Combination Effect of Notch1 and PI3K / AKT / mTOR Signaling Pathways Inhibitors on T-ALL Cell Lines

  • Halimeh Khoshamooz Department of Hematology and Blood Banking, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran
  • Saeid Kaviani Department of Hematology, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran
  • Amir Atashi Department of Basic Sciences, School of Medicine, Shahroud University of Medical Sciences, Shahrood, Iran
  • Seyed Hossein Mirpour Hassankiadeh Department of Internal Medicine, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
Keywords:
Synergistic interaction; AZD5363; Compound E; Acute T-lymphoblastic leukemia

Abstract

Background: Acute T lymphoblastic Leukemia (T-ALL) is a highly aggressive hematologic malignancy. Chemotherapy resistance is one of the most important challenges in T-ALL treatment. Alterations in cellular signaling pathways such as Notch1 and PI3K / AKT / mTOR play a role in cell proliferation, survival, and resistance to chemotherapy. Combination of Notch1 and PI3K / AKT / mTOR inhibitors is an interesting and rational strategy in treatment of T-ALL. Interaction of AZD5363 as an inhibitor of PI3k / AKT / mTOR and Compound E as an inhibitor of Notch1 signaling pathway was investigated in a T-ALL pre-clinical model.

Materials and Methods: T-ALL cell lines included Jurkat, Molt-4, and HPB- ALL cells were treated with AZD5363 and Compound E alone and in combination. Cell viability was determined by MTT assay. Flow cytometry was used to measure apoptosis. Interaction between AZD5363 and Compound E was assessed by Chou-Talalay method.

Results: Combination treatment with AZD5363 and Compound E decreased cell viability with synergistic effect in all cell lines at 72 hours. Drug combination increased apoptosis even in Jurkat and HPB-ALL cells resistant to Compound E and AZD5363, respectively.

Conclusion: Combination of AZD5363 with Compound E in T-ALL cell lines exhibited a synergistic effect. Cytotoxicity of drug combination increased in all T-ALL cell lines compared to each as a single drug. Simultaneous inhibition of Notch1 and PI3K / AKT signaling pathways as a possible treatment of T-ALL, provides a basis for future investigations.

Author Biography

Saeid Kaviani, Department of Hematology, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran

Department of Hematology,Faculty of Medicine,Tarbiat Modares University,Tehran,Iran.

