Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor

  • Authors:
    • Chie Ishikawa
    • Masachika Senba
    • Naoki Mori
  • View Affiliations

  • Published online on: August 1, 2018     https://doi.org/10.3892/ijo.2018.4513
  • Pages: 1681-1690
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Adult T‑cell leukemia/lymphoma (ATLL) constitutes an aggressive malignancy caused by human T‑cell leukemia virus type 1 (HTLV‑1) that is resistant to available chemotherapeutics. The constitutive activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is an important feature of ATLL, and spleen tyrosine kinase (SYK) is overexpressed in HTLV‑1-transformed T‑cell lines. In this study, we evaluated the effects of SYK- (PRT060318) or JAK- (JAK inhibitor 1) selective inhibitors and the dual SYK/JAK inhibitor, cerdulatinib, on the viability of HTLV‑1-transformed and ATLL-derived T‑cell lines. Cell proliferation, viability, cell cycle, apoptosis and intracellular signaling cascades were analyzed by the water-soluble tetrazolium-8 assay, flow cytometry and western blot analysis. HTLV‑1-infected T‑cell lines were sensitive to both SYK-selective and pan-JAK inhibitors, whereas cerdulatinib more potently suppressed cell proliferation and reduced cell viability than either of these agents alone. By contrast, the cytotoxic effects of cerdulatinib on uninfected T‑cell lines and peripheral blood mononuclear cells from a healthy donor were less pronounced. Cerdulatinib induced cell cycle arrest in the G2/M phase, which was associated with a decreased cyclin-dependent kinase 1 and cyclin B1, and an increased p21 and p27 expression. Hoechst staining revealed chromatin condensation and nuclear fragmentation in the cells treated with cerdulatinib, and an increased fraction of apoptotic APO2.7-stained cells was detected by flow cytometry. This corresponded to the activation of caspase-8, -9 and -3, and decreased levels of the anti-apoptotic factors, Bcl-xL, survivin, X-linked inhibitor of apoptosis (XIAP) and c‑FLIP. The cerdulatinib-induced decrease in cell viability was partly reversed by the caspase inhibitor, z‑VAD‑FMK. These anti-ATLL effects were associated with the suppression of SYK and JAK/STAT signaling, along with that of the downstream factors, AKT, ERK, activator protein‑1 and nuclear factor-κB. Finally, oral dosing with cerdulatinib lowered the tumor burden in a murine model of ATLL. Thus, our findings indicate that the simultaneous inhibition of therapeutically relevant targets, such as SYK and JAK is a more effective approach than single-agent therapy for the treatment of ATLL.

References

1 

Iwanaga M, Watanabe T and Yamaguchi K: Adult T-cell leukemia: A review of epidemiological evidence. Front Microbiol. 3:3222012. View Article : Google Scholar : PubMed/NCBI

2 

Katsuya H and Ishitsuka K: Treatment advances and prognosis for patients with adult T-cell leukemia-lymphoma. J Clin Exp Hematop. 57:87–97. 2017. View Article : Google Scholar : PubMed/NCBI

3 

Yssel H, de Waal Malefyt R, Duc Dodon MD, Blanchard D, Gazzolo L, de Vries JE and Spits H: Human T cell leukemia/lymphoma virus type I infection of a CD4+ proliferative/cytotoxic T cell clone progresses in at least two distinct phases based on changes in function and phenotype of the infected cells. J Immunol. 142:2279–2289. 1989.PubMed/NCBI

4 

Miyazaki T and Taniguchi T: Coupling of the IL2 receptor complex with non-receptor protein tyrosine kinases. Cancer Surv. 27:25–40. 1996.PubMed/NCBI

5 

Rochman Y, Spolski R and Leonard WJ: New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 9:480–490. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Migone TS, Lin JX, Cereseto A, Mulloy JC, O'Shea JJ, Franchini G and Leonard WJ: Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science. 269:79–81. 1995. View Article : Google Scholar : PubMed/NCBI

7 

Xu X, Kang SH, Heidenreich O, Okerholm M, O'Shea JJ and Nerenberg MI: Constitutive activation of different Jak tyrosine kinases in human T cell leukemia virus type 1 (HTLV-1) tax protein or virus-transformed cells. J Clin Invest. 96:1548–1555. 1995. View Article : Google Scholar : PubMed/NCBI

