AmNA-Modified Antisense Oligonucleotide Targeting MCM8 as a Cancer-Specific Chemosensitizer for Platinum Compounds

IF 4.5 2区 医学 Q1 ONCOLOGY
Cancer Science Pub Date : 2025-03-17 DOI:10.1111/cas.70024
Yuki Uchibori, Masaki Suekuni, Yuko Kokaji, Kazumasa Yoshida, Tohru Kiyono, Yuuya Kasahara, Masatoshi Fujita
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引用次数: 0

Abstract

MCM8 and MCM9 participate in homologous recombination with long-tract gene conversion to repair double-strand breaks caused by replication stress, which is generally higher in cancer cells than in normal cells. MCM8 is highly expressed in certain cancer cells, where it is necessary for maintaining cell growth, migration, and invasion, although the molecular mechanisms remain unclear. Knockdown with siRNAs or knockout of MCM8 or MCM9 selectively sensitizes cancer cells to cisplatin. Thus, drugs inhibiting MCM8 or MCM9 could serve as novel anti-neoplastic agents and/or chemosensitizers that selectively sensitize cancer cells to platinum compounds. The present study describes the development of an amido-bridged nucleic acid (AmNA)-modified gapmer antisense oligonucleotide (ASO) targeting MCM8, called ASO 8–3419. In vitro, ASO 8–3419 inhibited MCM8 expression in several human cell lines and selectively sensitized cancer cells to cisplatin. Moreover, ASO 8–3419 modestly suppressed the growth of several cancer cell lines whose proliferation has been reported to depend on MCM8. In vivo, ASO 8–3419 inhibited the expression of MCM8 in xenografted tumors of colon cancer-derived HCT116 cells in nude mice and increased tumor sensitivity to cisplatin with minimal toxicity. These findings suggest that AmNA-modified, MCM8-specific ASOs hold promise as novel anti-cancer agents.

Abstract Image

靶向MCM8的amna修饰反义寡核苷酸作为铂类化合物的癌症特异性化学增敏剂。
MCM8和MCM9参与同源重组和长路基因转换,修复复制应激引起的双链断裂,在癌细胞中普遍高于正常细胞。MCM8在某些癌细胞中高度表达,这是维持细胞生长、迁移和侵袭所必需的,尽管分子机制尚不清楚。用sirna敲低或敲除MCM8或MCM9选择性地使癌细胞对顺铂敏感。因此,抑制MCM8或MCM9的药物可以作为新型抗肿瘤药物和/或化学增敏剂,选择性地使癌细胞对铂化合物增敏。本研究描述了一种靶向MCM8的氨基桥核酸(AmNA)修饰间隙子反义寡核苷酸(ASO)的开发,称为ASO 8-3419。在体外,ASO 8-3419抑制了几种人类细胞系中MCM8的表达,并选择性地使癌细胞对顺铂敏感。此外,ASO 8-3419适度抑制了几种癌细胞系的生长,这些癌细胞系的增殖依赖于MCM8。在体内,ASO 8-3419抑制裸鼠结肠癌源性HCT116细胞异种移植肿瘤中MCM8的表达,增加肿瘤对顺铂的敏感性,且毒性很小。这些发现表明,amna修饰的mcm8特异性aso有望成为新型抗癌药物。
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来源期刊
Cancer Science
Cancer Science 医学-肿瘤学
自引率
3.50%
发文量
406
审稿时长
2 months
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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