3K/AKT/mTOR, and MAPK pathways, followed by regulation of Bcl-2 family members and cell cycle proteins CDK/- Cyclins. Flow cytometry analysis confirmed these results that ND-16-treated H9 cells showed cell apoptosis and cell cycle arrest at S-phase.

Conclusion: ND-16 may be of value in a potential therapy for the management of CTCL.

Keywords: Cutaneous T-cell lymphoma, ND-16, JAK2, growth, novel compound, apoptosis.

Graphical Abstract

[1]
Wu, C.H.; Yang, C.Y.; Wang, L.; Gao, H.X.; Rakhshandehroo, T.; Afghani, S.; Pincus, L.; Balassanian, R.; Rubenstein, J.; Gill, R.; Bandyopadhyay, S.; McCormick, F.; Moasser, M.; Ai, W.Z. Cutaneous T-Cell lymphoma PDX drug screening platform identifies cooperation between inhibitions of PI3Kα/δ and HDAC. J. Invest. Dermatol., 2021, 141(2), 364-373.
[http://dx.doi.org/10.1016/j.jid.2020.05.110] [PMID: 32603749]
[2]
Durgin, J.S.; Weiner, D.M.; Wysocka, M.; Rook, A.H. The immunopathogenesis and immunotherapy of cutaneous T cell lymphoma: Pathways and targets for immune restoration and tumor eradication. J. Am. Acad. Dermatol., 2021, 84(3), 587-595.
[http://dx.doi.org/10.1016/j.jaad.2020.12.027] [PMID: 33352267]
[3]
Shea, L.; Mehta-Shah, N. Brentuximab vedotin in the treatment of peripheral T Cell lymphoma and cutaneous T cell lymphoma. Curr. Hematol. Malig. Rep., 2020, 15(1), 9-19.
[http://dx.doi.org/10.1007/s11899-020-00561-w] [PMID: 32016790]
[4]
Hin Tang, J.J.; Hao Thng, D.K.; Lim, J.J.; Toh, T.B. JAK/STAT signaling in hepatocellular carcinoma. Hepat. Oncol., 2020, 7(1), HEP18.
[http://dx.doi.org/10.2217/hep-2020-0001] [PMID: 32273976]
[5]
Hashimoto, R.; Kakigi, R.; Miyamoto, Y.; Nakamura, K.; Itoh, S.; Daida, H.; Okada, T.; Katoh, Y. JAK-STAT-dependent regulation of scavenger receptors in LPS-activated murine macrophages. Eur. J. Pharmacol., 2020, 871, 172940.
[http://dx.doi.org/10.1016/j.ejphar.2020.172940] [PMID: 31968212]
[6]
Anand, S.; Stedham, F.; Gudgin, E.; Campbell, P.; Beer, P.; Green, A.R.; Huntly, B.J. Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms. Blood, 2011, 118(6), 1610-1621.
[http://dx.doi.org/10.1182/blood-2011-02-335042] [PMID: 21653937]
[7]
O’Sullivan, J.M.; Harrison, C.N. JAK-STAT signaling in the therapeutic landscape of myeloproliferative neoplasms. Mol. Cell. Endocrinol., 2017, 451, 71-79.
[http://dx.doi.org/10.1016/j.mce.2017.01.050] [PMID: 28167129]
[8]
Choi, J.; Goh, G.; Walradt, T.; Hong, B.S.; Bunick, C.G.; Chen, K.; Bjornson, R.D.; Maman, Y.; Wang, T.; Tordoff, J.; Carlson, K.; Overton, J.D.; Liu, K.J.; Lewis, J.M.; Devine, L.; Barbarotta, L.; Foss, F.M.; Subtil, A.; Vonderheid, E.C.; Edelson, R.L.; Schatz, D.G.; Boggon, T.J.; Girardi, M.; Lifton, R.P. Genomic landscape of cutaneous T cell lymphoma. Nat. Genet., 2015, 47(9), 1011-1019.
[http://dx.doi.org/10.1038/ng.3356] [PMID: 26192916]
[9]
Yumeen, S.; Mirza, F.N.; Lewis, J.M.; King, A.L.O.; Kim, S.R.; Carlson, K.R.; Umlauf, S.R.; Surovtseva, Y.V.; Foss, F.M.; Girardi, M. JAK inhibition synergistically potentiates BCL2, BET, HDAC, and proteasome inhibition in advanced CTCL. Blood Adv., 2020, 4(10), 2213-2226.
[http://dx.doi.org/10.1182/bloodadvances.2020001756] [PMID: 32437546]
[10]
Panagopoulos, I.; Gorunova, L.; Spetalen, S.; Bassarova, A.; Beiske, K.; Micci, F.; Heim, S. Fusion of the genes ataxin 2 like, ATXN2L, and Janus kinase 2, JAK2, in cutaneous CD4 positive T- cell lymphoma. Oncotarget, 2017, 8(61), 103775-103784.
[http://dx.doi.org/10.18632/oncotarget.21790] [PMID: 29262599]
[11]
Sacha, T.; Saglio, G. Nilotinib in the treatment of chronic myeloid leukemia. Future Oncol., 2019, 15(9), 953-965.
[http://dx.doi.org/10.2217/fon-2018-0468] [PMID: 30547682]
[12]
Pan, X.; Wang, F.; Zhang, Y.; Gao, H.; Hu, Z.; Wang, S.; Zhang, J. Design, synthesis and biological activities of Nilotinib derivates as antitumor agents. Bioorg. Med. Chem., 2013, 21(9), 2527-2534.
