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.

A transcriptional program associated with cell cycle regulation predominates in the anti-inflammatory effects of CX-5461 in macrophage

“…GO and KEGG analyses on the CX-5461-responsive genes similarly identified enrichment in biological processes related to cell cycle regulation (GO: cell cycle phase transition; KEGG: cell cycle), which were highly statistically significant (Table 1). Consistent with previous data suggesting that activation of the p53 pathway had a pivotal role in mediating the pharmacological effects of CX-5461 (Bywater et al, 2012;Tsai and Pederson, 2014;Ye et al, 2017;Cui et al, 2021;Pang et al, 2021;Xu et al, 2021), we also showed that a cluster of 6 genes associated with p53 signaling (KEGG: p53 signaling pathway) were significantly altered by CX-5461 in both LPSand IFN-γ-primed cells. These p53-related genes included CDKN1A (cyclin-dependent kinase inhibitor 1/p21 Cip1 ), CDK1 (cyclin-dependent kinase 1/Cdk1), CCNE2 (cyclin E2), CCNE1 (cyclin E1), RRM2 (ribonucleotide reductase regulatory subunit M2) and CCNB1 (cyclin B1).…”

“…According to the observations from our previous studies (Ye et al, 2017;Dai et al, 2018;Pang et al, 2021;Xu et al, 2021;Pan et al, 2022), activation of the p53 pathway following Pol I inhibition (rather than reduced productions of rRNAs and ribosomes) appears to have a predominant role in mediating CX-5461 effects. This phenomenon has also been recognized in cancer cells (Ferreira et al, 2020).…”

“…In addition to its anti-tumor activities, our previous studies have also revealed that CX-5461 has unique pharmacological effects on pathologic vascular remodeling and the accompanying vascular inflammation. For example, CX-5461 treatment effectively suppressed the arterial remodeling induced by orthotopic aortic transplantation and experimental pulmonary arterial hypertension ( Dai et al, 2018 ; Xu et al, 2021 ); in these experiments, CX-5461 significantly reduced the number of infiltrating adventitial macrophages. In vitro , CX-5461 inhibited macrophage proliferation, maturation, and lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines ( Dai et al, 2018 ).…”

Editorial: Drugging p53 for non-cancer diseases

“…In this Research Topic, Wang et al reported their work on identifying the molecular mechanisms underlying the anti-inflammatory effects of CX-5461, a novel selective RNA polymerase I inhibitor which induces nucleolar stress and p53 activation (phosphorylation), in macrophages. This study extended their previous findings that CX-5461, in addition to its anti-tumor activity, exhibited significant anti-inflammatory and immunosuppressive effects ( Dai et al, 2018 ; Xu et al, 2021 ; Pan et al, 2022 ). The authors utilized contemporary systemic biology techniques (genome-wide RNA sequencing).…”

G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions

“…Recently, Masud et al demonstrated that inhibition of the critical member of the DNA damage response, UBE2N , acted synergistically with CX-5461 increasing cell toxicity [ 70 ]. Further, this compound has shown the potential to suppress pulmonary arterial hypertension and associated vascular remodeling and pulmonary inflammation by inhibiting the RNA polymerase I [ 71 ]. For those reasons, the unique chemical qualities of RNA G4s, together with their location in key regions of the human transcriptome, have spurred the design and development of specific and selective RNA G4 ligands.…”