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Managing of Chronic Myeloid Leukemia via Au- nanoconjugates In TKIs Sensitive/Resistance CML Cells
Publication . Abdulmawjood, Bilal Rabah Qasim; Fernandes, Maria Alexandra; Baptista, Pedro
Chronic myeloid leukemia (CML) is a rare disease caused by the presence of Philadelphia
chromosome as a result of the fusion between the Breakpoint Cluster Region (BCR) gene in
chromosome 22 and the Abelson tyrosine-protein kinase1 (ABL1) gene in chromosome 9.
This fusion encodes a tyrosine kinase (TK) constitutively expressed in CML cells. Imatinib
(IM) is the first line TK inhibitor used in CML treatment. Molecular detection of BCR-ABL1
transcription is crucial for diagnosis and treatment strategies. Point mutations in the ABL1
gene contribute to resistance against TKIs, suggesting a need for modification in treatment
protocols. In a high percentage of CML patients, poor response with relapses and disease
progression is associated with resistance through various mechanisms, including dysregulation of the c-MYC proto-oncogene.
Gold nanoconjugates (Au-nanoconjugates) have shown improved efficacy in gene silencing approaches towards cancer therapy. Herein, we evaluated the silencing potential of
AuNPs functionalized with antisense oligonucleotides targeting e14a2BCR-ABL1 or the c-MYC alone and combination, demonstrating efficient silencing of gene expression and
downregulation of protein levels in IM-senstive and IM-resistant cell lines. Combining TK
inhibitor (IM) with other kinase inhibitors showed synergistic activity in IM-sensitive cell
line. Moreover, the effect of the Au-nanoconjugates with danusertib (Danu), volasertib (Vola)
and adavosertib (Adavo) on IM-resistant cells was also analyzed and showed a synergistic
effect.
These Au-nanoconjugates may be useful to tackle IM-resistance mechanisms and provide an additional tool for future combinatory schemes to fight CML with imatinib resistance.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
Concurso de Projetos de I&D em Todos os Domínios Científicos - 2022 - ICDT
Número da atribuição
2022.04315.PTDC