Dataset Information

Identification of Pimavanserin tartrate as a Potent Ca2+-Calcineurin-NFAT Pathway Inhibitor for Glioblastoma Therapy

ABSTRACT: Glioblastoma multiforme (GBM) is the most common and most malignant primary brain tumor. Although alkylating agents (such as temozolomide (TMZ)) are widely used as first-line treatments for GBM, they often cause chemoresistance and are poorly effective for recurrent GBM. Therefore, anti-GBM drugs with novel mechanism are urgently needed clinically. Here, we report an effective Ca2 +-calcineurin-NFAT signaling pathway inhibitor (Pimavanserin), which exhibits effective anti-tumor activity against GBM. Pimavanserin induces GBM cell cycle arrest in G1/S, promotes cell apoptosis and inhibits tumor cell proliferation and metastasis. Through an in-depth study of the mechanism, it is found that Pimavanserin eliminates NFAT nuclear translocation by inhibiting the formation of puncta of STIM1. Subsequent transcriptomic and proteomic analysis unveiled that PIM can down-regulate E2F, MYC ATR and AuroraA/B signaling pathways to inhibit GBM cancer growth both in vitro and in vivo. In addition, the upregulated genes were mainly associated with cholesterol homeostasis and fatty acid synthesis, which may underlie the mechanism of PIM’s phospholipidosis side effect. This article is the first report of Pimavanserin as an anti- GBM drug.

ORGANISM(S): Homo Sapiens

SUBMITTER: Ping Li

PROVIDER: PXD023207 | iProX | Thu Dec 17 00:00:00 GMT 2020

REPOSITORIES: iProX

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Identification of pimavanserin tartrate as a potent Ca<sup>2+</sup>-calcineurin-NFAT pathway inhibitor for glioblastoma therapy.

Liu Zhen-Zhen ZZ Liu Xiao-Ning XN Fan Rui-Cheng RC Jia Yu-Ping YP Zhang Qing-Ke QK Gao Xin-Qing XQ Wang Yu-Qing YQ Yang Meng-Qing MQ Ji Li-Zhen LZ Zhou Yong-Qing YQ Li Hong-Li HL Li Ping P Tang Bo B

Acta pharmacologica Sinica 20210806 11

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 pathw ...[more]

PMID: 34363007

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Project description:Glioblastomas (GBM) are poorly differentiated astrocytic tumors arising in the Central Nervous System (CNS), which despite aggressive treatments are still characterized by a fatal outcome. Several studies have shown the existence of a subpopulation of cells within glioma tumors displaying cancer stem cells properties. As the term âtumor initiating cellsâ (TICs) is frequentely used to describe cells as these with cancer stem cells capacity. Because TICs promotes the tumor chemo- and radio-resistance and angiogenesis it is conceivable that finding a mean to kill these cells would lead to a better therapy for GBM. The NOTCH gene has an important role during the CNS development, in the maintenance of dividing cells in promoting neural lineage entry of Embryonic Stem Cells and the differentiation of astroglia from the rat adult hippocampus-derived multipotent progenitors. The activation of the NOTCH signaling requires the proteolytic processing of this type I integral membrane protein by a two step process catalyzed first by a metalloprotease and then by the gamma-secretase. An increased activation of the NOTCH signaling has been implicated in several tumors types. Recently some studies showed that this pathway induces the survival/proliferation in GBM and glioma cells, and the expression of stem cell properties in glioma cells. Accordingly to these findings, the inhibition of this pathway leads to depletion of stem-like cells and blocks the engraftment in embryonal brain tumors. Furthermore, enhanced NOTCH signaling may lead to one of the tumor resistance mechanisms deployed by GBM. Targeting the NOTCH pathway specifically in GBM TICs appears therefore as a rational approach for exploring novel and hopefully more effective therapeutic strategies for the management of this malignancy. Several molecular tools are available for targeting the Notch pathway such as specific siRNAs, shRNAs or drugs such as gamma-secretase inhibitors. Among these tools, the latter are small peptides/molecules able to inhibit the gamma-secretase by distinct mechanisms. In this study we used two drugs known as gamma-secretase inhibitors, to investigate by gene expression profiling, their ability to interfere specifically with the proliferative properties of GBM TICs previously obtained in our laboratory. Our data show that one of these two drugs, LLNle, is effective in killing these cells in vitro by activating protein catabolic process mediated by the proteasome, suggesting that preclinical studies should definitely be carried on to evaluate whether LLNle is able to significantly improve the survival in hybrid human GBM-animal models. Gamma-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. In this study we employed two of such inhibitors, namely the z-Leu-leu-Nle-CHO (LLNle) and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to verify whether they were effective in vitro in the killing of human GBM tumor initiating cells (TICs). We first established that of the two drugs only LLNle reduces the viability of GBM TICs obtained from three different patients in the low micromolar range. Cells were treated with 7.5 Î¼M LLNle or DAPT or vehicle alone (DMSO 0.1%) and kept in a humidified 5% CO2 atmosphere at 37Â°C for the indicated time period (24 or 48 hours). To establish which cellular processes are activated in GBM TICs by LLNle we generated and analyzed the gene expression profile after treatment with this compound and with DAPT and DMSO (vehicle). Our data show that LLNle induces upregulation of genes coding for proteasome subunits and subsequently mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activation of genes acting as mitotic inhibitors. Our data are consistent with proteasome inhibition by LLNle, subsequent upregulation of proteasome activity and subsequent unleash of the apoptotic process in GBM TICs.

Dataset Information

Identification of Pimavanserin tartrate as a Potent Ca2+-Calcineurin-NFAT Pathway Inhibitor for Glioblastoma Therapy

Publications

Identification of pimavanserin tartrate as a potent Ca<sup>2+</sup>-calcineurin-NFAT pathway inhibitor for glioblastoma therapy.

Similar Datasets

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