Dataset Information

Therapeutic efficacy of the novel selective RNA polymerase I inhibitor CX-5461 on pulmonary arterial hypertension and associated vascular remodelling.

ABSTRACT:

Background and purpose

CX-5461 is a novel selective RNA polymerase I (Pol I) inhibitor. Previously, we found that CX-5461 could inhibit pathological arterial remodelling caused by angioplasty and transplantation. In the present study, we explored the pharmacological effects of CX-5461 on experimental pulmonary arterial hypertension (PAH) and PAH-associated vascular remodelling.

Experimental approach

PAH was induced in Sprague-Dawley rats by monocrotaline or Sugen/hypoxia.

Key results

We demonstrated that CX-5461 was well tolerated for in vivo treatments. CX-5461 prevented the development of pulmonary arterial remodelling, perivascular inflammation, pulmonary hypertension, and improved survival. More importantly, CX-5461 partly reversed established pulmonary hypertension. In vitro, CX-5461 induced cell cycle arrest in human pulmonary arterial smooth muscle cells. The beneficial effects of CX-5461 in vivo and in vitro were associated with increased activation (phosphorylation) of p53.

Conclusion and implications

Our results suggest that pharmacological inhibition of Pol I may be a novel therapeutic strategy to treat otherwise drug-resistant PAH.

SUBMITTER: Xu X

PROVIDER: S-EPMC9328314 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Therapeutic efficacy of the novel selective RNA polymerase I inhibitor CX-5461 on pulmonary arterial hypertension and associated vascular remodelling.

Xu Xia X Feng Hua H Dai Chaochao C Lu Weida W Zhang Jun J Guo Xiaosun X Yin Qihui Q Wang Jianli J Cui Xiaopei X Jiang Fan F

British journal of pharmacology 20210301 7

<h4>Background and purpose</h4>CX-5461 is a novel selective RNA polymerase I (Pol I) inhibitor. Previously, we found that CX-5461 could inhibit pathological arterial remodelling caused by angioplasty and transplantation. In the present study, we explored the pharmacological effects of CX-5461 on experimental pulmonary arterial hypertension (PAH) and PAH-associated vascular remodelling.<h4>Experimental approach</h4>PAH was induced in Sprague-Dawley rats by monocrotaline or Sugen/hypoxia.<h4>Key r ...[more]

PMID: 33486761

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Project description:Hyperactivation of RNA polymerase I (Pol I) transcription of ribosomal RNA (rRNA) genes (rDNA) is a key determinant of growth and proliferation and a consistent feature of cancer cells. We have demonstrated that inhibition of rDNA transcription by the Pol I transcription inhibitor CX-5461 selectively kills tumor cells in vivo. Moreover, the first-in human trial of CX-5461 has demonstrated CX-5461 is well-tolerated in patients and has single-agent anti-tumor activity in hematologic malignancies. However, the mechanisms underlying tumor cell sensitivity to CX-5461 remain unclear. Understanding these mechanisms is crucial for the development of predictive biomarkers of response that can be utilized for stratifying patients who may benefit from CX-5461. The rDNA repeats exist in four different and dynamic chromatin states: inactive rDNA can be either methylated silent or unmethylated pseudo-silent; while active rDNA repeats are described as either transcriptionally competent but non-transcribed or actively transcribed, depending on the level of rDNA promoter methylation, loading of the essential rDNA chromatin remodeler UBF and histone marks status. In addition, the number of rDNA repeats per human cell can reach hundreds of copies. Here, we tested the hypothesis that the number and/or chromatin status of the rDNA repeats, is a critical determinant of tumor cell sensitivity to Pol I therapy. We systematically examined a panel of ovarian cancer (OVCA) cell lines to identify rDNA chromatin associated biomarkers that might predict sensitivity to CX-5461. We demonstrated that an increased proportion of active to inactive rDNA repeats, independent of rDNA copy number, determines OVCA cell line sensitivity to CX-5461. Further, using zinc finger nuclease genome editing we identified that reducing rDNA copy number leads to an increase in the proportion of active rDNA repeats and confers sensitivity to CX-5461 but also induces genome-wide instability and sensitivity to DNA damage. We propose that the proportion of active to inactive rDNA repeats may serve as a biomarker to identify cancer patients who will benefit from CX-5461 therapy in future clinical trials. The data also reinforces the notion that rDNA instability is a threat to genomic integrity and cellular homeostasis.

Project description:Pulmonary arterial hypertension (PAH) is a lethal pulmonary vascular disease characterized by arteriolar pruning and occlusive vascular remodeling leading to increased pulmonary vascular resistance and eventually right heart failure. While endothelial cell (EC) injury and apoptosis are known triggers for this disease, the mechanisms by which they lead to complex arterial remodeling remain obscure. Aims: We employed multiplexed single-cell RNA sequencing at multiple timepoints during the onset and progression of disease in a model of severe PAH to identify mechanisms involved in the development of occlusive arterial lesions. Methods and Results: Single cell transcriptional analysis resolved 44 global lung cell populations, with widespread early transcriptomic changes at 1 week affecting endothelial, stromal and immune cell populations. In particular, two EC clusters were greatly expanded during PAH development and were identified as being disease specific: a relatively dedifferentiated (dD) EC population that was enriched for Cd74 expression while exhibiting a loss of endothelial identity; and an activated arterial EC (aAEC) population that uniquely exhibited persistent differential gene expression throughout PAH development consistent with a growth regulated state. dDECs were primed to undergo endothelial-mesenchymal transition as evidenced by reduced activity of master EC transcription factors, Erg and Fli1, and further supported by RNA velocity analysis showing vectors leading to fibroblast clusters. Of note, aAECs exhibited high expression of Tm4sf1, a gene implicated in cancer cell growth, that was also expressed by a smooth muscle (SM)-like pericyte cluster, and were highly localized to regions of arterial remodeling in both the rat model and PAH patients, contributing to intimal occlusive lesions and SM-like pericytes forming bands of medial muscularization. Conclusions: Together these findings implicate disease-specific vascular cells in PAH progression and suggest that TM4SF1 may be a novel therapeutic target for arterial remodeling. Translational Perspectives: Using single cell transcriptomic analysis in both human lung samples and a rat model of severe PAH we have identified disease-specific EC populations contributing to complex arterial remodeling, including growth-dysregulated, activated arterial ECs (aAECs) and dedifferentiated ECs (dDECs) that may be primed for endothelial to mesenchymal transition. In particular, aAECs exhibit high expression of a surface marker, TM4SF1, which is essential for their hyper-proliferative phenotype and represents a promising therapeutic target for RNA silencing approaches or as an antigen to guide immune-mediated ablation of this cancer-like EC population in PAH.

Dataset Information

Therapeutic efficacy of the novel selective RNA polymerase I inhibitor CX-5461 on pulmonary arterial hypertension and associated vascular remodelling.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Therapeutic efficacy of the novel selective RNA polymerase I inhibitor CX-5461 on pulmonary arterial hypertension and associated vascular remodelling.

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