在肝细胞癌中,l-Methionine通过表观遗传改变DUSP3/ERK通路来增强Sorafenib的抗癌活性
Swagata Pal1, Shaheen Wasil Kabeer1, Shivam Sharma1
1Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar (Mohali), Punjab, India.
Journal of biochemical and molecular toxicology
|February 17, 2024
概括
甲氨酸增强了索拉芬尼的功效.
科学领域:
- 肝细胞癌 (HCC) 研究研究
- 癌症治疗治疗 癌症治疗
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 肝细胞癌 (HCC) 是全球癌症死亡的主要原因.
- 索拉芬尼是HCC的标准治疗方法,但耐药性迅速发展.
- 需要制定策略来克服HCC中索拉芬尼布耐药性.
研究的目的:
- 调查L-甲氨酸对索拉费尼布在HCC中的抗癌活性的影响.
- 探索L-氨酸潜在逆转sorafenib耐药性的机制.
- 评估L-氨酸作为治疗策略对抗索拉费尼布的HCC.
主要方法:
- 使用HepG2细胞系进行体外研究,以评估IC50值和途径调节.
- 在体内研究中,使用了一种由二甲基尼托罗斯胺 (DEN) 诱导的耐索拉芬尼布HCC的老鼠模型.
- 对氧化应激,关键信号通路 (ERK/AMPK/AKT),DUSP3表达和表观遗传修饰 (H3K27me3,H3K36me2) 的分析.
主要成果:
- 在HepG2细胞中,L-氨酸显著降低了索拉费尼布的IC50,增加了氧化应激,并关闭了ERK/AMPK/AKT通路.
- 在体内,L-氨酸补充剂克服了索拉芬尼抗药性,减少了瘤负担,改善了大鼠的生存率.
- L-氨酸调节的表观遗传标记,包括防止H3K27me3甲基化和促进H3K36me2脱甲基化,特别是在DUSP3促进体,表明通过DUSP3.3抑制ERK通路的表观遗传调节.
结论:
- 通过增加化学敏感性,L-氨酸增强了索拉费尼布在HCC中的疗效.
- 该机制涉及调节ERK/AMPK/AKT通路并增加DUSP3表达.
- 由于L-氨酸能够改变表观遗传特征,这是一种有前途的治疗策略,用于克服HCC中索拉芬尼抗性.
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