Tyrosine kinase inhibition to improve anthracycline-based chemotherapy efficacy in T-cell lymphoma

Autor: Cristiana Carniti, Chiara Paolizzi, Giulia Biancon, Matteo Dugo, Martina Magni, Paolo Corradini, Sara Rizzitano, Alessandra Cavanè
Rok vydání: 2019
Předmět:
Cancer Research
Dasatinib
Gene Expression
Apoptosis
Mice
SCID
CHOP
Proto-Oncogene Proteins c-fyn
Tyrosine-kinase inhibitor
Jurkat Cells
0302 clinical medicine
Mice
Inbred NOD
hemic and lymphatic diseases
Antineoplastic Combined Chemotherapy Protocols
T-cell lymphoma
Etoposide
Non-hodgkin lymphoma
Molecular medicine
Cell Cycle
Drug Synergism
Protein-Tyrosine Kinases
Up-Regulation
Treatment Outcome
Oncology
Vincristine
030220 oncology & carcinogenesis
Tyrosine kinase
medicine.drug
Cell Survival
medicine.drug_class
Receptors
Antigen
T-Cell
Lymphoma
T-Cell
Article
Drug Administration Schedule
03 medical and health sciences
medicine
Animals
Humans
Doxorubicin
Cyclophosphamide
Protein Kinase Inhibitors
business.industry
Gene Expression Profiling
medicine.disease
Lymphoma
Cancer research
Prednisone
rhoA GTP-Binding Protein
business
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
Popis: Background Anthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOEP (CHOP + etoposide), represent the current standard of care for patients with newly diagnosed peripheral T-cell lymphomas (PTCLs), although responses are unsatisfactory. In this study, we investigated the pathways able to mitigate the sensitivity to CHOP-based regimens in preclinical models of T-cell lymphoma (TCL) to select agents for the development of CHOP-based drug combinations. Methods We performed gene expression profiling of malignant T-cell lines exposed to CHOEP; flow cytometry was employed to study the effects of drug combinations on cell viability, cell cycle distribution, apoptosis and mitochondrial membrane depolarisation. Western blot analyses were performed to study cell signalling downstream of the T-cell receptor and apoptosis. The in vivo effect of the drug combination was tested in xenograft models. Results We highlighted a modulation of tyrosine kinases belonging to the T-cell receptor pathway upon chemotherapy that provided the rationale for combining the tyrosine kinase inhibitor dasatinib with CHOEP. Dasatinib improves CHOEP activity and reduces viability in vitro. Furthermore, combination treatment results in tumour growth inhibition in in vivo xenograft mouse models. Conclusions Our data provide the rationale for clinical testing of the dasatinib–CHOEP combination in patients with T-cell lymphoma.
Databáze: OpenAIRE
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