Affiliation:
1. Gonçalo Moniz Institute Oswaldo Cruz Foundation (IGM‐FIOCRUZ/BA) Salvador Bahia Brazil
2. SENAI Institute for Innovation in Advanced Health Systems SENAI CIMATEC Salvador Bahia Brazil
3. Department of Propaedeutics, Faculty of Dentistry Federal University of Bahia (UFBA) Salvador Bahia Brazil
4. Center for Biotechnology and Cell Therapy D'Or Institute for Research and Education (IDOR) Salvador Bahia Brazil
Abstract
AbstractAcute myelogenous leukaemia (AML) originates and is maintained by leukaemic stem cells (LSCs) that are inherently resistant to antiproliferative therapies, indicating that a critical strategy for overcoming chemoresistance in AML therapy is to eradicate LSCs. In this work, we investigated the anti‐AML activity of bortezomib (BTZ), emphasizing its anti‐LSC potential, using KG‐1a cells, an AML cell line with stem‐like properties. BTZ presented potent cytotoxicity to both solid and haematological malignancy cells and reduced the stem‐like features of KG‐1a cells, as observed by the reduction in CD34‐ and CD123‐positive cells. A reduction in NF‐κB p65 nuclear staining was observed in BTZ‐treated KG‐1a cells, in addition to upregulation of the NF‐κB inhibitor gene NFΚBIB. BTZ‐induced DNA fragmentation, nuclear condensation, cell shrinkage and loss of transmembrane mitochondrial potential along with an increase in active caspase‐3 and cleaved PARP‐(Asp 214) level in KG‐1a cells. Furthermore, BTZ‐induced cell death was partially prevented by pretreatment with the pancaspase inhibitor Z‐VAD‐(OMe)‐FMK, indicating that BTZ induces caspase‐mediated apoptosis. BTZ also increased mitochondrial superoxide levels in KG‐1a cells, and BTZ‐induced apoptosis was partially prevented by pretreatment with the antioxidant N‐acetylcysteine, indicating that BTZ induces oxidative stress‐mediated apoptosis in KG‐1a cells. At a dosage of 0.1 mg/kg every other day for 2 weeks, BTZ significantly reduced the percentage of hCD45‐positive cells in the bone marrow and peripheral blood of NSG mice engrafted with KG‐1a cells with tolerable toxicity. Taken together, these data indicate that the anti‐LSC potential of BTZ appears to be an important strategy for AML treatment.
Funder
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Fundação Oswaldo Cruz
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Fundação de Amparo à Pesquisa do Estado da Bahia
Cited by
1 articles.
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