MAPK signaling mediates sinomenine hydrochloride-induced human breast cancer cell death via both reactive oxygen species-dependent and -independent pathways: an in vitro and in vivo study.
MAPK signaling mediates sinomenine hydrochloride-induced human breast cancer cell death via both reactive oxygen species-dependent and -independent pathways: an in vitro and in vivo study.
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MAPK 信号通过活性氧依赖性和非依赖性途径介导盐酸青藤碱诱导的人乳腺癌细胞死亡：一项体外和体内研究
DOI：
10.1038/cddis.2014.321
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发表时间：
2014-07-31
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
青藤碱是从药用植物青藤中提取的主要生物碱，以其抗炎作用而闻名。最近的研究表明，它对滑膜肉瘤、肺癌和肝癌具有抗癌作用。然而，其抗癌作用的潜在分子机制仍不清楚。本研究考察了盐酸青藤碱(SH)在体内外对人乳腺癌细胞的抗肿瘤活性。我们发现SH有效地抑制了广泛的乳腺癌细胞系的细胞活力。以ER(-)/PR(-)MDA-MB-231和ER(+)/PR(+)MCF-7两个有代表性的乳腺癌细胞株为研究对象。结果表明，SH可诱导MDAMB-231和MCF-7细胞周期停滞，诱导细胞凋亡，并诱导ATM/Chk2和ATR/Chk1介导的DNA损伤反应。SH的抗癌作用是通过上调p-ERK、p-JNK和p-38MAPK的表达来实现的。进一步研究表明，SH可增加乳腺癌细胞内ROS含量，N-乙酰-L半胱氨酸(NAC)对ROS的抑制作用几乎可阻断SH诱导的DNA损伤，但仅能减轻SH诱导的MAPK表达变化，提示SH诱导的乳腺癌细胞死亡可能是通过ROS依赖和非依赖途径实现的。体内研究表明，SH有效地抑制了肿瘤的生长，且无明显毒性。综上所述，SH通过ROS依赖和非依赖途径诱导乳腺癌细胞死亡，并上调MAPKs的表达，提示SH可能是一种潜在的乳腺癌治疗药物。
Sinomenine, the main alkaloid extracted from the medicinal plant Sinomenium acutum, is known for its anti-inflammatory effects. Recent studies have suggested its anti-cancer effect in synovial sarcoma, lung cancer and hepatic cancer. However, the underlying molecular mechanism for its anti-cancer effect still remains unclear. This study investigated the anti-tumor activity of sinomenine hydrochloride (SH), a hydrochloride form of sinomenine, in human breast cancer cells in vitro and in vivo. We found that SH potently inhibited cell viability of a broad panel of breast cancer cell lines. Two representative breast cancer cell lines, namely ER(-)/PR(-) MDA-MB-231 and ER(+)/PR(+) MCF-7, were used for further investigation. The results showed that SH induced G1/S cell cycle arrest, caused apoptosis and induced ATM/Chk2- and ATR/Chk1-mediated DNA-damage response in MDA-MB-231 and MCF-7. The anti-cancer effect of SH was regulated by increased expression levels of p-ERK, p-JNK and p-38 MAPK. Further studies showed that SH resulted in an increase in reactive oxygen species (ROS) and inhibition of ROS by N-acetyl-L-cysteine (NAC) almost blocked SH-induced DNA damage but only mitigated SH-induced MAPK expression changes, suggesting that both ROS-dependent and -independent pathways were involved in MAPK-mediated SH-induced breast cancer cell death. The in vivo study demonstrated that SH effectively inhibited tumor growth without showing significant toxicity. In conclusion, SH induced breast cancer cell death through ROS-dependent and -independent pathways with an upregulation of MAPKs, indicating that SH may be a potential anti-tumor drug for breast cancer treatment.
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影响因子：
7.8
作者：
Miller, T M;Moulder, K L;Knudson, C M;Creedon, D J;Deshmukh, M;Korsmeyer, S J;Johnson, E M Jr
通讯作者：
Johnson, E M Jr
影响因子：
10.5
作者：
Guo, ZJ;Kumagai, A;Dunphy, WG
通讯作者：
Dunphy, WG
影响因子：
4.3
作者：
Hui, Lijian;Bakiri, Latifa;Wagner, Erwin F.
通讯作者：
Wagner, Erwin F.
影响因子：
2.6
作者：
Anderson, Benjamin O.;Jakesz, Raimund
通讯作者：
Jakesz, Raimund
影响因子：
4.8
作者：
Kim, GY;Mercer, SE;Friedman, E
通讯作者：
Friedman, E