Novel inhibitor of hematopoietic cell kinase as a potential therapeutic agent for acute myeloid leukemia.

Autor: Roversi FM; Hematology and Transfusion Medicine Center, University of Campinas/Hemocentro-Unicamp, Universitária Zeferino Vaz - Barão Geraldo, Rua Carlos Chagas, 480 - Cidade Campinas, São Paulo, Brazil., Bueno MLP; Hematology and Transfusion Medicine Center, University of Campinas/Hemocentro-Unicamp, Universitária Zeferino Vaz - Barão Geraldo, Rua Carlos Chagas, 480 - Cidade Campinas, São Paulo, Brazil., da Silva JAF; Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham-UAB, Birmingham, AL, USA., Assis-Mendonça GR; Department of Pathology, Faculty of Medical Sciences, University of Campinas-Unicamp, Campinas, São Paulo, Brazil., Torello CO; Hematology and Transfusion Medicine Center, University of Campinas/Hemocentro-Unicamp, Universitária Zeferino Vaz - Barão Geraldo, Rua Carlos Chagas, 480 - Cidade Campinas, São Paulo, Brazil., Shiraishi RN; Hematology and Transfusion Medicine Center, University of Campinas/Hemocentro-Unicamp, Universitária Zeferino Vaz - Barão Geraldo, Rua Carlos Chagas, 480 - Cidade Campinas, São Paulo, Brazil., Pericole FV; Hematology and Transfusion Medicine Center, University of Campinas/Hemocentro-Unicamp, Universitária Zeferino Vaz - Barão Geraldo, Rua Carlos Chagas, 480 - Cidade Campinas, São Paulo, Brazil., Ferro KP; Hematology and Transfusion Medicine Center, University of Campinas/Hemocentro-Unicamp, Universitária Zeferino Vaz - Barão Geraldo, Rua Carlos Chagas, 480 - Cidade Campinas, São Paulo, Brazil., Duarte ASS; Hematology and Transfusion Medicine Center, University of Campinas/Hemocentro-Unicamp, Universitária Zeferino Vaz - Barão Geraldo, Rua Carlos Chagas, 480 - Cidade Campinas, São Paulo, Brazil., Rego EM; Division of Hematology, Hospital das Clínicas da Faculdade de Medicina (HCFMUSP), University of São Paulo Medical School, University of São Paulo, São Paulo, Brazil., Saad STO; Hematology and Transfusion Medicine Center, University of Campinas/Hemocentro-Unicamp, Universitária Zeferino Vaz - Barão Geraldo, Rua Carlos Chagas, 480 - Cidade Campinas, São Paulo, Brazil. sara@unicamp.br.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2022 Aug; Vol. 71 (8), pp. 1909-1921. Date of Electronic Publication: 2022 Jan 18.
DOI: 10.1007/s00262-021-03111-2
Abstrakt: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are characterized by risk of relapses, poor survival, unwanted side effects and high toxicity with the current therapies. In light of these facts, there are efforts to develop new drugs specific for deregulated molecules that participate in leukemia pathogenesis. Hematopoietic cell kinase (HCK), an Src kinase family member, is overexpressed on hematopoietic stem cells of MDS and de novo AML patients and involved in the oncogenic process. Thus, we investigated in vitro, ex vivo and in vivo effects of a novel chemical compound targeting HCK inhibition (iHCK-37), in combination with the most used drugs for the treatment of MDS and de novo AML, 5-Azacytidine and Cytarabine. Herein, the combination treatment with iHCK-37 and 5-Azacytidine or Cytarabine demonstrated additive effects against leukemia cells, compared to either drug alone. iHCK-37 plus 5-Azacytidine or Cytarabine treatment was able to reduce the activation of oncogenic pathways, MAPK/ERK and PI3K/AKT, leading to reduction of ERK and AKT phosphorylation, and increased BAX and decreased BCL-XL protein expression. Moreover, treatment with iHCK-37 reduced MDS and AML CD34-positive cell numbers inside a 3D-structure but did not affect normal CD34-positive cell numbers. In vivo analysis showed that leukemic mice treated with iHCK-37 had reduced ERK and AKT proteins phosphorylation levels and leukocyte numbers. In conclusion, the iHCK-37 inhibitor has anti-neoplastic activity in leukemia cells without altering apoptosis and survival rate of normal cells, suggesting on-target malignant cell killing activity as a single agent or in combination with 5-Azacytidine or Cytarabine.
(© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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