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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 inhibits MDM2 and induces apoptosis in breast cancer cells through a p53-independent pathway.

Author information

1
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
2
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
3
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: zuodaiying@163.com.
4
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: yingliang_1016@163.com.

Abstract

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.

KEYWORDS:

Apoptosis; Breast cancer; Combretastatin A-4; MDM2; p53

PMID:
27693458
DOI:
10.1016/j.canlet.2016.09.011
[Indexed for MEDLINE]

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