8 

Takemoto S, Mulloy JC, Cereseto A, Migone T-S, Patel BKR, Matsuoka M, Yamaguchi K, Takatsuki K, Kamihira S, White JD, et al: Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins. Proc Natl Acad Sci USA. 94:13897–13902. 1997. View Article : Google Scholar

9 

Ju W, Zhang M, Jiang J-K, Thomas CJ, Oh U, Bryant BR, Chen J, Sato N, Tagaya Y, Morris JC, et al: CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP. Blood. 117:1938–1946. 2011. View Article : Google Scholar :

10 

Zhang M, Mathews Griner LA, Ju W, Duveau DY, Guha R, Petrus MN, Wen B, Maeda M, Shinn P, Ferrer M, et al: Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2-dependent adult T-cell leukemia. Proc Natl Acad Sci USA. 112:12480–12485. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Weil R, Levraud J-P, Dodon MD, Bessia C, Hazan U, Kourilsky P and Israël A: Altered expression of tyrosine kinases of the Src and Syk families in human T-cell leukemia virus type 1-infected T-cell lines. J Virol. 73:3709–3717. 1999.PubMed/NCBI

12 

Coffey G, Betz A, DeGuzman F, Pak Y, Inagaki M, Baker DC, Hollenbach SJ, Pandey A and Sinha U: The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther. 351:538–548. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Ma J, Xing W, Coffey G, Dresser K, Lu K, Guo A, Raca G, Pandey A, Conley P, Yu H, et al: Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma. Oncotarget. 6:43881–43896. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Blunt MD, Koehrer S, Dobson RC, Larrayoz M, Wilmore S, Hayman A, Parnell J, Smith LD, Davies A, Johnson PWM, et al: The dual Syk/JAK inhibitor cerdulatinib antagonizes B-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia. Clin Cancer Res. 23:2313–2324. 2017. View Article : Google Scholar

15 

Guo A, Lu P, Coffey G, Conley P, Pandey A and Wang YL: Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment. Oncotarget. 8:12953–12967. 2017.PubMed/NCBI

16 

Liu D and Mamorska-Dyga A: Syk inhibitors in clinical development for hematological malignancies. J Hematol Oncol. 10:1452017. View Article : Google Scholar : PubMed/NCBI

17 

Stapper NJ, Stuschke M, Sak A and Stüben G: Radiation-induced apoptosis in human sarcoma and glioma cell lines. Int J Cancer. 62:58–62. 1995. View Article : Google Scholar : PubMed/NCBI

18 

Mori N and Prager D: Transactivation of the interleukin-1alpha promoter by human T-cell leukemia virus type I and type II Tax proteins. Blood. 87:3410–3417. 1996.PubMed/NCBI

19 

Ishikawa C, Senba M and Mori N: Butein inhibits NF-κB, AP-1 and Akt activation in adult T-cell leukemia/lymphoma. Int J Oncol. 51:633–643. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Tomayko MM and Reynolds CP: Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol. 24:148–154. 1989. View Article : Google Scholar : PubMed/NCBI

21 

Mócsai A, Ruland J and Tybulewicz VL: The SYK tyrosine kinase: A crucial player in diverse biological functions. Nat Rev Immunol. 10:387–402. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Zheng Z, Li Z, Chen S, Pan J and Ma X: Tetramethylpyrazine attenuates TNF-α-induced iNOS expression in human endothelial cells: Involvement of Syk-mediated activation of PI3K-IKK-IκB signaling pathways. Exp Cell Res. 319:2145–2151. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Hatton O, Lambert SL, Krams SM and Martinez OM: Src kinase and Syk activation initiate PI3K signaling by a chimeric latent membrane protein 1 in Epstein-Barr virus (EBV)+ B cell lymphomas. PLoS One. 7:e426102012. View Article : Google Scholar : PubMed/NCBI

24 

Wang LH, Kirken RA, Erwin RA, Yu C-R and Farrar WL: JAK3, STAT, and MAPK signaling pathways as novel molecular targets for the tyrphostin AG-490 regulation of IL-2-mediated T cell response. J Immunol. 162:3897–3904. 1999.PubMed/NCBI

25 

Sherr CJ: Cancer cell cycles. Science. 274:1672–1677. 1996. View Article : Google Scholar : PubMed/NCBI

26 

Karimian A, Ahmadi Y and Yousefi B: Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst). 42:63–71. 2016. View Article : Google Scholar

