Table I.
Experimental potential senolytic drugs that target senescent alveolar epithelial cells and lung fibroblasts.
| First author/s, year | Target | Potential therapeutic drugs | Mechanism | (Refs.) |
|---|---|---|---|---|
| Le Saux et al, 2013; | Telomere | Raloxifene | Induces telomerase activity and maintains telomere length | (129) |
| Calado et al, 2009; | (130) | |||
| Arish et al, 2019; | Androgens | (131) | ||
| Townsley et al, 2016 | GRN510 | The small molecule telomerase activator GRN510 attenuates fibrosis in mice with bleomycin- induced PF | (132) | |
| Danazol | Danazol, a synthetic androgen, increases telomere length and stabilizes diffusing capacity for carbon monoxide and forced vital capacity | |||
| Sanders et al, 2014; | Epigenetics | Vorinostat | Inhibits ubiquitin-histone deacetylase and induces apoptosis of fibroblasts | (139) |
| Korfei et al, 2018; | (140) | |||
| Mora et al, 2017; | (141) | |||
| Coward et al, 2014; | 5'-azacytidine | Decreases DNA methylation and fibrosis | (142) | |
| Korfei et al, 2015 | (138) | |||
| BIX-01294 and 3-deazaneplanocin | Inhibitors of euchromatic histone-lysine N-methyltransferase 2 and enhancer of zeste homolog 2 histone methyltransferases; increase cyclooxygenase -2 expression in IPF fibroblasts, which may enhance production of anti-fibrotic prostanoid PGE2 | |||
| LBH589 and SAHA | LBH589 downregulates mRNA expression of ACTA2 and ECM genes COL1A1, COL3A1 and FN in primary IPF fibroblasts and interferes with fibroblast-to- myofibroblast differentiation. SAHA induces apoptosis of IPF myofibroblasts, an effect that is mediated, at least in part, by upregulation of pro-apoptotic gene Bcl-2 antagonist/killer 1 and downregulation of anti- apoptotic gene Bcl-xL | |||
| Panobinostat | The pan-histone deacetylase- inhibitor panobinostat decreases profibrotic phenotypes, as well as inducing cell cycle arrest and apoptosis in IPF fibroblasts | |||
| Sosulski et al, 2017; | Mitochondria | Hexafluoro | Increases the expression of NAD-dependent deacetylase sirtuin-3 | (47) |
| Sato et al, 2016 | (145) | |||
| Metformin | Prevents PF with NADPH oxidase 4 inhibitors | |||
| Liu et al, 2016 | ER | 4-phenylbutyrate | A chemical ER chaperone that ameliorates ER stress, interstitial damage, collagen deposition and apoptosis in unilateral ureteral obstruction rat kidney | (125) |
| Romero et al, 2016; | Autophagy | Rebamycin | Inhibits mTOR complex 1 and activates autophagy | (72) |
| Lavieu et al, 2006; | (121) | |||
| Lawson et al, 2008 | Sphingosine 1-phosphate Berberine | Inhibits activation of mTOR complex and increases autophagy Antagonizes TGF-β1-mediated PIK3/Akt/mTOR signaling and increases autophagy | (122) | |
| Lehmann et al, 2017; | SASP | Dasatinib and quercitin | Inhibit tyrosine kinases, induce clearance of senescent cells, decrease fibrosis and SASP production. | (149) |
| Feng et al, 2019 | (151) | |||
| Citrus basic extract | Downregulates expression of SASP factors in etoposide- induced fibroblasts by activating cyclooxygenase 2 | |||
| Glassberg et al, 2017; | Stem cell transplantation | MSC intravenous injection | Following in vivo transplantation, MSCs home in on injured lung tissue, release paracrine factors and extracellular vesicles, regulate function of immune cells, decrease the local inflammatory response, inhibit fibrous proliferation and promote endogenous lung injury resistance. MSCs decrease bleomycin-induced lung tissue inflammatory response, cell infiltration and cytokine expression, extracellular matrix production and collagen deposition and improve Ashcroft score | (159) |
| Zhao et al, 2021 | (156) |
IPF, idiopathic pulmonary fibrosis; SAHA, suberoylanilide hydroxamic acid; ER, endoplasmic reticulum; MSC, mesenchymal stem cell; SASP, senescence-Associated Secretory Phenotype.