A novel hydrogen sulfide-releasing donor, HA-ADT, suppresses the growth of human breast cancer cells through inhibiting the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways
A novel hydrogen sulfide-releasing donor, HA-ADT, suppresses the growth of human breast cancer cells through inhibiting the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling pathways
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一种新型的硫化氢释放供体 HA-ADT 通过抑制 PI3K/AKT/mTOR 和 Ras/Raf/MEK/ERK 信号通路来抑制人乳腺癌细胞的生长
DOI：
10.1016/j.canlet.2019.04.031
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Duan, Shao-Feng
中科院分区：
文献类型：
--
作者：
Dong, Qian;Yang, Bo;Duan, Shao-Feng
乳腺癌是全世界女性中最常见的癌症之一。透明质酸（HA）是目前安全性最好的生物聚合物之一，在药物传递和组织工程中有着广泛的应用。5-（4-羟基苯基）- 3h -1,2-二硫代1-3-硫酮（ADT-OH）是一种常用的H2S供体。在本研究中，我们通过化学反应将HA与ADT-OH连接，设计并合成了一种共轭物HA- adt。结果表明，HA-ADT比NaHS和GYY4137产生更多的H2S。HA-ADT对人乳腺癌细胞的增殖、活力、迁移和侵袭的抑制作用强于NaHS和GYY4137。在人乳腺癌细胞的凋亡和磷酸化(p)-PI3K、p- akt、p- mtor、H-RAS、p- raf、p- mek和p- erk蛋白水平上也观察到类似的趋势。此外，HA-ADT对裸鼠人乳腺癌异种移植瘤的生长有更强的抑制作用。综上所述，HA-ADT可通过抑制PI3K/AKT/mTOR和RAS/RAF/MEK/ERK信号通路抑制人乳腺癌细胞的生长。HA-ADT及其衍生物在治疗不同类型的癌症方面可能具有很大的潜力。
Breast cancer is one of the most frequent cancers among women worldwide. Hyaluronic acid (HA) is one of the best biopolymers in terms of safety issues and has been widely used in drug delivery and tissue engineering. 5-(4-hydroxyphenyl)-3H-1,2-dithio1-3-thione (ADT-OH) is a commonly used H2S donor. In this study, we designed and synthesized a conjugate, HA-ADT, by connecting HA with ADT-OH through chemical reactions. Our results indicated that HA-ADT could produce more H2S than NaHS and GYY4137. HA-ADT exerted more potent inhibitory effects than NaHS and GYY4137 in the proliferation, viability, migration, and invasion of human breast cancer cells. Similar trends were observed in the apoptosis and the protein levels of phospho (p)-PI3K, p-AKT, p-mTOR, H-RAS, p-RAF, p-MEK, and p-ERK in human breast cancer cells. Furthermore, HA-ADT exhibited more powerful inhibitory effects on the growth of human breast cancer xenograft tumors in nude mice. In conclusion, HA-ADT could suppress the growth of human breast cancer cells through the inhibition of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK signaling pathways. HA-ADT and its derivatives might be of great potential in the treatment of different types of cancer.