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ASP210: a potent oligonucleotide-based inhibitor effective against TKI-resistant CML cells.
Nemethova, Veronika; Babiakova, Petra; Teglasova, Boglarka; Uhelska, Lucia; Babelova, Andrea; Selc, Michal; Jakic, Kristina; Mitrovsky, Ondrej; Myslivcova, Denisa; Zackova, Marketa; Poturnayova, Alexandra; Batorova, Angelika; Drgona, Lubos; Razga, Filip.
Afiliação
  • Nemethova V; Selecta Biotech SE, Bratislava, Slovakia.
  • Babiakova P; Department of Hematology and Transfusiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
  • Teglasova B; Selecta Biotech SE, Bratislava, Slovakia.
  • Uhelska L; Selecta Biotech SE, Bratislava, Slovakia.
  • Babelova A; Selecta Biotech SE, Bratislava, Slovakia.
  • Selc M; Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
  • Jakic K; Centre for Advanced Materials Application, Slovak Academy of Sciences, Bratislava, Slovakia.
  • Mitrovsky O; Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
  • Myslivcova D; Centre for Advanced Materials Application, Slovak Academy of Sciences, Bratislava, Slovakia.
  • Zackova M; Department of Nanobiology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
  • Poturnayova A; Department of Proteomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
  • Batorova A; Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
  • Drgona L; Department of Proteomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
  • Razga F; Department of Proteomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
Am J Physiol Cell Physiol ; 327(1): C184-C192, 2024 Jul 01.
Article em En | MEDLINE | ID: mdl-38826137
ABSTRACT
Clinical experience with tyrosine kinase inhibitors (TKIs) over the past two decades has shown that, despite the apparent therapeutic benefit, nearly 30% of patients with chronic myelogenous leukemia (CML) display primary resistance or intolerance to TKIs, and approximately 25% of those treated are forced to switch TKIs at least once during therapy due to acquired resistance. Safe and effective treatment modalities targeting leukemic clones that escape TKI therapy could hence be game changers in the professional management of these patients. Here, we aimed to investigate the efficacy of a novel therapeutic oligonucleotide of unconventional design, called ASP210, to reduce BCR-ABL1 mRNA levels in TKI-resistant CML cells, with the assumption of inducing their apoptosis. Imatinib- and dasatinib-resistant sublines of BCR-ABL1-positive MOLM-7 and CML-T1 cells were established and exposed to 0.25 and 2.5 µM ASP210 for 10 days. RT-qPCR showed a remarkable reduction of the target mRNA level by >99% after a single application. Cell viability was monitored daily by trypan blue staining. In response to the lack of driver oncoprotein BCR-ABL1, TKI-resistant CML cells underwent apoptosis regardless of the presence of the clinically relevant T315I mutation by day 5 after redosing with ASP210. The effect was selective for cancer cells, indicating a favorable safety profile for this therapeutic modality. Furthermore, the spontaneous uptake and high intracellular concentrations of ASP210 suggest its potential to be effective at relatively low doses. The present findings suggest that ASP210 is a promising therapeutic avenue for patients with CML who fail to respond to TKI therapy.NEW & NOTEWORTHY Effective treatment modalities targeting leukemic clones that escape tyrosine kinase inhibitor (TKI) therapy could be game changers in the professional management of patients displaying primary resistance, intolerance, or acquired resistance to TKIs. Although delivering authentic innovations today is more complex than ever, we developed a highly potent and safe oligonucleotide-based modality against BCR-ABL1 mRNA named ASP210 that effectively induces cell death in BCR-ABL1-positive TKI-resistant cells while sparing BCR-ABL1-negative healthy cells.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligonucleotídeos / Leucemia Mielogênica Crônica BCR-ABL Positiva / Proteínas de Fusão bcr-abl / Apoptose / Resistencia a Medicamentos Antineoplásicos / Inibidores de Proteínas Quinases / Mesilato de Imatinib Limite: Humans Idioma: En Revista: Am J Physiol Cell Physiol Assunto da revista: FISIOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Eslováquia

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligonucleotídeos / Leucemia Mielogênica Crônica BCR-ABL Positiva / Proteínas de Fusão bcr-abl / Apoptose / Resistencia a Medicamentos Antineoplásicos / Inibidores de Proteínas Quinases / Mesilato de Imatinib Limite: Humans Idioma: En Revista: Am J Physiol Cell Physiol Assunto da revista: FISIOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Eslováquia