Zheng Jie, Son Dong Ju, Lee Hye Lim, Lee Hee Pom, Kim Tae Hoon, Joo Jung Heun, Ham Young Wan, Kim Wun Jae, Jung Jae Kyung, Han Sang-Bae, Hong Jin Tae
College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
Department of Chemistry, Utah Valley University 800 W, University Pkwy, Orem, Utah.
Mol Carcinog. 2017 Sep;56(9):2003-2013. doi: 10.1002/mc.22648. Epub 2017 Mar 30.
In the present study, we synthesized several non-aldehyde analogues of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal which showed anti-cancer effect. Interestingly, among the 16 compounds, we found that (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) showed the most significant anti-proliferative effect on PA-1 and SK-OV-3 ovarian epithelial cancer cells. MMPP treatment (0-15 µg/mL) induced apoptotic cell death, enhanced the expression of cleaved caspase-3, and cleaved caspase-9 in a concentration dependent manner. Notably, DNA binding activity of STAT3, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 was significantly decreased by MMPP treatment. However, ERK siRNA augmented MMPP-induced inhibitory effect on cell growth rather than p38 siRNA or JNK siRNA. Moreover, combination treatment of MMPP with ERK inhibitor U0126 (10 µM) augmented MMPP-induced inhibitory effect on cell growth and DNA binding activity of STAT3, and enhanced expression of cleaved caspase-3 and cleaved caspase-9. In addition, STAT3 siRNA transfection augmented MMPP-induced cell growth inhibition. In PA-1 bearing xenograft mice model, MMPP (5 mg/kg) suppressed tumor growth significantly. Immunohistochemistry staining showed that the expression levels of p-ERK, PCNA, p-STAT3 were decreased while the expression level of caspase-3 was increased by MMPP treatment. Thus, MMPP may be a promising anti-cancer agent in ovarian epithelial cancer treatment.
在本研究中，我们合成了几种显示出抗癌作用的（E）-2,4-双（对羟基苯基）-2-丁烯醛的非醛类似物。有趣的是，在这16种化合物中，我们发现（E）-2-甲氧基-4-（3-（4-甲氧基苯基）丙-1-烯-1-基）苯酚（MMPP）对PA-1和SK-OV-3卵巢上皮癌细胞显示出最显著的抗增殖作用。MMPP处理（0-15µg/mL）以浓度依赖性方式诱导凋亡细胞死亡，增强了裂解的caspase-3和裂解的caspase-9的表达。值得注意的是，MMPP处理显著降低了STAT3的DNA结合活性、细胞外信号调节激酶（ERK）和p38的磷酸化。然而，ERK siRNA增强了MMPP诱导的对细胞生长的抑制作用，而不是p38 siRNA或JNK siRNA。此外，MMPP与ERK抑制剂U0126（10µM）联合处理增强了MMPP诱导的对细胞生长的抑制作用以及STAT3的DNA结合活性，并增强了裂解的caspase-3和裂解的caspase-9的表达。此外，STAT3 siRNA转染增强了MMPP诱导的细胞生长抑制。在携带PA-1异种移植小鼠模型中，MMPP（5mg/kg）显著抑制肿瘤生长。免疫组织化学染色显示，MMPP处理后p-ERK、PCNA、p-STAT3的表达水平降低，而caspase-3的表达水平升高。因此，MMPP可能是卵巢上皮癌治疗中有前景的抗癌药物。
