Combination Effect of Notch1 and PI3K / AKT / mTOR Signaling Pathways Inhibitors on T-ALL Cell Lines
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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.
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| Files | ||
| Issue | Vol 14, No 2 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v14i2.2673 | |
| Keywords | ||
| Synergistic interaction; AZD5363; Compound E; Acute T-lymphoblastic leukemia | ||
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