Novel Epigenetics Control (EpC) Nanocarrier for Cancer Therapy Through Dual-Targeting Approach to DNA Methyltransferase and Ten-Eleven Translocation Enzymes.

IF 2.5 Q3 GENETICS & HEREDITY
Risa Mitsuhashi, Kiyoshi Sato, Hiroyoshi Kawakami
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引用次数: 0

Abstract

Background/objectives: Aberrant hypermethylation in the promoter regions of tumor suppressor genes facilitates the pathogenesis and progression of cancer. Therefore, inhibitors targeting DNA methyltransferase (DNMT) have been tested in clinical studies. However, the current monotherapy of DNMT inhibitors shows limited efficacy. Furthermore, the mechanism of action of DNMT inhibitors is DNA replication-dependent. To address these limitations, we developed a novel core-shell-type "epigenetics control (EpC) nanocarrier" that encapsulated decitabine (5-aza-dC) in the PLGA core nanoparticle and hybridized TET1 gene-encoding pDNA on the lipid shell surface. This study aimed to evaluate whether the dual delivery of DNMT inhibitors and pDNA of TET1 could synergistically enhance tumor suppressor gene expression and induce cell cycle arrest and/or apoptosis in cancer cells. Herein, we demonstrate the potential of the EpC carrier in HCT116 human colon cancer cells to upregulate tumor suppressor gene expression and rapidly achieve cell cycle arrest.

Methods: PLGA core nanoparticles were prepared by the W/O/W double emulsion method. The formation of core-shell nanoparticles and complexation with pDNA were investigated and optimized by dynamic light scattering, zeta potential measurement, and agarose gel electrophoresis. The cellular uptake and transfection efficiency were measured by confocal laser scanning microscopy and a luciferase assay, respectively. The expression of p53 protein was detected by Western blotting. The anti-tumor effects of the EpC nanocarrier were evaluated by cell cycle analysis and an apoptosis assay.

Results: The EpC nanocarrier delivered the DNMT inhibitor and TET gene-encoding pDNA into HCT116 cells. It promoted the expression of the tumor suppressor protein p53 and induced rapid cell cycle arrest in the G2/M phase in HCT116 cells.

Conclusions: Our findings suggest that the dual-targeting of DNMT and TET enzymes effectively repairs aberrant DNA methylation and induces growth arrest in cancer cells, and the dual-targeting strategy may contribute to the advancement of epigenetic cancer therapy.

基于DNA甲基转移酶和10 - 11易位酶双靶向的新型表观遗传控制(EpC)纳米载体
背景/目的:肿瘤抑制基因启动子区域的异常高甲基化促进了癌症的发病和进展。因此,靶向DNA甲基转移酶(DNMT)的抑制剂已经在临床研究中进行了测试。然而,目前单药治疗DNMT抑制剂的疗效有限。此外,DNMT抑制剂的作用机制是DNA复制依赖的。为了解决这些限制,我们开发了一种新的核-壳型“表观遗传学控制(EpC)纳米载体”,该载体将地西他滨(5-aza-dC)包裹在PLGA核心纳米颗粒中,并在脂质外壳表面杂交TET1基因编码的pDNA。本研究旨在评估双重递送DNMT抑制剂和TET1的pDNA是否能协同增强肿瘤抑制基因表达,诱导癌细胞周期阻滞和/或凋亡。在此,我们证明了EpC载体在HCT116人结肠癌细胞中上调肿瘤抑制基因表达并快速实现细胞周期阻滞的潜力。方法:采用W/O/W双乳液法制备PLGA芯纳米颗粒。采用动态光散射、zeta电位测定和琼脂糖凝胶电泳等方法对核壳纳米颗粒的形成和与pDNA的络合进行了研究和优化。分别用共聚焦激光扫描显微镜和荧光素酶测定法测定细胞摄取和转染效率。Western blotting检测p53蛋白的表达。通过细胞周期分析和细胞凋亡实验评价EpC纳米载体的抗肿瘤作用。结果:EpC纳米载体将DNMT抑制剂和TET基因编码的pDNA送入HCT116细胞。它促进了肿瘤抑制蛋白p53的表达,并诱导HCT116细胞在G2/M期快速细胞周期阻滞。结论:我们的研究结果表明,双靶向DNMT和TET酶可以有效地修复异常DNA甲基化并诱导癌细胞生长停滞,双靶向策略可能有助于推进表观遗传癌症治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Epigenomes
Epigenomes GENETICS & HEREDITY-
CiteScore
3.80
自引率
0.00%
发文量
38
审稿时长
11 weeks
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