Priority Research Papers:
Identification of a new class of natural product MDM2 inhibitor: In vitro and in vivo anti-breast cancer activities and target validation
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Jiang-Jiang Qin1,*, Wei Wang1,2,*, Sukesh Voruganti1, Hui Wang3, Wei-Dong Zhang4 and Ruiwen Zhang1,2
1 Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
2 Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
3 Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China
4 School of Pharmacy, Shanghai Jiao Tong University, Shanghai, PR China
* These authors contributed equally to this work
Ruiwen Zhang, email:
Keywords: MDM2 inhibitor, p53-independent, breast cancer, lung metastasis
Received: November 20, 2014 Accepted: December 25, 2014 Published: December 30, 2014
The MDM2 oncogene has been suggested as a molecular target for treating human cancers, including breast cancer. Most MDM2 inhibitors under development are targeting the MDM2-p53 binding, and have little or no effects on cancers without functional p53, such as advanced breast cancer. The present study was designed to develop a new class of MDM2 inhibitors that exhibit anticancer activity in MDM2-dependent and p53-independent manners. The selective MDM2 inhibitors were discovered by a computational structure-based screening, yielding a lead compound, termed JapA. We further found that JapA inhibited cell growth, decreased cell proliferation, and induced G2/M phase arrest and apoptosis in breast cancer cells through an MDM2-dependent mechanism, regardless of p53 status. It also inhibited the tumor growth and lung metastasis in breast cancer xenograft models without causing any host toxicity. Furthermore, JapA directly bound to MDM2 protein and reduced MDM2 levels in cancer cells in vitro and in vivo by promoting MDM2 protein degradation and inhibiting MDM2 transcription, which is distinct from the existing MDM2 inhibitors. In conclusion, JapA represents a new class of MDM2 inhibitor that exerts its anticancer activity through directly down-regulating MDM2, and might be developed as a novel cancer therapeutic agent.
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