范德特尼布对大鼠叶红细胞瘤PC12细胞中甲基胺合成的抑制作用
Yoshihiko Itoh1, Kenichi Inagaki1, Tomohiro Terasaka1
1Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
作为RET抑制剂的万达丁尼布,通过抑制RET-ERK和RET-AKT信号通路,直接降低了染细胞细胞中catecholamine的合成. 这种对甲基荷胺水平的影响比对细胞增殖的影响更为明显.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 内分泌学 在内分泌学.
背景情况:
- 在转移 (RET) 过程中重新排列的受体氨酸激酶中,功能获取突变驱动骨髓性甲状腺癌 (MTCs) 和色细胞瘤和偏角细胞瘤 (PPGLs).
- 氨酸激酶抑制剂 (TKI) 向RET,在MTC和PPGL中显示出有效性,其中一些可以降低甲基醇胺水平而不会降低瘤大小.
研究的目的:
- 为了研究范德坦尼布的作用,一个多目标的TKI与RET相关的MTC,对细胞增殖和catecholamine合成大鼠染细胞PC12细胞.
- 阐明调解范德坦尼布对 катехо胺合成影响的信号通路.
主要方法:
- 用vandetanib对大鼠染细胞PC12细胞的治疗.
- 测量细胞活力,多巴胺和上腺素水平.
- 抑制Ret的RNA,并抑制下游的ERK和AKT信号通路.
主要成果:
- 范德特尼布以度依赖的方式降低了可活细胞和甲基荷兰胺水平 (多巴胺和诺亚上腺素).
- 抑制甲基胺合成比减少细胞增殖更为突出,特别是在较低的范迪塔尼布度下.
- RET信号抑制被确定为抑制甲基荷胺合成的主要机制.
- 范德特尼布降低了ERK和AKT的酸化;MEK和PI3K/AKT抑制剂也抑制了甲基醇胺的合成,而不会影响细胞活力.
结论:
- 范德特尼布在临床前模型中直接抑制了甲胺的合成.
- RET-ERK和RET-AKT信号通路是万迪塔尼布对 кате荷胺产生的影响的关键调解者.
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