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Identification of pimavanserin tartrate as a potent Ca2+-calcineurin-NFAT pathway inhibitor for glioblastoma therapy


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-HT2A 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.

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Fig. 1: Identification of pimavanserin tartrate as a potent NFAT pathway inhibitor.
Fig. 2: Pimavanserin tartrate inhibits TG-induced NFAT nuclear translocation independent of the 5-HT2A receptor.
Fig. 3: Pimavanserin tartrate inhibits NFAT nuclear translocation by targeting store-operated calcium entry.
Fig. 4: Pimavanserin tartrate prevents STIM1 puncta formation to inhibit store-operated calcium entry.
Fig. 5: Pimavanserin tartrate impedes the growth, migration and mobility of glioblastoma cells in vitro.
Fig. 6: Molecular signature of pimavanserin tartrate treatment in glioblastoma U87 cells, as assessed by transcriptomic and proteomic profiling.
Fig. 7: Pimavanserin tartrate inhibits the growth of subcutaneous and orthotopic glioblastoma xenografts in vivo.

Data availability

Additional experimental data are provided as Supplementary Information and are available from the corresponding author upon request. Raw RNA-Seq data are available in NCBI’s Sequence Read Archive (SRA) database under accession number PRJNA689001. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium ( via the iProX partner repository with the dataset identifier PXD023207 [51].


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This work was supported by the National Natural Science Foundation of China (21927811, 91753111, 21907061, 62006144), the Key Research and Development Program of Shandong Province (2018YFJH0502), the Postdoctoral Research Foundation of China (2017M622225), Postdoctoral Innovation Foundation of Shandong Province (201703009) and Jinan Innovative Team Project (2019GXRC039).

Author information




ZZL, XNL, PL and BT designed the research. ZZL, XNL, HLL, YPJ, RCF, LZJ, and YQZ conducted experiments and acquired the data. ZZL, XNL, HLL, YPJ, RCF, QKZ, LZJ, XQG, YQW, and MQY performed data analysis. ZZL, XNL, HLL, PL, and BT wrote and revised the manuscript.

Corresponding authors

Correspondence to Hong-li Li, Ping Li or Bo Tang.

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The authors declare no competing interests.

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Liu, Zz., Liu, Xn., Fan, Rc. et al. Identification of pimavanserin tartrate as a potent Ca2+-calcineurin-NFAT pathway inhibitor for glioblastoma therapy. Acta Pharmacol Sin 42, 1860–1874 (2021).

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  • pimavanserin tartrate
  • drug repurposing
  • SOCE
  • NFAT signaling pathway
  • glioblastoma


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