title: Identification of lineariifolianoid A as a novel dual NFAT1 and MDM2 inhibitor for human cancer therapy.
abstract: There is an increasing interest in development of novel anticancer agents that target oncogenes. We have recently discovered that nuclear factor of activated T cells 1 (NFAT1) is a novel regulator of the Mouse Double Minute 2 (MDM2) oncogene and the NFAT1-MDM2 pathway has been implicated in human cancer development and progression, justifying that targeting the NFAT1-MDM2 pathway could be a novel strategy for discovery and development of novel cancer therapeutics. The present study was designed to examine the anticancer activity and underlying mechanisms of action of lineariifolianoid A (LinA), a novel natural product inhibitor of the NFAT1-MDM2 pathway. The cytotoxicity of LinA was first tested in various human cancer cell lines in comparison with normal cell lines. The results showed that the breast cancer cells were highly sensitive to LinA treatment. We next demonstrated the effects of LinA on cell proliferation, colony formation, cell cycle progression, and apoptosis in breast cancer MCF7 and MDA-MB-231 cells, in dose-dependent and p53-independent manners. LinA also inhibited the migration and invasion of these cancer cells. Our mechanistic studies further indicated that its anticancer activities were attributed to its inhibitory effects on the NFAT1-MDM2 pathway and modulatory effects on the expression of key proteins involved in cell cycle progression, apoptosis, and DNA damage. In summary, LinA is a novel NFAT1-MDM2 inhibitor and may be developed as a preventive and therapeutic agent against human cancer.
authors.affiliation: Department of Pharmaceutical Sciences.|Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Jiang-Jiang
authors.initials: JJ
authors.lastname: Qin
authors.affiliation: Department of Pharmaceutical Sciences.
authors.forename: Sushanta
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Department of Pharmaceutical Sciences.
authors.forename: Sukesh
authors.initials: S
authors.lastname: Voruganti
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Department of Pharmaceutical Sciences.|Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences.|Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; ruiwen.zhang@ttuhsc.edu.
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
keywords: MDM2; NFAT1; apoptosis; breast cancer; lineariifolianoid A; p53