[http://dx.doi.org/10.1016/j.bmc.2013.02.036] [PMID: 23538233]
[13]
Lokau, J.; Schoeder, V.; Haybaeck, J.; Garbers, C. Jak-stat signaling induced by interleukin-6 family cytokines in hepatocellular carcinoma. Cancers (Basel), 2019, 11(11), 1704.
[http://dx.doi.org/10.3390/cancers11111704] [PMID: 31683891]
[14]
Reddy, D.; Kumavath, R.; Ghosh, P.; Barh, D. Lanatoside C induces G2/M cell cycle arrest and suppresses cancer cell growth by attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR signaling pathways. Biomolecules, 2019, 9(12), 792.
[http://dx.doi.org/10.3390/biom9120792] [PMID: 31783627]
[15]
Li, K.; Yuan, D.; Yan, R.; Meng, L.; Zhang, Y.; Zhu, K. Stigmasterol exhibits potent antitumor effects in human gastric cancer cells mediated via inhibition of cell migration, cell cycle arrest, mitochondrial mediated apoptosis and inhibition of JAK/STAT signalling pathway. J. BUON, 2018, 23(5), 1420-1425.
[PMID: 30570868]
[16]
Liu, J.S.; Huo, C.Y.; Cao, H.H.; Fan, C.L.; Hu, J.Y.; Deng, L.J.; Lu, Z.B.; Yang, H.Y.; Yu, L.Z.; Mo, Z.X.; Yu, Z.L. Aloperine induces apoptosis and G2/M cell cycle arrest in hepatocellular carcinoma cells through the PI3K/Akt signaling pathway. Phytomedicine, 2019, 61, 152843.
[http://dx.doi.org/10.1016/j.phymed.2019.152843] [PMID: 31039533]
[17]
Fisher, D.A.C.; Miner, C.A.; Engle, E.K.; Hu, H.; Collins, T.B.; Zhou, A.; Allen, M.J.; Malkova, O.N.; Oh, S.T. Cytokine production in myelofibrosis exhibits differential responsiveness to JAK-STAT, MAP kinase, and NFκB signaling. Leukemia, 2019, 33(8), 1978-1995.
[http://dx.doi.org/10.1038/s41375-019-0379-y] [PMID: 30718771]
[18]
Owen, K.L.; Brockwell, N.K.; Parker, B.S. JAK-STAT signaling: A double-edged sword of immune regulation and cancer progression. Cancers (Basel), 2019, 11(12), 2002.
[http://dx.doi.org/10.3390/cancers11122002] [PMID: 31842362]
[19]
Xia, L.; Wu, L.; Xia, H.; Bao, J.; Li, Q.; Chen, X.; Xia, R. miR-337 suppresses cutaneous T-cell lymphoma via the STAT3 pathway. Cell Cycle, 2019, 18(14), 1635-1645.
[http://dx.doi.org/10.1080/15384101.2019.1629789] [PMID: 31213131]
[20]
Zhang, Y.; Liu, Z. STAT1 in cancer: friend or foe? Discov. Med., 2017, 24(130), 19-29.
[PMID: 28950072]
[21]
Jiang, L.; Zhao, X.H.; Mao, Y.L.; Wang, J.F.; Zheng, H.J.; You, Q.S. Long non-coding RNA RP11-468E2.5 curtails colorectal cancer cell proliferation and stimulates apoptosis via the JAK/STAT signaling pathway by targeting STAT5 and STAT6. J. Exp. Clin. Cancer Res., 2019, 38(1), 465.
[http://dx.doi.org/10.1186/s13046-019-1428-0] [PMID: 31718693]
[22]
Zhang, Z.H.; Li, M.Y.; Wang, Z.; Zuo, H.X.; Wang, J.Y.; Xing, Y.; Jin, C.; Xu, G.; Piao, L.; Piao, H.; Ma, J.; Jin, X. Convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer. Phytomedicine, 2020, 68, 153172.
[http://dx.doi.org/10.1016/j.phymed.2020.153172] [PMID: 32004989]
[23]
Machado-Neto, J.A.; Coelho-Silva, J.L.; Santos, F.P.S.; Scheucher, P.S.; Campregher, P.V.; Hamerschlak, N.; Rego, E.M.; Traina, F. Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2V617F cells. Invest. New Drugs, 2020, 38(3), 733-745.
[http://dx.doi.org/10.1007/s10637-019-00812-5] [PMID: 31286322]
[24]
Warren, C.F.A.; Wong-Brown, M.W.; Bowden, N.A. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis., 2019, 10(3), 177.
[http://dx.doi.org/10.1038/s41419-019-1407-6] [PMID: 30792387]
[25]
Matsumoto, Y.; Maller, J.L. A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry. Science, 2004, 306(5697), 885-888.
[http://dx.doi.org/10.1126/science.1103544] [PMID: 15514162]
[26]
Silva Cascales, H.; Burdova, K.; Middleton, A.; Kuzin, V.; Müllers, E.; Stoy, H.; Baranello, L.; Macurek, L.; Lindqvist, A. Cyclin A2 localises in the cytoplasm at the S/G2 transition to activate PLK1. Life Sci. Alliance, 2021, 4(3), e202000980.
[http://dx.doi.org/10.26508/lsa.202000980] [PMID: 33402344]