TY - JOUR
T1 - Tackling Imatinib Resistance via Au-nanoconjugates using A Cml Resistant Cell Line
AU - Abdulmawjood, Bilal
AU - Roma-Rodrigues, Catarina
AU - Baptista, Pedro V.
AU - Fernandes, Alexandra R.
N1 - Funding Information:
The authors thank P. Rodrigues for western blot data for MDR1. The authors also thank V. Barreto for allowing the use of the equipment BD accuri C6 for flow cytometry analysis. This work was financed by national funds from FCT – Fundação para a Ciência e a Tecnologia, I.P., in the scope of the project UIDP/0 4378/2020 and UIDB/0 4378/2020 of the Research Unit on Applied Molecular Biosciences – UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy – i4HB and project NANOHEAT (2022.04315.PTDC). CRR was funded by FCT/MCTES, grant number SFRH/BPD/124 612/2016.
Publisher Copyright:
© 2023 Wiley-VCH GmbH.
PY - 2024/1
Y1 - 2024/1
N2 - Chronic myeloid leukemia (CML) is a rare malignant proliferative hematopoietic disease due to overexpression of a tyrosine kinase (TK) derived from the breakpoint cluster region (BCR)-abelson tyrosine-protein kinase 1 (ABL1) gene fusion. Imatinib (IM), blocks this tyrosine kinase, and is the first line TK inhibitor (TKI) used in CML treatment. In a high percentage of CML patients, a poor response with relapse and disease progression is associated to acquisition of resistance through different mechanisms, including dysregulation of c-MYC proto-oncogene. Gold nanoparticles (AuNPs) are shown to allow improved efficacy in gene silencing approaches toward cancer therapy. Herein, the silencing potential of AuNPs functionalized with antisense oligonucleotides selectively targeting the e14a2 BCR-ABL1 or the c-MYC, alone and combination is evaluated. It is demonstrated efficient silencing of gene expression that translated to a downregulation of protein levels in IM resistant CML cells (K562-IM). This combination allowed for increased death of the malignant cells. These Au-nanoconjugates may be useful to tackle IM-resistance mechanisms, providing an additional tool for future combinatory schemes to fight CML with imatinib resistance.
AB - Chronic myeloid leukemia (CML) is a rare malignant proliferative hematopoietic disease due to overexpression of a tyrosine kinase (TK) derived from the breakpoint cluster region (BCR)-abelson tyrosine-protein kinase 1 (ABL1) gene fusion. Imatinib (IM), blocks this tyrosine kinase, and is the first line TK inhibitor (TKI) used in CML treatment. In a high percentage of CML patients, a poor response with relapse and disease progression is associated to acquisition of resistance through different mechanisms, including dysregulation of c-MYC proto-oncogene. Gold nanoparticles (AuNPs) are shown to allow improved efficacy in gene silencing approaches toward cancer therapy. Herein, the silencing potential of AuNPs functionalized with antisense oligonucleotides selectively targeting the e14a2 BCR-ABL1 or the c-MYC, alone and combination is evaluated. It is demonstrated efficient silencing of gene expression that translated to a downregulation of protein levels in IM resistant CML cells (K562-IM). This combination allowed for increased death of the malignant cells. These Au-nanoconjugates may be useful to tackle IM-resistance mechanisms, providing an additional tool for future combinatory schemes to fight CML with imatinib resistance.
KW - anti-sense oligonucleotides
KW - BCR-ABL1
KW - c-MYC
KW - chronic myeloid leukemia
KW - gold nanoparticles
UR - http://www.scopus.com/inward/record.url?scp=85168320671&partnerID=8YFLogxK
U2 - 10.1002/ppsc.202300090
DO - 10.1002/ppsc.202300090
M3 - Article
AN - SCOPUS:85168320671
SN - 0934-0866
VL - 41
JO - Particle and Particle Systems Characterization
JF - Particle and Particle Systems Characterization
IS - 1
M1 - 2300090
ER -