References

REFERENCES
1. Fielding AK, Banerjee L, Marks DI, et al. Recent developments in the management of T-cell precursor acute lymphoblastic leukemia/lymphoma. Curr Hematol Malig Rep.2012; 7( 2): 160–9.
2. Bongiovanni D, Saccomani V, Piovan E, et al. Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia. Int J Mol Sci. 2017; 18( 9). pii: E1904.
3. Marks DI, Rowntree C. Management of adults with T-cell lymphoblastic leukemia. Blood. 2017; 129( 9): 1134–1142.
4. Paganin M, Ferrando A. Molecular pathogenesis and targeted therapies for NOTCH1-induced T-cell acute lymphoblastic leukemia. Blood Rev. 2011; 25( 2): 83–90.
5. Mokhtari RB, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. Oncotarget. 2017; 8(23): 38022–38043.
6. Hales EC, Taub JW, Matherly LH, et al. New insights into Notch1 regulation of the PI3K–AKT–mTOR1 signaling axis: Targeted therapy of γ-secretase inhibitor resistant T-cell acute lymphoblastic leukemia. Cell Signal. 2014; 26( 1): 149–61.
7. Girardi T, Vicente C, Cools J, et al. The genetics and molecular biology of T-ALL. Blood. 2017; 129( 9):1113–1123.
8. Tzoneva G, Ferrando AA. Recent advances on NOTCH signaling in T-ALL. Curr Top Microbiol Immunol. 2012;360:163-82.
9. Cani A, Simioni C, Martelli AM, et al. Triple Akt inhibition as a new therapeutic strategy in T-cell acute lymphoblastic leukemia. Oncotarget. 2015; 6(9): 6597–6610.
10. Fransecky L, Mochmann LH, Baldus CD, et al. Outlook on PI3K/AKT/mTOR inhibition in acute leukemia. Mol Cell Ther. 2015; 3: 2.
11. Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med.2007; 13 (10): 1203–10.
12. Mendes RD, Canté-Barrett K, Pieters R, et al. The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia.Haematologica. 2016; 101 (9): 1010–1017.
13. Roti G, Stegmaier K.New Approaches to Target T-ALL. Front Oncol. 2014; 4:170.
14. Yoon SO, Zapata MC, Singh A, et al. Gamma secretase inhibitors enhance vincristine-induced apoptosis in T-ALL in a NOTCH-independent manner. Apoptosis. 2014; 19( 11): 1616–26.
15. Zhang Y, Zheng Y, Faheem A, et al. A novel AKT inhibitor , AZD5363 , inhibits phosphorylation of AKT downstream molecules , and activates phosphorylation of mTOR and SMG ‑1 dependent on the liver cancer cell type. Oncol Lett. 2016; 11(3): 1685–1692.
16. Chou TC.Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies. Pharmacol Rev. 2006; 58(3):621-81.
17. García-Fuente A,Vázquez F, Viéitez JM, et al. CISNE: An accurate description of dose-effect and synergism in combination therapies. Sci Rep. 2018;8(1):4964
18. Goto S, Goto H, Yokosuka T.The combination effects of bendamustine with antimetabolites against childhood acute lymphoblastic leukemia cells. Int J Hematol. 2016; 103( 5): 572–83.
19. Cosenza M, Civallero M, Fiorcari S, et al.The histone deacetylase inhibitor romidepsin synergizes with lenalidomide and enhances tumor cell death in T-cell lymphoma cell lines. Cancer Biol Ther. 2016; 17(10): 1094–1106.
20. Raetz EA, Teachey DT.T-cell acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2016; 2016(1):580-588.
21. Bertacchini J, Heidari N, Mediani L, et al.Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cell Mol Life Sci. 2015;72(12):2337-47.
22. Yoon S, Zapata MC, Singh A, et al. Gamma secretase inhibitors enhance vincristine-induced apoptosis in T-ALL in a NOTCH-independent manner. Apoptosis. 2014; 19(11):1616-26.
23. Lewis HD, Leveridge M, Strack PR, et al. Apoptosis in T Cell Acute Lymphoblastic Leukemia Cells after Cell Cycle Arrest Induced by Pharmacological Inhibition of Notch Signaling. Chem Biol. 2007;14(2):209-19.
24. Keersmaecker KD, Lahortiga I, Mentens N, et al. In vitro validation of γ-secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia. Haematologica. 2008; 93(4): 533–42.
25. Knoechel B, Roderick JE, Williamson KE, et al. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet. 2014;46(4):364-70.
26. Zuurbier L, Petricoin EF, Vuerhard MJ, et al.The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia. Haematologica. 2012; 97 (9): 1405–13.
27. Choi AR, Kim JH, Woo YH, et al. Co-treatment of LY294002 or MK-2206 with AZD5363 attenuates AZD5363-induced increase in the level of phosphorylated AKT. Anticancer Res. 2016;36(11):5849-5858.
28. Lynch JT, McEwen R, Crafter C, et al. Identification of differential PI3K pathway target dependencies in T-cell acute lymphoblastic leukemia through a large cancer cell panel screen. Oncotarget. 2016; 7 (16): 22128–39.
Published
2020-04-07
How to Cite
1.
Khoshamooz H, Kaviani S, Atashi A, Mirpour Hassankiadeh SH. Combination Effect of Notch1 and PI3K / AKT / mTOR Signaling Pathways Inhibitors on T-ALL Cell Lines. Int J Hematol Oncol Stem Cell Res. 14(2):99-109.
Section
Original Article(s)