Xu Jingwen, Han Mengting, Shen Jiwei, Guan Qi, Bai Zhaoshi, Lang Binyue, Zhang Huijuan, Li Zengqiang, Zuo Daiying, Zhang Weige, Wu Yingliang
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Cancer Lett. 2016 Dec 1;383(1):9-17. doi: 10.1016/j.canlet.2016.09.011. Epub 2016 Sep 28.
2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ) is a novel synthesized combretastatin A-4 (CA-4) analog that can be classified as a microtubule inhibitor. Our previous study demonstrated that SQ induced G2/M phase arrest and promoted apoptosis progression in breast cancer cells. In the present study, we found that SQ dissociated the MDM2-p53 complex and directly induced MDM2 degradation through the ubiquitin-dependent proteasome pathway in MCF-7 and MDA-MB-231 cells. Further, p53 was activated by SQ through regulation of its transcription, translation, and post-translation modification. More specifically, we demonstrated that SQ induced caspase-dependent but p53-independent apoptosis, and this apoptosis is associated with the inhibition of MDM2. We also showed that SQ exhibited superior in vivo efficacy and low toxicity than CA-4. The immunofluorescence histochemistry study indicated that SQ also inhibited MDM2 expression in vivo. In summary, we report for the first time that SQ shows excellent anti-breast cancer activity in vivo and in vitro and induces p53-independent apoptosis, which is associated with MDM2 inhibition. Therefore, the novel compound SQ has potential for therapeutic treatment of both wild-type and mutant p53 breast cancer.
2-甲氧基-5-((3,4,5-三甲氧基苯基)亚硒酰基)苯酚(SQ)是一种新合成的康普他汀A-4(CA-4)类似物，可归类为微管抑制剂。我们之前的研究表明，SQ在乳腺癌细胞中诱导G2/M期阻滞并促进凋亡进程。在本研究中，我们发现SQ在MCF-7和MDA-MB-231细胞中解离MDM2-p53复合物，并通过泛素依赖性蛋白酶体途径直接诱导MDM2降解。此外，p53通过其转录、翻译和翻译后修饰的调节被SQ激活。更具体地说，我们证明了SQ诱导caspase依赖性但p53非依赖性凋亡，并且这种凋亡与MDM2的抑制有关。我们还表明，SQ在体内表现出比CA-4更高的疗效和更低的毒性。免疫荧光组织化学研究表明，SQ在体内也抑制MDM2表达。总之，我们首次报道SQ在体内和体外均显示出优异的抗乳腺癌活性，并诱导p53非依赖性凋亡，这与MDM2抑制有关。因此，新型化合物SQ具有治疗野生型和突变型p53乳腺癌的潜力。
