Vinhas Raquel, Fernandes Alexandra R, Baptista Pedro V
UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus da Caparica, 2829-516 Caparica, Portugal.
UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus da Caparica, 2829-516 Caparica, Portugal.
Mol Ther Nucleic Acids. 2017 Jun 16;7:408-416. doi: 10.1016/j.omtn.2017.05.003. Epub 2017 May 8.
Introduction of tyrosine kinase inhibitors for chronic myeloid leukemia treatment is associated with a 63% probability of maintaining a complete cytogenetic response, meaning that over 30% patients require an alternative methodology to overcome resistance, tolerance, or side effects. Considering the potential of nanotechnology in cancer treatment and the benefits of a combined therapy with imatinib, a nanoconjugate was designed to achieve BCR-ABL1 gene silencing. Gold nanoparticles were functionalized with a single-stranded DNA oligonucleotide that selectively targets the e14a2 BCR-ABL1 transcript expressed by K562 cells. This gold (Au)-nanoconjugate showed great efficacy in gene silencing that induced a significant increase in cell death. Variation of BCL-2 and BAX protein expression, an increase of caspase-3 activity, and apoptotic bodies in cells treated with the nanoconjugate demonstrate its aptitude for inducing apoptosis on K562 BCR-ABL1-expressing cells. Moreover, the combination of the silencing Au-nanoconjugate with imatinib prompted a decrease of imatinib IC. This Au-nanoconjugate was also capable of inducing the loss of viability of imatinib-resistant K562 cells. This strategy shows that combination of Au-nanoconjugate and imatinib make K562 cells more vulnerable to chemotherapy and that the Au-nanoconjugate alone may overcome imatinib-resistance mechanisms, thus providing an effective treatment for chronic myeloid leukemia patients who exhibit drug tolerance.
引入酪氨酸激酶抑制剂治疗慢性粒细胞白血病，维持完全细胞遗传学缓解的概率为63%，这意味着超过30%的患者需要采用其他方法来克服耐药性、耐受性或副作用。考虑到纳米技术在癌症治疗中的潜力以及与伊马替尼联合治疗的益处，设计了一种纳米缀合物以实现BCR-ABL1基因沉默。金纳米颗粒用单链DNA寡核苷酸功能化，该寡核苷酸选择性靶向K562细胞表达的e14a2 BCR-ABL1转录本。这种金（Au）-纳米缀合物在基因沉默方面显示出巨大功效，可诱导细胞死亡显著增加。纳米缀合物处理的细胞中BCL-2和BAX蛋白表达的变化、caspase-3活性的增加以及凋亡小体，证明了其在表达K562 BCR-ABL1的细胞上诱导凋亡的能力。此外，沉默性金纳米缀合物与伊马替尼联合使用可降低伊马替尼的IC。这种金纳米缀合物还能够诱导伊马替尼耐药的K562细胞活力丧失。该策略表明，金纳米缀合物与伊马替尼联合使用可使K562细胞对化疗更敏感，并且单独使用金纳米缀合物可能克服伊马替尼耐药机制，从而为表现出药物耐受性的慢性粒细胞白血病患者提供有效治疗。
