Inulanolide A as a new dual inhibitor of NFAT1-MDM2 pathway for breast cancer therapy
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Jiang-Jiang Qin1,2,*, Wei Wang1,2,*, Sushanta Sarkar1, Sukesh Voruganti1, Rajesh Agarwal3,4, Ruiwen Zhang1,2
1Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
2Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
3Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA
4University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO 80045, USA
*These authors contributed equally to this work
Ruiwen Zhang, email: [email protected]
Wei Wang, email: [email protected]
Keywords: Inulanolide A, NFAT1-MDM2 pathway, p53-independent, breast cancer orthotopic tumor model, metastasis
Received: January 27, 2016 Accepted: March 31, 2016 Published: April 20, 2016
The transcription factor NFAT1 and the oncogene MDM2 have crucial roles in breast cancer development, progression, and metastasis. We have recently discovered that NFAT1 activates MDM2 expression. Here, we identified a small molecule (named Inulanolide A) that dually inhibited both NFAT1 and MDM2 in breast cancer cells in vitro and in vivo. Unlike conventional MDM2 inhibitors, Inulanolide A (InuA) exerted its selective anticancer activity in both p53-dependent and -independent manners. InuA decreased cell proliferation and induced G2/M phase arrest and apoptosis in breast cancer cells; it also led to a decrease in MDM2, NFAT1 and proteins associated with cell proliferation, and an increase in apoptotic signal related proteins. In a mouse orthotopic model, JapA suppressed tumor growth and lung metastasis without host toxicity. Thus, InuA is a novel NFAT1 and MDM2 dual targeting agent and may be a clinical candidate for breast cancer therapy. This study also validates the effectiveness of dually targeting NFAT1 and MDM2 in breast cancer.
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