Combined SRPK and AKT pharmacological inhibition is synergistic in T-cell acute lymphoblastic leukemia cells
| Autor: | Ana Paula Martins de Souza, Luciana Ângelo de Souza, Raoni Pais Siqueira, Abelardo Silva-Júnior, Juliana Lopes Rangel Fietto, Leandro Licursi de Oliveira, Marcus Vinícius de Andrade Barros, Gustavo Costa Bressan, Róbson Ricardo Teixeira, Patrícia Maria Siqueira dos Passos, Felipe R. Teixeira, Natália Borges Simaroli, Mônica Maria Magalhães Caetano |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Vincristine HL60 Cell Survival Antineoplastic Agents Apoptosis SRPK1 Protein Serine-Threonine Kinases Toxicology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Jurkat cells 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Cell Line Tumor Chlorocebus aethiops medicine Animals Humans Protein kinase B Protein Kinase Inhibitors Vero Cells Kinase Chemistry Drug Synergism General Medicine medicine.disease ErbB Receptors Leukemia 030104 developmental biology 030220 oncology & carcinogenesis Cancer research NIH 3T3 Cells Phosphorylation Proto-Oncogene Proteins c-akt medicine.drug |
| Zdroj: | Toxicology in vitro : an international journal published in association with BIBRA. 65 |
| ISSN: | 1879-3177 |
| Popis: | The serine/arginine protein kinases respond to the EGFR-PI3K-AKT signaling module in the context of pre-mRNA alternative splicing regulation. These enzymes (notably SRPK1 and SRPK2) have been found dysregulated in a variety of cancers, which suggests them as promising drug targets in oncology. SRPK2 has been related to leukemia cells proliferation and found preferentially overexpressed in T-cell acute lymphoblastic leukemia (T-ALL). Previously, synergistic combination between vincristine and SRPK inhibitors has been observed in leukemia cells in vitro. Herein we sought to evaluate the in vitro combinatory effects of inhibiting SRPK and multiple other kinase targets from the EGFR pathway in T-ALL, a hematological malignancy with a still poor prognosis. We found that the combined SRPK and AKT pharmacological inhibition is synergistic in Jurkat, CCRF-CEM, and TALL-1 (all T-ALL) but not in HL60, an acute myelogenous leukemia cell lineage. Combined treatments also impaired SR proteins phosphorylation in accordance with an improved suppression of SRPK activity. Furthermore, the synergism of treatments seemed associated with apoptosis triggering, as revealed by flow cytometry analyses. Taken together, these results suggest the therapeutic potential of the combined SRPK and AKT pharmacological inhibition against T-ALL. |
| Databáze: | OpenAIRE |
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