Oprelvekin

Radiotherapy and chemotherapy are widely employed as primary non-surgical cancer treatments; however, their non-selective cytotoxicity often leads to adverse events such as oral mucositis (OM), particularly in head and neck cancer therapies. International guidelines provide recommendations for managing chemoradiotherapy-induced OM in various clinical contexts. Subsequently, emerging researches have introduced evidence supporting novel approaches or existing regimens for OM prevention and treatment. The repurposing of established drugs has garnered significant interest due to its shorter development timeline, improved safety profiles, and lower costs compared to new drug development. For example, clinical trials assessing established drugs such as melatonin, clonidine, and pentoxifylline indicate promising potential for managing OM. Additionally, several emerging pharmacological interventions have demonstrated considerable efficacy; SAMITAL and rhIL-11 are supported by phase II clinical trials and prospective studies, while probiotics like Streptococcus salivarius K12 and curcumin have shown effectiveness in randomized clinical trials. Furthermore, recent high-level studies have reinforced the efficacy of non-pharmacological interventions, such as photobiomodulation (PBM) and cryotherapy, over the past two years. In all, given the evidence supporting different strategies, PBM and oral cryotherapy are highly recommended for managing OM when feasible. Topical clonidine, melatonin, oral pentoxifylline, topical SAMITAL or rhIL-11, oral SsK12, and curcumin may also be utilized but would benefit from validation in larger trials. Besides, Verbascoside, Palifermin, Amifostine, and Avasopasem manganese can be suggested for OM management, while the side effects should be monitored. The accessibility and cost/effectiveness of specific managing strategies of OM should be considered when selecting appropriate options.

Interleukin 11 (IL11) was initially thought important for platelet production, which led to recombinant IL11 being developed as a drug to treat thrombocytopenia. IL11 was later found to be redundant for haematopoiesis, and its use in patients is associated with unexplained and severe cardiac side effects. Here, we aim to identify, for the first time, direct cardiomyocyte toxicities associated with IL11, which was previously believed cardioprotective.

We injected recombinant mouse lL11 (rmIL11) into mice and studied its molecular effects in the heart using immunoblotting, qRT-PCR, bulk RNA-seq, single nuclei RNA-seq (snRNA-seq), and assay for transposase-accessible chromatin with sequencing (ATAC-seq). The physiological impact of IL11 was assessed by echocardiography in vivo and using cardiomyocyte contractility assays in vitro. To determine the activity of IL11 specifically in cardiomyocytes, we made two cardiomyocyte-specific Il11ra1 knockout (CMKO) mouse models using either AAV9-mediated and Tnnt2-restricted (vCMKO) or Myh6 (m6CMKO) Cre expression and an Il11ra1 floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition on rmIL11-induced cardiac toxicities. Injection of rmIL11 caused acute and dose-dependent impairment of left ventricular ejection fraction (saline: 62.4% ± 1.9; rmIL11: 32.6% ± 2.9, P < 0.001, n = 5). Following rmIL11 injection, myocardial STAT3 and JNK phosphorylation were increased and bulk RNA-seq revealed up-regulation of pro-inflammatory pathways (TNFα, NFκB, and JAK/STAT) and perturbed calcium handling. snRNA-seq showed rmIL11-induced expression of stress factors (Ankrd1, Ankrd23, Xirp2), activator protein-1 (AP-1) transcription factor genes, and Nppb in the cardiomyocyte compartment. Following rmIL11 injection, ATAC-seq identified the Ankrd1 and Nppb genes and loci enriched for stress-responsive, AP-1 transcription factor binding sites. Cardiomyocyte-specific effects were examined in vCMKO and m6CMKO mice, which were both protected from rmIL11-induced left ventricular impairment and molecular pathobiologies. In mechanistic studies, inhibition of JAK/STAT signalling with either ruxolitinib or tofacitinib prevented rmIL11-induced cardiac dysfunction.

Injection of IL11 directly activates IL11RA/JAK/STAT3 in cardiomyocytes to cause acute heart failure. Our data overturn the earlier assumption that IL11 is cardioprotective and explain the serious cardiac side effects associated with IL11 therapy.