Zheng Jie, Park Mi Hee, Lee Hee Pom, Hyun Byung Kook, Chun Hyung Ok, Jung Sung Hee, Seo Hyun Ok, Ham Young Wan, Han Sang-Bae, Hong Jin Tae
College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea.
Current address: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
Oncotarget. 2017 Aug 24;8(53):91258-91269. doi: 10.18632/oncotarget.20440. eCollection 2017 Oct 31.
Here we report that a novel synthesized compound (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) which exhibits better stability, drug-likeness and anti-cancer effect than (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB) that we previously reported. Of all newly synthesized BHPB analogues, MMPP showed the most significant inhibitory effect on colon cancer cell growth. Thus, we evaluated the anti-cancer effects and possible mechanisms of MMPP and . MMPP treatment (0-15 μg/mL) induced apoptotic cell death and enhanced the expression of cleaved caspase-3 and cleaved caspase-8 in a concentration dependent manner. Notably, the expression of death receptor (DR)5 and DR6 was significantly increased by MMPP treatment. Moreover, DR5 siRNA or DR6 siRNA transfection partially abolished MMPP-induced cell growth inhibition. Pull down assay and docking experiment showed that MMPP bound directly to IkappaB kinase β (IKKβ). It was noteworthy that IKKβ mutant (C99S) partially abolished MMPP-induced cell growth inhibition and enhanced expression of DR5 and DR6. In addition, MMPP enhanced TRAIL-induced apoptosis, cell growth inhibition and expression of DRs. In xenograft mice model, MMPP (2.5-5 mg/kg) suppressed tumor growth in a dose dependent manner. Immunohistochemistry analysis showed that the expression levels of DR5 and DR6 and active caspase-3 were increased while the expression levels of PCNA and p-IKKβ were decreased in a dose dependent manner. Thus, MMPP may be a promising anti-cancer agent in colon cancer treatment.
在此我们报告，一种新合成的化合物（E）-2-甲氧基-4-（3-（4-甲氧基苯基）丙-1-烯-1-基）苯酚（MMPP），其稳定性、类药性和抗癌效果均优于我们之前报道的（E）-2,4-双（对羟基苯基）-2-丁烯醛（BHPB）。在所有新合成的BHPB类似物中，MMPP对结肠癌细胞生长的抑制作用最为显著。因此，我们评估了MMPP的抗癌效果及可能的作用机制。MMPP处理（0 - 15μg/mL）以浓度依赖性方式诱导凋亡细胞死亡，并增强了裂解的caspase-3和裂解的caspase-8的表达。值得注意的是，MMPP处理显著增加了死亡受体（DR）5和DR6的表达。此外，DR5 siRNA或DR6 siRNA转染部分消除了MMPP诱导的细胞生长抑制。下拉分析和对接实验表明，MMPP直接与IκB激酶β（IKKβ）结合。值得注意的是，IKKβ突变体（C99S）部分消除了MMPP诱导的细胞生长抑制，并增强了DR5和DR6的表达。此外，MMPP增强了TRAIL诱导的凋亡、细胞生长抑制和DRs的表达。在异种移植小鼠模型中，MMPP（2.5 - 5mg/kg）以剂量依赖性方式抑制肿瘤生长。免疫组织化学分析表明，DR5和DR6以及活性caspase-3的表达水平呈剂量依赖性增加，而PCNA和p-IKKβ的表达水平呈剂量依赖性降低。因此，MMPP可能是结肠癌治疗中有前景的抗癌药物。
