Identification of pimavanserin tartrate as a potent Ca2+-calcineurin-NFAT pathway inhibitor for glioblastoma therapy
| Autor: | Li-zhen Ji, Xin-qing Gao, Hong-li Li, Yongqing Zhou, Yu-qing Wang, Meng-qing Yang, Qing-ke Zhang, Zhenzhen Liu, Bo Tang, Xiaoning Liu, Rui-cheng Fan, Ping Li, Yu-ping Jia |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Calcineurin Inhibitors Mice Nude Article Mice Piperidines NFAT Pathway Cell Movement Cell Line Tumor hemic and lymphatic diseases Animals Humans Urea Medicine Pharmacology (medical) Calcium Signaling U87 E2F Pharmacology Mice Inbred BALB C Temozolomide Dose-Response Relationship Drug NFATC Transcription Factors Brain Neoplasms business.industry Calcineurin Calcium-Binding Proteins Membrane Proteins NFAT General Medicine Xenograft Model Antitumor Assays Drug repositioning Targeted drug delivery Cancer research Female Signal transduction Glioblastoma business HeLa Cells medicine.drug |
| Zdroj: | Acta Pharmacol Sin |
| ISSN: | 1745-7254 1671-4083 |
| DOI: | 10.1038/s41401-021-00724-2 |
| Popis: | Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor, and 95% of patients die within 2 years after diagnosis. In this study, aiming to overcome chemoresistance to the first-line drug temozolomide (TMZ), we carried out research to discover a novel alternative drug targeting the oncogenic NFAT signaling pathway for GBM therapy. To accelerate the drug’s clinical application, we took advantage of a drug repurposing strategy to identify novel NFAT signaling pathway inhibitors. After screening a set of 93 FDA-approved drugs with simple structures, we identified pimavanserin tartrate (PIM), an effective 5-HT(2A) receptor inverse agonist used for the treatment of Parkinson’s disease-associated psychiatric symptoms, as having the most potent inhibitory activity against the NFAT signaling pathway. Further study revealed that PIM suppressed STIM1 puncta formation to inhibit store-operated calcium entry (SOCE) and subsequent NFAT activity. In cellula, PIM significantly suppressed the proliferation, migration, division, and motility of U87 glioblastoma cells, induced G1/S phase arrest and promoted apoptosis. In vivo, the growth of subcutaneous and orthotopic glioblastoma xenografts was markedly suppressed by PIM. Unbiased omics studies revealed the novel molecular mechanism of PIM’s antitumor activity, which included suppression of the ATR/CDK2/E2F axis, MYC, and AuroraA/B signaling. Interestingly, the genes upregulated by PIM were largely associated with cholesterol homeostasis, which may contribute to PIM’s side effects and should be given more attention. Our study identified store-operated calcium channels as novel targets of PIM and was the first to systematically highlight the therapeutic potential of pimavanserin tartrate for glioblastoma. |
| Databáze: | OpenAIRE |
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