Inulanolide A as a new dual inhibitor of NFAT1-MDM2 pathway for breast cancer therapy.
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.
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.|Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Jiang-Jiang
JJ
Qin
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.|Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Wei
W
Wang
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Sushanta
S
Sarkar
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Sukesh
S
Voruganti
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO 80045, USA.
Rajesh
R
Agarwal
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.|Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Ruiwen
R
Zhang
D000072283:A549 Cells; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D012717:Sesquiterpenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
Inulanolide A; NFAT1-MDM2 pathway; breast cancer orthotopic tumor model; metastasis; p53-independent