Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data

Abstract

The highest risk factor for chronic diseases is chronological age, and age-related chronic diseases account for the majority of deaths worldwide. Targeting senescent cells that accumulate in disease-related tissues presents a strategy to reduce disease burden and to increase healthspan.Our goal was the computational identification of senotherapeutic repurposing candidates that potentially eliminate senescent cells, based on their similarity in gene expression effects to dasatinib, a tyrosine-kinase inhibitor that induces apoptosis in certain senescent cell types, and that is frequently used as a senolytic together with quercetin.The natural senolytic piperlongumine (a compound found in long pepper), and the natural senomorphics parthenolide, phloretin and curcumin (found in various edible plants) were identified as potential substitutes of dasatinib. The gene expression changes underlying the repositioning highlight apoptosis-related genes and pathways. The four compounds, and in particular the top-runner piperlongumine, may be combined with quercetin to obtain natural formulas emulating the dasatinib + quercetin (D+Q) formula that is frequently used in clinical trials targeting senescent cells.

Plant-Derived Senotherapeutics for the Prevention and Treatment of Intervertebral Disc Degeneration and Aging

“…Rat caudal vertebrae needle-stab model activity in ionizing radiation-induced senescent normal human WI-38 fibroblasts [150] and having emerged as the top-runner in a computational screening for natural senotherapeutic repurposing candidates that mimic dasatinib based on gene expression data [282]-has been reported to rescue IL1β-induced elevated levels of oxidative stress in cartilage explants and to reduce the expression of major inflammatory markers in a goat ex vivo OA model [283]; (x) sesamin has been found to protect against IDD based on a network pharmacology analysis [284] and to inhibit LPS-induced inflammation and ECM catabolism in the rat IVD in vitro and ex vivo [285], while its intradiscal injection in a rat tail disc has been shown to protect from lesion-induced IDD in vivo [286]; (xi) wogonin has been reported to suppress inflammatory mediators and ECM-degrading enzymes and to up-regulate type II collagen in IL-1β-stimulated rat NP IVD cells and to ameliorate IDD in an in vivo rat caudal vertebrae needle-stab model [287].…”

Amide Alkaloids as Privileged Sources of Senomodulators for Therapeutic Purposes in Age-Related Diseases

“…53 This senolytic potential was further confirmed using other cellular models, 54,55 and a recent computational analysis has suggested that the use of piperlongumine combined with quercetin can have similar effects as the combo dasatinib + quercetin, frequently used in senolytic clinical trials. 56 Senomodulating and Anti-Aging Properties of Piperlongumine. While the mechanism(s) by which piperlongumine and analogs can exert their senolytic effects are still not fully deciphered, several cellular targets have been already identified (Figure 3, Table 1), suggesting alternative pathways to those used for its antitumoral function.…”

“…The senolytic activity of piperlongumine and some of its analogs was first described by Wang et al, using WI-38 fibroblasts and gastric cells . This senolytic potential was further confirmed using other cellular models, , and a recent computational analysis has suggested that the use of piperlongumine combined with quercetin can have similar effects as the combo dasatinib + quercetin, frequently used in senolytic clinical trials …”