27 

Hu X and Moscinski LC: Cdc2: A monopotent or pluripotent CDK? Cell Prolif. 44:205–211. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Guadagno TM and Newport JW: Cdk2 kinase is required for entry into mitosis as a positive regulator of Cdc2-cyclin B kinase activity. Cell. 84:73–82. 1996. View Article : Google Scholar : PubMed/NCBI

29 

Yadav S, Kalra N, Ganju L and Singh M: Activator protein-1 (AP-1): A bridge between life and death in lung epithelial (A549) cells under hypoxia. Mol Cell Biochem. 436:99–110. 2017. View Article : Google Scholar : PubMed/NCBI

30 

Zhang Y-X, Li X-F, Yuan G-Q, Hu H, Song X-Y, Li J-Y, Miao X-K, Zhou T-X, Yang W-L, Zhang X-W, et al: β-Arrestin 1 has an essential role in neurokinin-1 receptor-mediated glioblastoma cell proliferation and G2/M phase transition. J Biol Chem. 292:8933–8947. 2017. View Article : Google Scholar : PubMed/NCBI

31 

Manning BD and Cantley LC: AKT/PKB signaling: Navigating downstream. Cell. 129:1261–1274. 2007. View Article : Google Scholar : PubMed/NCBI

32 

Roy SK, Srivastava RK and Shankar S: Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal. 5:102010. View Article : Google Scholar : PubMed/NCBI

33 

Das D, Pintucci G and Stern A: MAPK-dependent expression of p21(WAF) and p27(kip1) in PMA-induced differentiation of HL60 cells. FEBS Lett. 472:50–52. 2000. View Article : Google Scholar : PubMed/NCBI

34 

Kim R, Tanabe K, Uchida Y, Emi M, Inoue H and Toge T: Current status of the molecular mechanisms of anticancer drug-induced apoptosis. The contribution of molecular-level analysis to cancer chemotherapy. Cancer Chemother Pharmacol. 50:343–352. 2002. View Article : Google Scholar : PubMed/NCBI

35 

Krueger A, Baumann S, Krammer PH and Kirchhoff S: FLICE-inhibitory proteins: Regulators of death receptor-mediated apoptosis. Mol Cell Biol. 21:8247–8254. 2001. View Article : Google Scholar : PubMed/NCBI

36 

Catlett-Falcone R, Dalton WS and Jove R: STAT proteins as novel targets for cancer therapy. Signal transducer an activator of transcription. Curr Opin Oncol. 11:490–496. 1999. View Article : Google Scholar : PubMed/NCBI

37 

Zheng HC: The molecular mechanisms of chemoresistance in cancers. Oncotarget. 8:59950–59964. 2017.PubMed/NCBI

38 

Allan LA, Morrice N, Brady S, Magee G, Pathak S and Clarke PR: Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol. 5:647–654. 2003. View Article : Google Scholar : PubMed/NCBI

39 

Asselin E, Mills GB and Tsang BK: XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer Res. 61:1862–1868. 2001.PubMed/NCBI

40 

Liang YL, Wang LY, Wu H, Ma DZ, Xu Z and Zha XL: PKB phosphorylation and survivin expression are cooperatively regulated by disruption of microfilament cytoskeleton. Mol Cell Biochem. 254:257–263. 2003. View Article : Google Scholar : PubMed/NCBI

41 

Vaira V, Lee CW, Goel HL, Bosari S, Languino LR and Altieri DC: Regulation of survivin expression by IGF-1/mTOR signaling. Oncogene. 26:2678–2684. 2007. View Article : Google Scholar

42 

Hamlin PA, Farber CM, Fenske TS, Khatcheressian JL, Miller CB, Munoz J, Patel MR, Schreeder MT, Smith SM, Stevens DA, et al: The dual SYK/JAK inhibitor cerdulatinib demonstrates rapid tumor responses in a phase 2 study in patients with relapsed/refractory B-cell malignancies. Hematol Oncol. 35:742017. View Article : Google Scholar

Related Articles

Journal Cover

October 2018
Volume 53 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Ishikawa, C., Senba, M., & Mori, N. (2018). Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor. International Journal of Oncology, 53, 1681-1690. https://doi.org/10.3892/ijo.2018.4513
MLA
Ishikawa, C., Senba, M., Mori, N."Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor". International Journal of Oncology 53.4 (2018): 1681-1690.
Chicago
Ishikawa, C., Senba, M., Mori, N."Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor". International Journal of Oncology 53, no. 4 (2018): 1681-1690. https://doi.org/10.3892/ijo.2018.4513